Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
RESPONSE TO ELECTION/RESTRICTION
Applicant’s election without traverse of the following chemical species:
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in the reply filed on 8/10/2026 is acknowledged. However Applicant did not set forth a single disclosed disorder as also required. The examiner contacted the attorney of record to request the aforementioned information but the attorney did not respond to the examiner’s request. For the sake of compact prosecution, the examiner will focus on the disorders stated in claim 103 as the species of choice.
The requirement is still deemed proper and is therefore made FINAL.
Claim 96 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
An action on the merits of claims 93-95 and 97-103 is contained herein. Applicant’s elected species was found free of the art and the search expanded to cover the full scope of formula I.
Priority
This application claims the benefit of priority to and is a continuation of U.S. Serial No. 17/684,030, filed March 1, 2022, which claims the benefit of priority to and is a continuation of U.S. Serial No. 17/278,553, filed March 22, 2021, which claims the benefit of priority to and is a continuation-in-part of PCT International Application No.
PCT/CN2018/121165, filed on December 14, 2018.
However, an original and certified English version of the foreign priority document was not received.
Failure to provide the latter may result in no benefit being accorded for the non-English application (i.e., the examiner respectfully requests submission of the appropriate English translated version of the foreign priority document if benefit is sought). See MPEP 213.04.
Information Disclosure Statement
The examiner has considered the references cited in the information disclosure statement filed of record.
Specification
Applicant is reminded of the proper content of an Abstract of the Disclosure, see MPEP 608.01(b).
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., "The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics." Exemplification of a species could be illustrative of members of the class. For processes, the type reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
It is recommended that the structure of Formula I be inserted into the abstract to accurately illustrate the claimed invention.
Claim Objections
Claims 101-102 are objected to for lacking commas between species and not having the word “and” before the last recited compound. Thus the claim and claims dependent on it are objected to. Correction is required.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 93-95 and 97-103 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-13 of US Patent 11,981,663. Although the conflicting claims are not identical, they are not patentably distinct from each other because there is significant overlap between the two applications.
The instant claims may be drawn to a method of treating diseases selected from cancer, inflammatory diseases, immune-mediated diseases, and related diseases thereof using the claimed compounds of formula I. The patent simply claims the compounds of formula I themselves (including the elected species, see claim 10). However, the specification teaches that the claimed compounds of formula I may be used in the manner claimed in the instant application (see col. 44, lines 10-13). Thus the claimed method of use would have been considered obvious since the specification in the patent suggested the compounds of formula I being used as currently claimed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 93-95, 97-100, and 103 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
In the instant claim 93, the scope of “pharmaceutically acceptable form” is indefinite. This term is not defined or articulated in the specification or the claims themselves and one of ordinary skill would not readily ascertain the metes and bounds of the claim language. Additionally there are no guidelines as to ascertain the boundaries of “related diseases.. thereof” as recited in claim 103. Thus the scope of the claim and claims dependent on it which do not rectify the issue are considered indefinite.
See In re Zletz, 13 USPQ2d 1320, 1322, “An essential purpose of patent examination is to fashion claims that are precise, clear, correct and unambiguous.” Correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of
carrying out his invention.
Claims 93-95 and 97-103 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The method of treating/reducing diseases selected from cancer, inflammatory diseases, immune-mediated diseases, and related diseases thereof generally cannot possibly be considered enabled with the provided information stated within the specification.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
For example in reference to cancer, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to “The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors” using a small genus of compounds. The Court decided that human testing “limited to one compound and two types of cancer” was not “commensurate with the broad scope of utility asserted and claimed”.
. In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to “the treatment of certain specified cancers in humans” by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted “affidavits, publications and data” for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to “A therapeutic method for reducing metastasis and neoplastic growth in a mammal” using a single species. The decision notes that such utility “is no longer considered to be “incredible”, but that “the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence. Note also that there is also a dependent claim 5 which specified “wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma.” The decision notes that “even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy.”
In Ex parte Stevens, 16 USPQ2d 1379 a claim to “A method for therapeutic or prophylactic treatment of cancer in mammalian hosts” was refused because there was “no actual evidence of the effectiveness of the claimed composition and process in achieving that utility.”
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(1) Breadth of claims.
(a) Scope of the compounds.
(b) Scope of the diseases covered. The claims cover a myriad of unrelated disorders such as inflammatory diseases, immune-mediated diseases, and cancer. For one, cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. Here are some assorted categories:
A. CNS cancers cover a very diverse range of cancers in many categories and subcategories. There are an immense range of neuroepithelial tumors. Gliomas, the most common subtype of primary brain tumors, most of which are aggressive, highly invasive, and neurologically destructive tumors are considered to be among the deadliest of human cancers. These are any cancers which show evidence (histological, immunohistochemical, ultrastructural) of glial differentiation These fall mostly into five categories. There are the astrocytic tumors (astrocytomas): pilocytic astrocytoma (including juvenile pilocytic astrocytoma, JPA, and pediatric optic nerve glioma) diffuse astrocytomas (including fibrillary astrocytomas, protoplasmic astrocytomas and gemistocytic astrocytomas), anaplastic astrocytomas (including adult optic nerve glioma), Glioblastoma multiforme (GBM), gliosarcoma and giant cell glioblastoma, and pleomorphic xanthoastrocytoma. GBM exists in two forms, primary and secondary, which have very different clinical histories and different genetics, but GBM is considered to be one clinical entity. Second, there are the oligodendroglial tumors (oligodendrogliomas): low grade oligodendroglioma and anaplastic oligodendroglioma. Third, there is oligoastrocytomas (“mixed glioma”), a type of tumor with both astrocytoma & oligodendroglioma features. The fourth type is the ependymomas, which are intracranial gliomas, including papillary ependymoma, myxopapillary ependymoma, tanycytic ependymoma, anaplastic ependymoma and subependymal giant-cell astrocytomas. A fifth type is the gangliogliomas (glioneuronal tumors or glioneurocytic tumors), which have both glial and neuronal components, and are extremely varied, based in part on what types of glial and what types of neuronal components are present. These include Papillary Glioneuronal Tumor (PGNT), a range of supratentorial gangliogliomas, assorted intramedullary spinal cord gangliogliomas, pineal ganglioglioma, hypothalamic ganglioglioma, cerebellar ganglioglioma, ganglioglioma of the right optic tract, rosetted glioneuronal tumor (“glioneurocytic tumor with neuropil rosettes”), composite pleomorphic xanthoastrocytoma (PXA)-ganglioglioma, desmoplastic ganglioglioma (both infantile (DIG) and non- infantile), angioganglioglioma, and others. There are also some glial tumors which do not comfortably fit into these five categories, notably astroblastoma, gliomatosis cerebri, and chordoid glioma, which are found solely in the hypothalamus and anterior third ventricle. Other neuroepithelial tumors include astrocytic tumors (e.g. astrocytomas) oligodendroglial tumors, ependymal cell tumors (e.g. myxopapillary ependymoma), mixed gliomas (e.g. mixed oligoastrocytoma and ependymo-astrocytomas) tumors of the choroid plexus(choroid plexus papilloma, choroid plexus carcinoma), assorted neuronal and neuroblastic tumors (e.g. gangliocytoma, central neurocytoma, dysembryoplastic neuroepithelial tumor, esthesioneuroblastoma, olfactory neuroblastoma, olfactory neuroepithelioma, and neuroblastomas of the adrenal gland), pineal parenchyma tumors (e.g. pineocytoma, pineoblastoma, and pineal parenchymal tumor of intermediate differentiation), embryonal tumors (e.g. medulloepithelioma, neuroblastoma, ependymoblastoma, atypical teratoid/rhabdoid tumor, desmoplastic medulloblastoma, large cell medulloblastoma, medullomyoblastoma, and melanotic medulloblastoma) and others such as polar spongioblastoma and gliomatosis cerebri. A second Division is tumors of the meninges. this includes tumors of the meningothelial cells, including meningiomas (meningothelial, fibrous (fibroblastic), transitional (mixed), psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, metaplastic, clear cell, chordoid, atypical, papillary, rhabdoid, anaplastic meningioma) and the non- meningioma tumors of the meningothelial cells (malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid haemangioendothelioma, haemangiopericytoma, angiosarcoma, kaposi sarcoma). There are also mesenchymal, non-meningothelial tumors (liposarcoma, (intracranial) solitary fibrous tumor, and fibrosarcoma) as well as primary melanocytic lesions (diffuse melanocytosis, melanocytoma, malignant melanoma, and meningeal melanomatosis). A third division are the tumors of cranial and spinal nerves. This includes cellular schwannomas, plexiform schwannomas and the melanotic schwannomas (e.g. psammomatous melanotic schwannoma , neuro-axial melanotic schwannoma, dorsal dumb-bell melanotic schwannoma). There is also Perineurioma (Intraneural and Soft tissue) and malignant peripheral nerve sheath tumor (MPNST), including Epithelioid, MPNST with divergent mesenchymal differentiation, and MPNST with epithelial differentiation. A fourth division are germ cell tumors, including germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma (mature teratoma, immature teratoma, and teratoma with malignant transformation). A fifth division are the tumors of the sellar Region, viz. pituitary adenoma, pituitary carcinoma, granular cell myoblastoma and craniopharyngiomas (adamantinomatous and papillary). Yet another division are local extensions from regional tumors, including paraganglioma, chodroma, chordoma, and chondrosarcoma. There are also Primitive Neuroectodermal Tumors (PNETs) including medulloblastomas, medulloepitheliomas, ependymoblastomas and polar spongioblastomas. There are Vascular brain Tumors e.g. the hemangioblastomas. Primary central nervous system lymphoma (PCNSL), including Primary ocular lymphoma, is a form of extranodal high-grade non-Hodgkin B-cell neoplasm, usually large cell or immunoblastic type. Secondary central nervous system lymphoma (SCNSL) is most commonly from Burkitt’s lymphoma and lymphoblastic lymphoma. There is also Meningeal Carcinomatosis, plasmacytoma, and granulocytic sarcoma. And there are many, many others.
B. Leukemia is any malignant neoplasm of the blood-forming tissues. Leukemia can arise from many different sources. These include viruses such as EBV, which causes Burkitt's lymphoma, and HTLV-1, linked to certain T cell leukemias. Others are linked to genetic disorders, such as Fanconi's anemia, which is a familial disorder, and Down's Syndrome. Other leukemias are caused by exposure to carcinogens such as benzene, and some are actually caused by treatment with other neoplastic agents. Still other leukemias arise from ionizing radiation, and many are idiopathic. Leukemias also differ greatly in the morphology, degree of differentiation, body location (e.g. bone marrow, lymphoid organs, etc.) There are dozens of leukemias. There are B-Cell Neoplasms such as B-cell prolymphocytic leukemia and Hairy cell leukemia (HCL, a chronic Lymphoid leukemia). There are T-Cell Neoplasms such as T-cell prolymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma (ATLL), and T-cell granular Lymphocytic leukemia. There are different kinds of acute myeloid leukemias (undifferentiated AML, acute myeloblastic, acute myelomonocytic leukemia, acute monocytic leukemias, acute monoblastic, acute megakaryoblastic (AmegL), acute promyelocytic leukemia (APL), and erythroleukemia). There is also lymphoblastic leukemia, hypocellular acute myeloid leukemia, Ph-/BCR- myeloid leukemia, and acute basophilic leukemia. Chromic leukemias include chronic lymphocytic leukemia (CLL, which exists in a B-cell and a T-cell type), prolymphocytic leukemia (PLL), large granular lymphocytic leukemia (LGLL, which goes under several other names as well), chronic myelogenous leukemia(CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL), and many others.
C. Carcinomas of the Liver include hepatocellular carcinoma, combined hepatocellular cholangiocarcinoma, cholangiocarcinoma (intrahepatic), bile duct cystadenocarcinoma and undifferentiated carcinoma of the liver. There is also cancer of the blood vessels in the liver (hemangioendothelioma), primary non-hodgkin's lymphoma of the liver, undifferentiated liver sarcoma (also known as undifferentiated embryonal sarcoma), primary pleomorphic liver sarcoma, angiosarcoma of the liver, and primary malignant melanoma of the liver. Most liver cancers are secondary, especially those originating in the breast, lung, or gallbladder, as well as both Hodgkin's or non-Hodgkin's lymphoma.
D. The main types of lung and pleural cancer are small cell (i.e. oat cell, including combined oat cell), adenocarcinomas, bronchioloalveolar carcinomas (nonmucinous, mucinous, and mixed mucinous and nonmucinous or indeterminate cell type), acinar, papillary carcinoma, solid adenocarcinoma with mucin, adenocarcinoma with mixed subtypes, well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma), squamous cell (papillary, clear cell, small cell and basaloid), mesothelioma (including epithelioid, sarcomatoid, desmoplastic and biphasic) and large cell carcinoma (which include large-cell neuroendocrine carcinoma, combined large-cell neuroendocrine carcinoma, basaloid carcinoma, clear cell carcinoma lymphoepithelioma-like carcinoma, and large-cell carcinoma with rhabdoid phenotype). In addition there are also the carcinomas with pleomorphic, sarcomatoid or sarcomatous elements, including carcinomas with spindle and/or giant cells, spindle cell carcinoma, carcinosarcoma and pulmonary blastoma. The non-small cell lung carcinomas also include adenosquamous carcinoma, the carcinoid tumor (both typical carcinoid and atypical carcinoid) as well as carcinomas of salivary-gland type, including mucoepidermoid carcinoma and adenoid cystic carcinoma. There are some soft tissue tumors including localized fibrous tumor (formerly called benign fibrous mesothelioma); epithelioid haemangioendothelioma; pleuropulmonary blastoma (which occurs three fairly different sub-types); chondroma; calcifying fibrous pseudotumor of the visceral pleura); congenital peribronchial myofibroblastic tumors, diffuse pulmonary lymphangiomyomatosis and desmoplastic round cell tumor. There are assorted bronchial adenomas (e.g. adenoid cystic carcinomas, mucoepidermoid carcinomas, mucous gland adenomas, and oncocytomatous bronchial mucous gland adenoma) as well as other adenomas, including papillary adenoma. There are some papillomas, including squamous cell papilloma and glandular papilloma. There is also melanoma of the lung, cylindroma (cylindroadenoma), some germ cell tumors, thymoma and sclerosing haemangioma and many others as well. Lung cancers are quite diverse. Thus, for example, oat cell carcinoma, Signet ring adenocarcinoma, pleuropulmonary blastoma, cylindroma, and malignant mesothelioma really have very little in common, other than being cancers of the lung.
E. Thyroid cancer comes in four forms: papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer.
F. Cancer of the skin cells is melanoma. Malignant melanomas come in four fundamental forms: superficial spreading melanoma, nodular melanoma (including its variant, Polypoid melanoma), lentigo maligna melanoma and acral melanoma. Mucosal melanomas are sometimes malignant. These sometime occur in amelanotic form, such as in desmoplastic melanoma.
G. Non-melanoma skin cancers are quite varied. There is a very wide range of carcinomas of the skin, most notably the basal cell carcinomas (BCC), including superficial BCC, nodular BCC (solid, adenoid cystic), infiltrating BCC, sclerosing BCC (desmoplastic, morpheic), fibroepithelial BCC, BCC with adnexal differentiation, follicular BCC, eccrine BCC, basosquamous carcinoma, keratotic BCC, pigmented BCC, BCC in basal cell nevus syndrome, micronodular BCC. Another important family is the squamous cell carcinomas (SCC) which include spindle cell (sarcomatoid) SCC, acantholytic SCC, verrucous SCC, SCC with horn formation, and lymphoepithelial SCC, along with less well classified SCCs such as papillary SCC, clear cell SCC, small cell SCC, posttraumatic (e.g., Marjolin ulcer) and metaplastic (carcinosarcomatous) SCC. Another family is the eccrine carcinomas including sclerosing sweat duct carcinoma (syringomatous carcinoma, microcystic adnexal carcinoma), malignant mixed tumor of the skin (malignant chondroid syringoma), porocarcinoma, malignant nodular hidradenoma, malignant eccrine spiradenoma, mucinous eccrine carcinoma, adenoid cystic eccrine carcinoma, and aggressive digital papillary adenoma/adenocarcinoma. Other carcinomas of the skin include epidermal carcinomas, Paget disease, mammary Paget disease, merkel cell carcinoma (neuroendocrine cancer of the skin), extramammary paget disease adnexal carcinomas, apocrine carcinoma, sebaceous carcinoma, tricholemmocarcinoma and malignant pilomatricoma (matrical carcinoma). There are also skin sarcoma’s, most notably Kaposi's sarcoma, but also granulocytic sarcoma of the skin, hemangiopericytoma (HPC), fibroblastic/myofibroblastic sarcoma of the skin, primary extraosseus Ewing's sarcoma of the skin. Cutaneous lymphomas come in four categories. A) Primary Cutaneous T-cell lymphomas come in numerous forms: Mycosis fungoides, Pagetoid reticulosis, Sézary syndrome, Granulomatous slack skin, Lymphomatoid papulosis, Pityriasis lichenoides chronica, Pityriasis lichenoides et varioliformis acuta, CD30+ cutaneous T-cell lymphoma, Secondary cutaneous CD30+ large cell lymphoma, Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma, Pleomorphic T-cell lymphoma, Lennert lymphoma, Subcutaneous T-cell lymphoma, Angiocentric lymphoma, and Blastic NK-cell lymphoma. B) There is also secondary cutaneous peripheral T-cell lymphoma, including secondary cutaneous peripheral T-cell lymphoma. C) Primary Cutaneous B-Cell Lymphoma comes in several forms. There is Primary cutaneous marginal zone B-cell lymphoma (MALT-type), which comes in some variant forms, including Immunocytoma and Primary cutaneous plasmacytoma; Primary cutaneous follicle center lymphoma, which comes in variant forms including Follicular, Follicular and diffuse, and Diffuse; and Primary cutaneous diffuse large B-cell Lymphoma. D) Finally, there is secondary Cutaneous B-Cell Lymphoma. This is commonly from Intravascular large B-cell lymphoma (IVLBL), or Lymphomatoid granulomatosis, but can also come from Mantle cell lymphoma, Burkitt lymphoma, and Hodgkin Lymphoma. In addition to that secondary form of cutaneous Hodgkin’s Lymphoma, there is also a primary cutaneous Hodgkin’s Lymphoma. Also there is Granular cell tumor (Abrikossoff's tumor, Granular cell myoblastoma, Granular cell nerve sheath tumor, Granular cell schwannoma) all of neural derivation; these are sometimes malignant and have no pharmacological treatment, only surgical. There is also is Leukemia cutis, infiltration of leukemia cells into the skin, usually from acute myeloid leukemia, but also from acute lymphoblastic leukemia, Chronic lymphocytic leukemia, and some other forms. There is also neuroma cutis.
H. There are many types of colorectal cancers. The carcinomas include
adenocarcinoma; mucinous adenocarcinoma; signet-ring cell carcinoma;
small cell carcinoma; adenosquamous carcinoma; medullary carcinoma; choriocarcinoma; and undifferentiated carcinoma. The malignant lymphomas include marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type; mantle cell lymphoma; Diffuse large B-cell lymphoma; Burkitt lymphoma; and Burkitt-like/atypical Burkitt lymphoma. There are also some carcinoid tumors, sarcomas (including GISTs, leiomyosarcoma, hemangiosarcoma, angiosarcoma, Kaposi sarcoma, fibrosarcoma, neurofibrosarcoma and Leiomyosarcoma), primary plasmacytoma of the colon and primary malignant melanoma of the colon. A wide variety of cancers are secondary to the colon, e.g. ovarian carcinoma.
I. Renal carcinomas comprise the papillary renal cell carcinoma (which has two subtypes, type 1 and type 2, with very different prognostic values), clear cell renal carcinoma, chromophobe renal carcinoma, collecting duct renal carcinoma, and some unclassified carcinomas. Renal sarcomas include leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma, liposarcoma of the kidney, malignant hemangiopericytoma, angiosarcoma of the kidney, osteosarcoma, synovial sarcoma, chondrosarcoma of the kidney, malignant mesenchymoma, and clear cell sarcoma of the kidney. Lymphomas include Primary Renal Non-Hodgkin's Lymphoma, primary renal MALT lymphoma, primary renal Hodgkin's lymphoma, and secondary renal lymphomas, which can be of either Hodgkin's or Non-Hodgkin's type. Other kidney cancers include transitional cell carcinoma, Wilms Tumor, malignant rhabdoid tumor of the kidney, renal melanoma, primitive neuroectodermal tumor of the kidney, neuroepithelial tumor of the kidney, and congenital mesoblastic nephroma, some renal adenomas, and oncocytomas.
J. Prostate Cancer is not a single disease or group of very closely related disorders, but ranges over a very wide variety of cancer types. It embraces various adenocarcinomas of the prostate, including prostatic ductal adenocarcinoma, adenocarcinoma with paneth-like cells, clear cell adenocarcinoma, foamy gland adenocarcinoma, adenocarcinoma of Cowper’s glands, and atrophic adenocarcinoma. It includes a huge variety of carcinomas, including mucinous carcinomas of the prostate, prostatic carcinoma of xanthomatous type, signet ring cell carcinoma of the prostate, neuroendocrine small cell carcinoma of the prostate, and other small cell carcinomas of the prostate, adenosquamous and squamous cell carcinomas, basaloid and adenoid cystic carcinoma, sarcomatoid carcinoma of the prostate, lymphoepithelioma-like carcinoma of the prostate, urothelial (transitional cell) carcinoma (which can be primary in the prostate gland or represent secondary spread from the urinary bladder), basaloid carcinoma, pseudohyperplastic carcinoma, and primary carcinoma of the seminal vesicles. There are also assorted sarcomas of the prostate, including Angiosarcoma, Embryonal rhabdomyosarcoma, Stromal sarcoma, Synovial sarcoma, Leiomyosarcoma, and chondrosarcoma of the prostate, which can be primary or secondary to the prostate. Also included is prostatic intraepithelial neoplasia (PIN), phyllodes tumor of the prostate, primitive peripheral neuroectodermal tumor (PNET) and malignant fibrous histiocytoma. There are also lymphomas, which are usually secondary, but primary ones include diffuse large B-cell lymphoma. The great majority of this list are not treatable with pharmaceuticals.
K. The carcinomas of the bile ducts are of numerous types, including carcinoma in situ, adenocarcinoma, papillary adenocarcinoma, adenocarcinoma (intestinal-type), mucinous adenocarcinoma, clear cell adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma (oat cell carcinoma), Cholangiocarcinoma and undifferentiated carcinoma of the bile ducts. There is also a primary malignant melanoma of the bile duct, a carcinoid tumor, as well as myeloid, nonleukemic granulocytic, and botryoid sarcomas of the bile ducts. There is also primary non-Hodgkin's lymphoma, diffuse large B cell lymphoma, and follicular lymphoma of the bile ducts.
L. Breast cancers come in great variety. The most important category of breast cancers is the ductal cancers. These come in an assortment of types. Presently, these are divided into the following categories: intraductal (in situ); invasive with predominant intraductal component; invasive, NOS; Comedo; Inflammatory (IBC); medullary with lymphocytic infiltrate; mucinous carcinoma (colloid carcinoma); papillary carcinoma; scirrhous; tubular; and other. Another category is the Lobular breast cancers, which can be in situ, Invasive with predominant in situ component, and Invasive. There is Paget’s disease of the nipple, which can be also with intraductal carcinoma or with invasive ductal carcinoma. There is adenomyoepithelioma , a dimorphic tumor characterized by the presence of both epithelial and myoepithelial cells. There is lymphoma of the breast (which exists in both Non-Hodgkin's lymphoma of the breast and Hodgkin's disease of the breast forms). There are some sarcomas, including giant cell sarcoma of the breast, leiomyosarcoma of the breast, angiosarcoma of the breast, cystosarcoma phylloides, and liposarcoma of the breast. There are carcinoid tumors which can be primary carcinoid tumors of the breast, or can arise from from nonmammary sources. There are breast salivary gland-like tumors, including acinic cell carcinoma, oncocytic carcinoma (mammary epithelial oncocytoma), and mucoepidermoid carcinoma. Other rare carcinomas include spindle cell carcinoma of the breast, squamous cell carcinoma of the breast, secretory carcinoma of the breast (juvenile secretory carcinoma), metaplastic carcinoma of the breast (a heterogeneous group of invasive breast cancers including types with squamous differentiation and those with heterologous elements), invasive micropapillary carcinoma of the breast, adenoid cystic carcinoma of the breast, cribriform carcinoma, myofibroblastoma of the breast (benign spindle stromal tumor of the breast) and glycogen-rich clear cell carcinoma of the breast. There are also nonmammary tumors, primarily adenocarcinomas, that can metastasize to the breast including bronchogenic carcinomas, malignant melanomas (primary and secondary), rhabdomyosarcomas, malignant mesotheliomas, thyroid carcinomas, renal cell carcinomas, malignant lymphomas, and gastrointestinal carcinomas (including those from the stomach, pancreas, esophagus, and colon). Complicating the treatment of breast carcinomas is the fact that a significant proportion of mammary carcinomas are not monoclonal.
M. Ovarian cancers are a heterogeneous group of tumors. The most important are the epithelial tumors. These are themselves fairly diverse, the categories being serous cystomas (serous benign cystadenomas, serous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth and serous cystadenocarcinomas); mucinous cystomas (divided the same three ways); clear cell tumors (mesonephroid tumors, again divided the same way), endometrioid tumors (similar to adenocarcinomas in the endometrium: endometrioid benign cysts, endometrioid tumors with proliferating activity of the epithelial cells and endometrioid adenocarcinomas), mixed mesodermal (now considered to be carcinomas with areas of sarcomatous differentiation), transitional cell carcinoma, the Brenner tumor, and mixed epithelials. Second, there are the granulosa-stromal cell tumors. These include the granulosa cell tumor (which exists in juvenile and adult forms) and the tumors in the thecoma-fibroma sub-group. This sub-group also includes thecoma-fibroma group typical: thecoma and luteinized thecoma, as well as fibroma, cellular fibroma, fibrosarcoma, stromal tumor with minor sex cord elements, sclerosing stromal tumor, signet ring cell stromal tumor and others. Third, there are the Sertoli stromal cell tumors: Sertoli-Leydig cell tumor of the ovary (which comes in three different levels of differentiation, as well as a retiform version); Sertoli cell tumor (tubular androblastoma), and Stromal- Leydig cell tumor. Fourth are the Sex cord-stromal tumors of mixed or unclassified cell types: sex cord tumor with annular tubules, gynandroblastoma of the ovary (composed of sex cord and stromal cells of both ovarian and testicular types), and sex cord-stromal tumor NOS. Fifth, there are the steroid cell tumors: Ovarian Leydig cell tumor, which comes in hilus and non-hilar types, Stromal luteoma, and steroid cell tumor, NOS. Sixth, there is an assortment of Germ Cell Tumors. These include dysgerminoma; yolk sac tumors (endodermal sinus tumor, and polyvesicular vitelline tumor, hepatoid and others); embryonal carcinoma; polyembryoma; choriocarcinoma, gonadoblastoma and a wide variety of teratomas. These tetromas include immature, cystic (dermoid cyst), retiform (homunculus), and Monodermal, including struma ovarii, carcinoid (insular and trabecular), struma carcinoid, mucinous carcinoid, neuroectodermal tumors, sebaceous tumors and others. There are also the teratocarcinomas which come in many mixture types. Finally, there are an assortment of other tumors which do not fit into the above categories. There is Tumors of Rete Ovarii (which can be adenomatoid tumor or a mesothelioma). There are some tumors of uncertain origin, including small cell carcinoma, tumors of probable wolffian origin, a hepatoid carcinoma and oncocytoma. There are some soft tissue tumors not specific to ovary, and there are assorted malignant lymphomas and leukemias which land up in the ovaries.
N. Testicular cancers. All of the germ cell tumors listed above except for dysgerminoma also appear as cancers of the testis. In addition, seminoma itself as well as spermatocytic seminoma and choriocarcinoma of the testis are germ cell cancers of the testis. There are both juvenile and adult forms of the Granulosa cell tumor, as well as other cancers of the gonadal stroma, including leiomyomas, and neurofibromas. In addition to the germ cell cancers, there are the Sex cord-gonadal stromal tumors, including Sertoli cell tumor, Leydig cell tumor, and mixed form called Sertoli-Leydig cell tumor, and Gynandroblastoma of the testis. There are both adenomas and adenocarcinomas of collecting ducts and rete testis. There is Primary malignant melanoma of testis. There are a range of secondary tumors of the testis, most commonly Lymphomas, but also leukemic infiltration of the Testis, malignant melanoma metastatic to the testis, and metastatic cancers from the prostate or lung.
O. Paratesticular cancers (cancers of the spermatic cord, epididymis, vestigial remnants, and tunica vaginalis) are commonly classified separately from testicular cancers, and are rather varied. These include rhabdomyosarcoma of the spermatic cord (which can occur in embryonal, alveolar, and pleomorphic subtypes), liposarcomas, leiomyosarcomas, ovarian-type epithelial tumors, the desmoplastic small round cell tumor, the melanotic neuroectodermal tumor of infancy, primary paratesticular neuroblastoma, primary hematopoietic tumors of the paratesticular structures, plasmacytoma and granulocytic sarcoma of the paratestis, malignant schwannoma, malignant fibrous histiocytoma, malignant spermatic cord fibrosarcoma, and pleomorphic hyalinizing angiectatic tumor. There are also an assortment of secondary tumors, especially from the prostate, testis, kidney, and stomach, and malignant melanoma.
P. Cancers of the vulva are mostly squamous carcinoma, but these also include melanoma, Bartholin's Adenocarcinoma, basal cell carcinoma and some sarcomas.
Q. Vaginal cancers are primarily squamous carcinoma, but some are adenocarcinoma, melanoma of the vagina; sarcoma of the vagina, bowen's disease and germ cell tumors. There is also primary malignant melanoma of the vagina.
R. The most important of the cancers of the uterus are the Endometrial Carcinomas. The great majority of these are endometrioid; others include uterine papillary serous tumor (upst), clear cell carcinoma, mucinous and squamous. There is also plexiform tumorlet, Intravenous leiomyomatosis, benign metastasizing leiomyoma, leiomyomatosis peritonealis disseminate and leiomyosarcoma. Endometrial Tumors include endometrial stromal nodule, endolymphatic stromal myosis, and endometrial stromal sarcoma. There are the mixed tumors: Müllerian adenosarcoma and Malignant mixed mesodermal tumors (MMMT). Other sarcomas are rhabdosarcoma, osteosarcoma, chondrosarcoma and hemangiopericytoma. Some uterine cancers are secondary, starting in e.g. the tissue that begins to develop immediately after conception: epithelioid trophoblastic tumor, choriocarcinoma , and placental site trophoblastic tumors (PSTT).
S. There are several main types of stomach cancers, which are very different from each other. (1) Lymphomas of the stomach are found in the wall of the stomach. These come in two main categories. One is the Non-Hodgkin's lymphomas of the stomach, including MALT lymphoma, and assorted Large Cell Lymphoma of the Stomach such as anaplastic Ki-1 (CD30) positive large cell lymphoma. The other is Hodgkin Lymphoma in the Stomach. These include both lymphomas which are primary to the stomach, and nodal lymphomas that have spread to the stomach from e.g. the spleen or liver and are thus secondary. There are Tertiary gastric lymphomas as well. (2) Gastric stromal tumors (GISTs) develop from the tissue of the stomach wall. There are an assortments of these; GISTs vary from cellular spindle cell tumors to epithelioid and pleomorphic ones. (3) Carcinoid tumors are tumors of hormone-producing cells of the stomach. These are classified into are classified into those that are associated with hypergastrinemic states (type 1, atrophic gastritis, pernicious anemia); Zollinger-Ellison syndrome [ZES] tumors (type 2), and tumors without hypergastrinemia (type 3 or sporadic). (4) Carcinoma of the Stomach exists in five types: papillary, tubular, mucinous, signet-ring cell adenocarcinoma and undifferentiated carcinoma. (5) There is a primary malignant melanoma of the stomach (6) Soft tissue sarcomas, most notably leiomyosarcoma of the stomach.
T. Cancer of the esophagus is most commonly a squamous cell carcinoma or an adenocarcinoma. However, malignant melanomas, both primary and secondary can occur, and spindle cell carcinoma and Kaposi’s sarcoma can also occur in the esophagus. There is also primary oat cell carcinoma of the esophagus, choriocarcinoma of the esophagus, carcinoid tumor of the esophagus, adenosquamous carcinoma of the esophagus and the related mucoepidermoid carcinoma of the esophagus, and cylindroma of the esophagus. In addition, verrucous carcinomas and pseudosarcomas of the esophagus have been reported.
U. Cancers of the spleen which are primary are commonly devided into vascular, lymphoid and non-lymphoid. Vascular tumors include hemangiosarcoma, lymphangiosarcoma, hemangioendothelial sarcoma and malignant hemangiopericytoma of the spleen, all of which are considered malignant. Lymphoid tumors include both Hodgkin's and Non-Hodgkin's lymphoma, plasmacytoma and Castleman's tumor. Nonlymphoid tumors are more diverse, and include malignant fibrous histiocytoma, fibrosarcomas, leiomyosarcomas, malignant teratomas, and Kaposi's sarcoma of the spleen. There are also metastatic tumors, secondary to tumors most typically from the lung, stomach, pancreas, liver, breast and colon. These are typically adenocarcinomas or squamous cell carcinomas, but large cell carcinoma, small cell carcinoma, hepatocellular carcinoma, melanoma, mesothelioma and choriocarcinoma are known as well.
V. Salivary gland carcinomas arguably represent the most heterogeneous group of tumors of any tissue in the body. The main four histopathologic types are: (1) mucoepidermoid carcinoma (2) adenoid cystic carcinoma (which has three histologic types: cribriform, tubular, and solid), (3) adenocarcinoma which includes acinic cell carcinoma, polymorphous low-grade adenocarcinoma, Sebaceous Lymphadenocarcinoma, adenocarcinoma not otherwise specified (NOS), Mucinous adenocarcinoma, and cystadenocarcinoma; (4) salivary duct carcinoma. In addition, there is an adenosquamous carcinoma, lymphoepithelial carcinoma, epithelial–myoepithelial carcinoma, basal cell adenocarcinoma, sebaceous carcinoma, oncocytic carcinoma, myoepithelial carcinoma, and clear cell carcinoma of the salivary glands NOS (hyalinizing clear cell carcinoma). In addition to the carcinomas, there are some adenomas, including carcinoma ex-pleomorphic adenoma, pleomorphic salivary adenoma, canalicular adenoma, oxyphilic adenoma, papillary cystadenoma, lymphadenoma, sebaceous adenoma, basal cell adenoma, and ductal cystadenoma. There are two ductal papillomas: inverted ductal papilloma and intraductal papilloma. There is also an assortment of perinatal salivary gland tumors. There are a group of haematolymphoid salivary Tumors: Hodgkin lymphoma, Diffuse large B-cell lymphoma and extranodal marginal zone B-cell lymphoma. In addition, there is a salivary haemangioma, warthin tumor, salivary carcinosarcoma, sialadenoma papilliferum, oncocytoma, and myoepithelioma of the salivary glands, Low-Grade Cribriform Cystadenocarcinoma (LGCCC), and sialoblastoma.
W. Cancers of the Heart (including pericardium, valves, etc.) include a wide range of primary cardiac sarcomas, including angiosarcomas, undifferentiated sarcomas, osteosarcomas, fibrosarcomas, malignant fibrous sarcomas, histiocytomas, leiomyosarcomas, myxosarcomas, synovial sarcomas, neurofibrosarcomas, rhabdomyosarcomas, reticulum cell sarcomas, desmoplastic small round cell tumors, and liposarcomas. Primary heart tumors also include melanoma, atrial myxoma, rhabdomyoma, papillary fibroelastoma of the endocardium, and teratoma. There is also Purkinje cell hamartoma of the conduction tissue. In the Pericardium, there is also malignant schwannoma, aberrant synoviosarcoma, neurofibroma and thymomas (invasive and non-invasive). Secondary tumors of the heart are more common, and can arrive by many pathways. For example, bronchogenic carcinoma can arrive by direct extension or by a combination of lymphatic and hematogenous dissemination. breast, lung and esophagus carcinomas, Hodgkin and non-Hodgkin lymphomas, melanomas, mesothelioma, renal cell carcinoma, leukemias, Kaposi sarcoma and osteosarcomas are the most common forms, but there are many more.
X. Odontogenic tumors are cancers of the jaw derived from primordial tooth-forming tissues. The epithelial tumors include squamous odontogenic tumor, adenomatoid odontogenic tumor, calcifying epithelial odontogenic tumor (Pindborg tumor), and ameloblastoma. And adamantinoma and adamantinomatous craniopharyngioma are included here as well. The mixed odontogenic tumors include ameloblastic fibro-odontoma, and ameloblastic fibroma. The mesenchymal
odontogenic tumors include cementoblastoma, and odontogenic myxoma. There is also ameloblastic fibrosarcoma, granular cell ameloblastic fibroma, ameloblastic sarcoma, malignant ameloblastoma, ameloblastic carcinoma, clear cell odontogenic carcinoma, odontoameloblastoma and squamous odontogenic tumors.
Y. Cancers of the oral cavity and oropharynx, including the tongue is most commonly squamous cell carcinoma and Verrucous carcinoma. There are also lymphomas of the tonsils and base of the tongue, Nasopharyngeal carcinoma (which exists in three subtypes), as well as neurofibroma, schwannoma and rhabdomyoma of the mouth, and primary melanoma melanoma of the oral cavity. In addition, HPV-positive oropharyngeal cancer is now considered a distinct disease entity. Salivary gland cancers and odontogenic tumors are discussed separately above.
Z. Cancers of the lymph glands are of course the lymphomas. There are also carcinomas of the lymph nodes, including large cell carcinoma of the lymph nodes, metastatic squamous cell carcinoma of the lymph nodes, primary neuroendocrine carcinoma of the lymph nodes and Merkel cell carcinoma of the lymph nodes. There is also generalized reticulum cell sarcoma of the lymph nodes, Kaposi's sarcoma of the lymph nodes and lymph node melanoma.
AA. Cancers of the adrenal glands include adrenocortical carcinoma, pheochromocytoma, adrenal neuroblastoma, and adrenal ganglioneuroma.
AB. Cancer of the eye is a very loose category, as the set of cancers involved depends very much on which structure of the eye or its adnexa is involved. Choroidal tumors include choroidal melanoma, ciliary body melanoma choroidal osteoma and metastatic choroidal tumors, including tumors from the lung, breast, prostate, kidney, thyroid and blood. Eyelid tumors include basal cell carcinoma, malignant melanoma of the eyelid, sebaceous carcinoma of the eyelid and squamous carcinoma of the eyelid. Iris tumors include iris melanoma, malignant iris melanocytoma, and anterior uveal metastasis, most commonly from breast, lung, prostate, skin, kidney, colon and thyroid. Optic nerve tumors include juxtapapillary choroidal melanoma (choroidal melanoma affecting the optic nerve), circumpapillary metastasis with optic neuropathy, and optic nerve melanocytoma. Retinal tumors include retinal pigment epithelium tumors, and retinoblastoma. Conjunctival tumors are quite varied, and include conjunctival kaposi's sarcoma, epibulbar dermoid, lymphoma of the conjunctiva, pigmented conjunctival tumors (a malignant melanoma), and squamous carcinoma (including intraepithelial neoplasia of the conjunctiva). Infiltrative intraocular tumors include chronic lymphocytic leukemia, infiltrative choroidopathy and intraocular lymphoma. Orbital tumors include adenoid cystic carcinoma of the lacrimal gland, lymphangioma of the orbit, orbital pseudotumor, and orbital rhabdomyosarcoma. Optic nerve gliomas are mentioned above in cancers of the brain.
AC. Cervical cancers. There are many different categories and sub-categories of cervical cancers. The majority of cervical cancers are Squamous Cell Carcinomas. These come in numerous types: large cell nonkeratinizing type; large cell keratinizing type; basaloid; verrucous; warty; papillary; lymphoepithelioma-like; and squamotransitional, Early invasive (microinvasive) squamous cell carcinoma; Squamous intraepithelial neoplasia (including Cervical intraepithelial neoplasia and Squamous cell carcinoma in situ). There are also a variety of adenocarcinomas, the most important of which are the mucinous adenocarcinoma, which include the endocervical, intestinal, signet-ring cell, minimal deviation, and villoglandular. There is also endometrioid adenocarcinoma, clear cell adenocarcinoma, serous adenocarcinoma, mesonephric adenocarcinoma, Early invasive adenocarcinoma, and adenocarcinoma in situ. In addition, there are neuroendocrine carcinomas, divided into Small Cell, large cell, classical carcinoid and atypical carcinoid. Other epithelial tumors include adenosquamous carcinoma, mixed adenosquamous carcinomas, which can be either well-differentiated or poorly differentiated, the latter including glassy cell carcinoma, adenoid cystic carcinoma, adenoid basal carcinoma and undifferentiated carcinoma. There are also some mixed carcinoma with signet-ring cells, and other types of other poorly differentiated mixed carcinomas. This group includes tumors sometimes called apudomas or argyrophil cell carcinomas. There are also an assortment of mesenchymal tumors of the cervix, including leiomyosarcoma; endometrioid stromal sarcoma, low grade; undifferentiated endocervical sarcoma; sarcoma botryoides; alveolar soft part sarcoma, angiosarcoma of the cervix, malignant peripheral nerve sheath tumor of the cervix; cervical leiomyoma; and rhabdomyoma of the cervix. There are also some mixed epithelial and mesenchymal tumors, including carcinosarcoma (malignant müllerian mixed tumor), adenosarcoma, Wilms tumor, typical and atypical polypoid adenomyoma, and papillary adenofibroma of the cervix. There are also melanocytic tumors, including primary malignant melanoma of the cervix and blue naevus of the cervix. There are also germ cell type tumors, including yolk sac tumor, dermoid cyst, and mature cystic teratoma of the cervix. There is also primary choriocarcinoma of the cervix, which does not fit well into any category. There are also numerous cancers secondary to the cervix.
AD. Gestational Trophoblastic Neoplasia is cancer of the placenta; it actually derives from the conceptus rather than from the pregnant woman. It has three different forms: choriocarcinoma, placental site trophoblastic tumor, epithelioid trophoblastic tumor
AE. Cancer of the throat is a loose term, depending on the particular structure. Cancers of the oropharynx are discussed above in cancers of the oral cavity. Hypopharyngeal cancer is usually a form of squamous cell carcinoma, including basaloid squamous cell carcinoma, superficial spreading cancer, sebaceous cancer, adenosquamous cancer, and signet-ring and verrucous types. Less common forms of hypopharyngeal cancer include adenocarcinoma, lymphoma, and sarcoma. Nasopharyngeal cancer is usually a carcinoma, and is commonly devided into three types: keratinizing squamous cell carcinoma, non-keratinizing carcinoma, and undifferentiated carcinoma. There are also rhabdomyosarcomas and lymphomas as well.
AF. Cancer of the thymus is normally a carcinoma, called thymoma, including Type C, also called thymic carcinoma, and a clear cell carcinoma of the thymus. There are also a series of germ cell tumors of the thymus as well as both Hodgkin and non-Hodgkin lymphomas. There are also carcinoid tumors of the Kulchitsky cells.
AG. Fallopian Tube Cancer most commonly takes the form of a papillary serous adenocarcinoma. These are also leiomyosarcomas (arising from smooth muscle in the fallopian tubes), squamous cell carcinoma, choriocarcinoma, and transitional cell carcinomas. Secondary cancers are more common, and come from the ovaries, the endometrium, the GI tract, the peritoneum, and the breast.
AH. Bladder cancers. Most cases of bladder cancers are transitional cell (urothelial) carcinoma, which includes non-invasive papillary urothelial carcinoma, flat urothelial carcinoma in situ (CIS), superficially invasive urothelial carcinoma, and muscle invasive tumors. Adenocarcinomas of the bladder include Primary Adenocarcinoma (urachal and non-urachal), Prostatic adenocarcinoma, Gastro-intestinal adenocarcinomas and Clear cell carcinoma. Squamous cell carcinomas include Verrucous carcinomas, and a secondary squamous cell carcinoma of the bladder, from the cervix. Small cell carcinomas include Primary small cell carcinoma of the bladder and the secondary small cell carcinoma ('reserve cell carcinoma') of the lung. Lymphomas include the primary lymphomas (Low grade B-cell lymphoma of MALT type, High grade B-cell lymphoma, and T-cell lymphoma), as well as secondary lymphomas, including mantle cell lymphomas. Melanomas include Primary malignant melanoma of the bladder, and secondary ones. The sarcomas of the bladder are leiomyosarcoma, osteosarcoma and rhabdomyosarcoma. There is also a primary primitive neuroectodermal tumor (PNET) of the bladder, Paraganglioma (which can metastasize), nephrogenic adenoma, metastatic renal cell carcinoma of the bladder, and both primary and secondary (from the uterus) choriocarcinoma of the bladder.
AI. Cancers of the gallbladder are most commonly adenocarcinomas, including non-papillary adenocarcinoma, papillary adenocarcinoma, and mucinous adenocarcinoma. There is also squamous cell, adenosquamous, and oat cell carcinoma, of the gallbladder. Primary non-Hodgkin's lymphoma of the gallbladder, exists in both MALT and non-MALT forms. Primary neuroendocrine tumors (NETs) of the gallbladder can be of either large-cell or small-cell type. Primary gallbladder sarcoma includes leiomyosarcomas, myxofibrosarcomas, epithelioid angiosarcomas, and botryoid embryonal rhabdomyosarcomas. There is also primary malignant melanoma of the gall bladder, although secondary melanoma of the gallbladder is much more common.
AJ. Cancers of the paranasal sinus and nasal cavity are most commonly squamous cell carcinoma, But other primary forms include adenocarcinoma, malignant lymphoma, malignant melanoma (including primary melanoma of the sphenoid sinus), esthesioneuroblastomas (olfactory neuroblastoma, which occurs in the upper cribriform region of the nasal cavity) and lethal midline granuloma (malignant granuloma). There are also tumors secondary to this area, especially from bone and cartilage.
AK. In the spinal cord (including the covering), intramedullary tumors are most commonly astrocytomas and ependymomas, while meningiomas and nerve-sheath tumors are the most common types of intradural extramedullary spinal tumor. There is a primary malignant melanoma of the leptomeninges. Extradural spinal tumors arise in the bones of the spine and include chordomas, osteosarcomas, chondrosarcomas and fibrosarcomas.
AL. Penile carcinoma is usually a squamous cell carcinoma (including carcinoma in situ or Bowen disease), but there is also primary melanoma of the penis, penile clear cell carcinoma, and sarcomatoid carcinoma. There is also primary reticulum cell sarcoma of the penis, Kaposi sarcoma of the penis, and Paget disease of the Penis.
AM. Primary cancers of the bone itself are of eight types. Osteosarcoma (Osteogenic Sarcoma), Chondrosarcoma (which actually develops in the cartilage tissue), Ewing's Sarcoma, Malignant fibrous histiocytoma, Fibrosarcoma, Giant cell tumor of the bone (Osteoclastoma), Adamantinoma (which develops almost exclusively in the long bones, and occurs in two forms, classic and differentiated) and Chordoma. Secondary bone cancers can come from a wide variety of sources, but most commonly arise in the breast, prostate, lung, kidney and thyroid.
AN. The Non-Hodgkin lymphomas fall into four categories. The first is the Precursor B-cell tumor, i.e. Precursor B-lymphoblastic leukemia/lymphoma. The second are the mature B-cell neoplasms: Chronic lymphocytic leukemia/small lymphocytic lymphoma; B-cell prolymphocytic leukemia; Splenic marginal zone lymphoma; Hairy cell leukemia; Splenic lymphoma/leukemia, unclassifiable (including Splenic diffuse red pulp small B-cell lymphoma and Hairy cell leukemia-variant); Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia); the Heavy chain diseases (Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease); Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseous plasmacytoma; Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma); Nodal marginal zone B-cell lymphoma (MZL, including Pediatric type nodal MZL); Follicular lymphoma (including Pediatric type follicular lymphoma); Primary cutaneous follicle center lymphoma; Mantle cell lymphoma; Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (including T cell/histiocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation, and Epstein-Barr virus DLBCL of the elderly); Lymphomatoid granulomatosis; Primary mediastinal (thymic) large B-cell lymphoma; Intravascular large B-cell lymphoma; Primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma; Plasmablastic lymphoma; Primary effusion lymphoma; Large B-cell lymphoma arising in HHV8-associated multicentric (including Castleman disease); Burkitt lymphoma; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma; and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. The third is Precursor T-cell tumor, i.e. Precursor T-lymphoblastic lymphoma/leukemia. The fourth category is the mature T-cell and NK-cell neoplasms: T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; Chronic lymphoproliferative disorder of NK-cells; Aggressive NK cell leukemia; Systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection); Hydroa vacciniforme-like lymphoma; Adult T-cell leukemia/ lymphoma; Extranodal NK/T cell lymphoma, nasal type; Enteropathy-associated T-cell lymphoma; Hepatosplenic T-cell lymphoma; Subcutaneous panniculitis-like T-cell lymphoma; Mycosis fungoides; Sézary syndrome; Primary cutaneous CD30+ T-cell lymphoproliferative disorder (including Lymphomatoid papulosis and Primary cutaneous anaplastic large-cell lymphoma); Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; Primary cutaneous gamma-delta T-cell lymphoma; Primary cutaneous small/medium CD4+ T-cell lymphoma; Peripheral T-cell lymphoma, not otherwise specified; Angioimmunoblastic T-cell lymphoma; Anaplastic large cell lymphoma (ALCL), ALK+; and Anaplastic large cell lymphoma (ALCL), ALK–. Note that this category overlaps to some degree with the leukemias, and also includes all of the cutaneous lymphomas listed above under non-melanoma cancers of the skin, except for primary and secondary cutaneous Hodgkin’s Lymphoma.
AO. Classical Hodgkin’s lymphoma comes in four forms: Nodular sclerosis classical Hodgkin lymphoma; Lymphocyte-rich classical Hodgkin lymphoma; Mixed cellularity classical Hodgkin lymphoma; and Lymphocyte-depleted classical Hodgkin lymphoma. Nodular lymphocyte-predominant Hodgkin lymphoma is also considered to be a subtype of Hodgkin lymphoma.
AP. Cancer of the Pancreas. These cancers are primarily carcinomas. There is duct cell carcinoma, acinar cell carcinoma, papillary mucinous carcinoma, signet ring carcinoma, medullary carcinoma, squamous carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, colloid carcinoma (mucinous carcinoma or mucinous non-cystic carcinoma), giant cell carcinoma, and small cell carcinoma. Cancers of the endocrine part of the pancreas (islet cell tumors) include insulinoma, glucagonoma, somatostatinoma, gastrinoma, VIPoma, carcinoid, ACTHoma, GRFoma, PTF-like-oma, neurotensinoma, and Multiple Endocrine Neoplasia Type 1 (MEN1). Neurofibromatosis (NF) Type 1 is usually included with this category. There are mixed types, notably pancreatoblastoma, as well as ductal-endocrine or acinar-endocrine types. There is also cystadenocarcinoma which comes in serous and mucinous types, pancreatic lymphoma, pseudopapillary solid tumor of the pancreas (Frantz’s tumor) and mucinous cystic tumor with dysplasia.
AQ. Cancers of the ear, including the temporal bone, are most commonly skin cancers of the outer ear, but there is also nonmelanoma skin cancer (NMSC) of the ear. There is also squamous cell carcinoma of the ear, adenoid cystic carcinoma of the ear, and ceruminomatous adenoid cystic carcinoma of the ear. Other cancers of the ear may arise from invasion from adjacent structures such as the parotid gland. Glomus tumours, which arise from the outer layers of the blood vessels in the middle ear, are sometimes malignant.
AR. Cancer of the small bowel. Adenocarcinoma, usually devided into non-ampullary and ampullary, is the most common type, and usually occurs in the duodenum. One variant of this is a small cell carcinoma Sarcomas include both the gastrointestinal stromal tumor, as well as assorted non-GIST sarcomas, including leiomyosarcomas, angiosarcomas, and malignant fibrous histocytomas. The neuroendocrine tumors of the small bowel are usually carcinoid tumors and are typically seen in the ileum; gastrin G-cell tumors account for a majority of the duodenal carcinoids. Lymphomas are most commonly diffuse large B-cell lymphomas, and there is a T-cell type sometimes is seen in patients with celiac disease, and MALT lymphoma can arise in the ileum, as well as Mediterranean lymphoma (IPSID, sometimes considered a form of MALT lymphoma), centrocytic Malignant lymphoma, and Burkitt-like lymphoma. In terms of secondary cancers, cancer arising from the breast, lung and especially melanomas metastasize to the small bowel hematogenously. Primary tumors of the colon, ovary, uterus and stomach usually enter the small bowel either by direct invasion or by intraperitoneal spread.
AS. Metastatic umbilical cancer sometimes goes by the name of “Sister Mary Joseph's nodule”, and is usually an adenocarcinoma. These arise from the stomach, colon or ovary. There is also primary malignant melanoma of the umbilicus and a primary basal cell carcinoma of the umbilicus.
Also the scope of treating inflammation generally is extraordinarily broad. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. It is one of the most pervasive of all body processes. Inflammation is a very general term which encompasses a huge variety of specific processes.
Inflammation is the reaction of vascularized tissue to local injury; it is the name given to the stereotyped ways tissues respond to noxious stimuli. These occur in two fundamentally different types. Acute inflammation is the response to recent or continuing injury. The principal features are dilatation and leaking of vessels, and recruitment of circulating neutrophils. Chronic inflammation or "late-phase inflammation" is a response to prolonged problems, orchestrated by T-helper lymphocytes. It may feature recruitment and activation of T- and B-lymphocytes, macrophages, eosinophils, and/or fibroblasts. The hallmark of chronic inflammation is infiltration of tissue with mononuclear inflammatory cells. Mechanistically, chronic inflammation encompasses a broad spectrum of immunologic processes, including antibody formation, antibody-dependent cell-mediated cytotoxicity, and cell-mediated immunity (delayed-type hypersensitivity). Granulomas are seen in certain chronic inflammation situations. They are clusters of macrophages which have stuck tightly together, typically to wall something off. Granulomas can form with foreign bodies such as aspirated food, toxocara, silicone injections, and splinters.
Otitis media is an inflammation of the lining of the middle ear and is commonly caused by Streptococcus pneumoniae and Haemophilus influenzae. Its numerous forms include acute suppurative otitis media, chronic tubotympanic suppurative otitis media, chronic atticoantral suppurative otitis media, acute nonsuppurative otitis media, chronic serous otitis media, chronic mucoid otitis media, allergic seromucinous otitis media, exudative transudative otitis media, catarrhal serous otitis media, allergic otitis media and chronic purulent otitis media.
Myringitis (sometimes included with otitis externa ) is inflammation of the tympanic membrane. It comes in numerous forms. Acute myringitis can occur because of direct trauma to the tympanic membrane through penetration by a foreign body. Primary myringitis may also be caused by unsuccessful removal of a foreign body, typically an insect, or by self-cleaning of the ear. Acute bullous myringitis and acute hemorrhagic myringitis can both be the consequence of a bacterial or viral infection. Fungal myringitis can be the consequence of a fungal infection.Eczematous myringitis can occur in cases of dermal eczema of the tympanic membrane's epidermis. Myringitis granulosa occurs when the tympanic membrane is covered with granulation tissue, and can result in destroying the tympanic membrane.
Idiopathic inflammatory medial meatal fibrotizing otitis is a disorder of the external auditory canal characterized by desquamation of the medial canal skin, chronic inflammation, and eventual canal stenosis.
Otitis externa (also known as "Swimmer's ear") is an inflammation of the outer ear and ear canal. The chronic form may be secondary to eczema, whereas the acute form tends to be in response to a microbial infection. Perichondritis of auricle, cholesteatoma of external ear and keratosis obturans are generally included with this.
Otitis interna (labyrinthitis) is an inflammation of the inner ear that typically results in severe vertigo and is generally thought to arise from a viral infection. from a viral inflammation. Treatment is generally with vestibular suppressants (suppression of symptoms), but antibiotics may be given in bacterial infection is suspected.
There is also Eustachian salpingitis, a general category of inflammation of the Eustachian tubes. It includes Otosalpingitis,
inflammation of the mucous membrane of the cartilagenous portion of the eustachian tube.
Petrositis is a type of inflammation of the temporal bone which may go all the way to the inner ear. Gradenigo's syndrome is a closely related disorder. Mastoiditis is an inflammation arising from infection of mastoid process, another portion of the temporal bone.
Cystitis is any inflammation of the bladder, often caused by bacteria. Two ordinary types are eosinophilic and tuberculous cystitis. Interstitial cystitis (IC) is a particularly severe form, an inflammation of the bladder wall which may include Glomerulations. The origins and mechanism are largely unknown, and it isn’t even clear whether there is just one form of the disease or several. There is no actual pharmaceutical treatment for the disease itself, although a few drugs can give some relief of symptoms, specifically Elmiron and DMSO.
Blepharitis is a chronic inflammation of the eyelids that is caused by a staphylococcus. Dacryocystitis is inflammation of the tear sac, and usually occurs after a long-term obstruction of the nasolacrimal duct and is caused by staphylococci or streptococci. Preseptal cellulitis is inflammation of the tissues around the eye, and Orbital cellulitis is an inflammatory process involving the layer of tissue that separates the eye itself from the eyelid. These life-threatening infections usually arise from staphylococcus. Hence, these types of inflammations are treated with antibiotics.
There is also a wide assortment of forms of conjunctivitis, including seasonal allergic conjunctivitis, perennial allergic conjunctivitis, giant papillary conjunctivitis (GPC) (a chronic yet poorly condition associated with contact lens wear), Vernal keratoconjunctivitis and atopic keratoconjunctivitis. In addition to types of allergic conjunctivitis there is also bacterial conjunctivitis (e.g. from Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus) and viral conjunctivitis (e.g. from gonorrhea, herpes simplex, chlamydia, adenoviruses or enteroviruses) Parasitic conjunctivitis (e.g. from Onchocerca volvulus, Loa loa, Wuchereria bancrofti or Trichinella spiralis), fungal conjunctivitis (e.g. from Candida albicans or Sporothrix schenckii), Phlyctenular Conjunctivitis, Inclusion Conjunctivitis, immunologic conjunctivitis, irritant conjunctivitis (e.g. from burns, chlorine or air pollutants ), Radiation conjunctivitis, and assorted forms of neonatal conjunctivitis (which can be caused by e.g. a blocked tear duct).
Cholecystitis is gallbladder inflammation usually caused by a gallstone that cannot pass through the cystic duct. In those cases, it normally cannot be treated by pharmaceuticals but instead the gallbladder is removed. Cholecystitis without the formation of gallstones, called acalculous cholecystitis, is caused by bacteria such as Salmonella, Staphylococcus, Streptococcus (as part of scarlet fever), and leptospirosis, and thus may be treatable by treating the underlying infectious agent. Acute inflammation of the gall bladder can also arise from typhoid; treatment is with antibiotics.
Arthritis is general term denoting group of conditions involving damage to the joints of the body, and may or may not involve inflammation of other parts of the body such as the nails.
Rheumatoid arthritis is an inflammatory disorder causing destruction of articular cartilage. It is an autoimmune condition where the body’s immune system attacks its joints. It is a multisystemic disease, having extra-articular manifestations (e.g anemia, Keratoconjunctivitis sicca, lung fibrosis) which distinguish this disease from osteoarthritis.
Osteoarthritis is a degenerative disease, primarily of the articular cartilage and subchondral bone. Primary osteoarthritis, which comes in 2 forms, nodal and erosive, has no clearly defined underlying cause, although genetic factors are believed relevant in more than half the cases. Secondary osteoarthritis arises from injuries, diseases such as Paget's disease, conditions such as Marfan syndrome and long-term obesity, congenital disorders of joints, etc.
In gouty arthritis, joint inflammation is caused by the formation of monosodium urate monohydrate (MSU) crystals, or uric acid crystals, within the joint space.
Pseudogout, another form of arthritis, arises from the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in synovial fluid or articular tissue.
In addition, CPPD deposition can cause Pseudo-osteoarthritis, a gradual onset of joint pain and stiffness, which commonly involves an unusually severe, oddly distributed, degenerative arthritis.
CPPD deposition can also cause Pseudo-rheumatoid arthritis, which features multiple joint involvement with symmetric distribution, morning stiffness, fatigue, and synovial thickening.
Finally, CPPD can cause Pseudo-neuropathic anthropathy, a severe destructive monarthritis similar to that seen in neuropathic joints.
Hydroxyapatite (also called Basic calcium phosphate (BCP)) induced arthritis, from Hydroxyapatite deposition disease (HADD), is a third category of crystal deposition disease. This can involve synovial effusions, acute inflammation in joints, idiopathic tumoral calcinosis, Milwaukee shoulder syndrome etc. There is also an erosive arthritis associated with BCP crystals.
A fourth form is calcium oxalate associated arthritis, typically arising from end stage renal disease, but also from short bowel syndrome; diets rich in rhubarb, spinach or ascorbic acid; thiamine or pyridoxine deficiency; and a metabolic problem, primary or secondary oxalosis.
Finally there are an assortment of other crystal-associated forms of arthritis. Calcium oxalate aluminum phosphate crystals can trigger an acute arthritis in patients on renal dialysis. Cholesterol, xanthine, cystine, cryoglobulins, Charcot-Leyden (lysophospho-lipase), and hypoxanthine crystals when depositing in joints produce their own forms of arthritis.
Lyme disease (Lyme borreliosis), which is caused by spirochetal bacteria from the genus Borrelia, triggers several forms of arthritis, including types of radiculoneuritis such as neuroretinitis, myelitis and encephalomyelitis, as well as Lyme arthritis and cerebral arteritis.
There is an assortment of other forms of infectious arthritis, i.e. arthritis caused by bacteria, rickettsiae, mycoplasmas, viruses (or vaccinations given to prevent viral infections), fungi, or parasites; it is also called septic arthritis. Included in this category are various types of mycotic arthritis, and viral arthritis, such as rubella arthritis, Mumps arthritis, arboviral arthritis, syphilitic arthritis, parvovirus arthritis, tuberculous arthritis, Varicella arthritis, gonococcal arthritis, rubella arthritis, etc. These assorted disorders can arise from quite varied sources. Moreover, there is also a poorly understood disorder, pseudoseptic arthritis.
Reactive arthritis (also been known as Reiter's Syndrome, arthritis urethritica, and polyarteritis enterica) is an autoimmune condition that develops in response to an infection in another part of the body, although reactive arthritis often shows up after the triggering infection is either gone or in remission. The most common triggers are Chlamydial infections, Nisseria gonorrhea; Salmonella, Shigella, and Campylobacter.
Another of the seronegative spondyloarthropathies is psoriatic arthritis, which is believed to be autoimmune in origin and whose exact cause is unknown, but there is a clear genetic component. It comes in several forms, including symmetric, asymmetric, arthritis mutilans, and “distal interphalangeal predominant”.
Enteropathic arthritis, also a seronegative spondyloarthropathy is secondary to IBD.
Other seronegative spondyloarthropathies are ankylosing spondylitis (also known as Bechterew syndrome; Marie Strumpell disease; and rheumatoid spondylitis), and undifferentiated seronegative arthritis. All of the seronegative spondyloarthropathies are distinct from rheumatoid arithitis, in that in RA, the Rf-factor is not absent.
Sjogren's syndrome, like RA an autoimmuine, Seropositive disorder, affects primarily the eyes and mouth, but extraglandular problems in Sjogren's syndrome include joint pain or inflammation. It is not entirely clear whether Sjogren's syndrome arthritis is actually different from RA.
Ochronotic arthritis is a degenerative form of arthritis, causing a color change in the joints, and hardening of tendons and ligaments can predispose them to rupture; microruptures cause further joint disease.
Lupus arthritis is the most common manifestation of Systemic Lupus Erythematosus (SLE), an auto-immune condition. The most commonly affected joints are the hands, wrists, and knees.
There is also Adult Still's disease (ASD or AOSD) which has in addition to joint inflammation, a salmon-pink rash and daily spiking fevers. Related is Systemic onset juvenile idiopathic arthritis (SOJIA, also known as Still's disease).
Menopausal arthritis is due to ovarian hormonal deficiency, typically arising from use of aromatase (estrogen synthetase) inhibitors, which lower levels of estrogen. This has been little studied.
Neuropathic arthritis (which comes in several forms, the most important of which is Charcot's joint disease or Charcot Arthropathy or Charcot's arthritis) can arise from sources as diverse as Diabetes Mellitus, steroid treatment, leprosy, chronic alcoholism, heavy metal poisoning and neoplastic peripheral neuropathy.
Hallux rigidus, of unknown etiology, is a degenerative type of arthritis that affects the large joint at the base of the big toe.
Arthritis secondary to Systemic Sclerosis (other than RA) is usually symmetrical polyarthritis with predominant hand involvement, and is frequently erosive.
Hemorrhagic Arthritis (including haemophilic arthritis) is a general term encompassing any disorder characterized by bleeding within a joint, leading to inflammation of the joint lining (e.g. chronic synovitis), and sometimes degeneration of joint cartilage. Depending on cause, it is either acute or chronic. The great majority of those suffering from severe hemophilia have haemophilic arthritis.
The Palmar Fasciitis and Polyarthritis Syndrome is a disabling, paraneoplastic condition of unknown pathogenesis.
Complicating matters further is that fibromyalgia is considered by some to be included in the term arthritis, but others do not consider it a form of arthritis.Sinusitis is the inflammation of the mucosal lining of one or more of the 4 cavities near the nasal passages (ethmoid, maxillary, frontal, and sphenoid sinuses). It commonly accompanies upper respiratory viral infections which obstruct the opening, but such obstruction can also arise from abnormalities in the structure of the nose, enlarged adenoids, diving/swimming, infections from a tooth, trauma to the nose, and foreign objects that are stuck in the nose. Bacteria, notably Streptococcus pneumonia, Haemophilus influenza, and Moraxella catarrhalis grown in the trapped secretions. In most cases it requires no treatment, but antibiotics may be given, along with acetaminophen for pain and nosedrops, for relief of symptoms.
Pharyngitis is infection and inflammation of the throat (including the nasopharynx, uvula, and soft palate)and tonsillitis is of the tonsils. These are caused by a variety of viruses (adenoviruses, influenza viruses, parainfluenza viruses, Epstein-Barr virus, enteroviruses, Herpes simplex virus), mycoplasmas (e.g. Mycoplasma pneumoniae), and bacteria (Group A Beta Hemolytic Streptococci (GABHS), Streptococcus pyogenes, Neisseria Gonorrhea, Hemophilus Influenza Type B) as well as fungal infections, parasitic infections, cigarette smoke, and unknown causes.
Similarly, Osteomyelitis is the inflammation of bones, often caused by bacteria (most commonly Staphylococcus Aureus), and sometimes by fungi or viruses. Chronic Recurrent Multifocal Osteomyelitis (CRMO), a chronic inflammatory disease of unknown etiology, results in recurrent fever and the development of multiple inflammatory bone lesions.
Dacryoadenitis, an inflammation of the tear gland, can arise from infectious mononucleosis, mumps, gonorrhea, or influenza.
Lung inflammation can take many forms.
Chronic Obstructive Pulmonary Disease (COPD) is a slowly progressive disease of the airways that is characterized by a gradual loss of lung function. COPD includes chronic obstructive Bronchitis (which involves inflammation and eventual scarring of the bronchi) and emphysema (enlargement and destruction of the alveoli). Emphysema comes in several forms, including Congenital Lobar Emphysema, Bullous Emphysema, Centrilobular Emphysema (Proximal acinar emphysema), Panacinar (panlobular), Distal acinar (paraseptal) as well as Alpha-1 antitrypsin (AAT) deficiency, which is the genetic form of emphysema; patients often have both a form of bronchitis and emphysema. Ordinary chronic bronchitis is sometimes included with COPD even if there is no actual obstruction, and asthmatic bronchitis is generally included in COPD as well. Persons with COPD typically develop smaller air passageways, which can become clogged with mucus and have partially destroyed alveoli. There is no pharmaceutical treatment for COPD per se. Instead, treatment is supportive and designed to relieve symptoms and improve quality of life. Thus, oxygen is often given to partially compensate for the loss of lung function. Bronchodilators can expand passageways in the lungs, Corticosteroids can reduce inflammation and Antibiotics can ward off bacterial infections, but none of these treat the COPD itself.
Another category of inflammatory disorders of the lung is Interstitial lung disease, or ILD, (interstitial pulmonary fibrosis), a term that includes more than 180 chronic lung disorders, which may be chronic, nonmalignant (non-cancerous) and noninfectious. Interstitial lung diseases are named after the tissue between the air sacs of the lungs called the interstitium -- the tissue affected by fibrosis (scarring). The common link between the many forms of ILD is that they all begin with an inflammation. The three main kinds are bronchiolitis - inflammation that involves the bronchioles (small airways); alveolitis - inflammation that involves the alveoli (air sacs); and vasculitis - inflammation that involves the small blood vessels (capillaries). More than 80 percent of interstitial lung diseases are diagnosed as pneumoconiosis, a drug-induced disease, or hypersensitivity pneumonitis. An important group of the ILDs are the Idiopathic interstitial pneumonias including idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, Respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia and lymphoid interstitial pneumonia. Other ILDs are bronchiolitis obliterans, histiocytosis X, chronic eosinophilic pneumonia, granulomatous vasculitis, Goodpasture's syndrome and pulmonary alveolar proteinosis. The cause of interstitial lung disease is not known, however, a major contributing factor is thought to be inhaling environmental pollutants. Other contributing factors include Sarcoidosis, certain drugs, radiation, connective tissue or collagen diseases and family history. Treatments may include corticosteroids, influenza or pneumococcal pneumonia vaccine but these are of limited effectiveness.
Lung inflammation includes most Occupational Lung Diseases, arising from repeated and long-term exposure to certain irritants on the job. These include for example asbestosis, coal worker’s pneumoconiosis (caused by inhaling coal dust), silicosis (caused by inhaling free crystalline silica), byssinosis (caused by dust from hemp, flax, and cotton processing, also known as brown lung disease), aluminosis, anthracosis (“collier's lung”, from the accumulation of carbon from inhaled smoke or coal dust in the lungs), chalicosis (stone-cutters' lung disease, due to inhaling stone dust), siderosis (occurring in iron workers, produced by the inhalation of particles of iron), tabacosis. Some of these are grouped together as hypersensitivity pneumonitis. These include Farmer's Lung arising from fungus spores from e.g. moldy hay, Bird-Breeder's Lung, arising from various bird proteins, Humidifier Lung, arising from bacterias fungi, and even amoebae found in mists, from standing water, Malt Worker's Lung from moldy barley, and many other forms.
There is also Radiation pneumonitis, a consequence of radiation therapy done to the chest, generally for lung or breast cancer.
Lung inflammation includes Pneumonia. Lobar pneumonia affects one or more sections (lobes) of the lungs. Bacterial pneumonia is caused by various bacteria notably Streptococcus pneumoniae. Viral pneumonia is caused by viruses (such as respiratory syncytial, parainfluenza, and influenza). There is no clearly effective treatment for viral pneumonia. Pneumonia can also occur as a hypersensitivity, or allergic response, or from mycoplasmas, rickettsias (especially Q fever), and Chlamydia.
Eosinophilic pneumonia, also called eosinophilic pneumonitis includes Löffler's syndrome and similar pneumonias such as tropical eosinophilia. These do not have alveoli infected by bacteria, viruses, or fungi, but instead, the alveoli and often the airways do fill with eosinophils. Why the eosinophils accumulate in the lungs is not well understood, and it can be triggered by things as varied as penicillin, fungi and parasites. Chronic eosinophilic pneumonia (CEP, also called Carrington's eosinophilic pneumonitis) is a related but somewhat different syndrome, and can easily be life threatening.
Asthma is a family of disorders the most important of which are extrinsic asthma (an allergic disorder mediated by IgE, generally considered an immune disorder), and intrinsic asthma (non-allergic, generally a response to irritants such as smog or cigarette smoke, but also can arise from some infections, such as forms of sinusitis, or from gastrointestinal reflux). Intrinsic asthma is associated with nasal polyps and massive eosinopillic infiltration of the respiratory mucous membrane, but serum levels of immunoglobulin E are within the normal range. There is also mixed asthma (both of the above), occupational asthma (a response to workplace chemicals such as toluene or certain metals), exercise induced asthma, and cough variant asthma. Asthma is characterized by bronchial wall hyperresponsiveness, viz., bronchoconstriction followed by bronchial inflammation.
Chronic bronchitis is a long-term inflammation of the bronchi, which results in increased production of mucus, as well as other changes. Chronic bronchitis has no specific organism recognized as the cause of the disease. Cigarette smoking is cited as the most common contributor to chronic bronchitis, followed by bacterial or viral infections and environmental pollution. Treatment is purely supportive and may include bronchodilators for inhaled medications, oxygen supplementation, lung reduction surgery and lung transplantation.
Acute bronchitis is the inflammation of mucous membranes of the bronchial tubes and is usually caused by infectious agents such as bacteria or viruses. It may also be caused by physical or chemical agents -- dusts, allergens, strong fumes -- and those from chemical cleaning compounds, or tobacco smoke. (Acute asthmatic bronchitis may happen as the result of an asthma attack, or it may be the cause of an asthma attack.) Acute bronchitis is usually a mild, and self-limiting condition, with complete healing and return to function. Most of the treatment is supportive of the symptoms, and may include analgesics, such as acetaminophen for fever and discomfort.
Another disease characterized by lung inflammation is Cystic fibrosis (CF), characterized by an abnormality in the glands that produce sweat and mucus. It is chronic, progressive, and is usually fatal. The basis for the problem with CF lies in an abnormal gene, which results in an atypical electrolyte transport system within the cells of the body. The abnormal transport system causes the cells in the respiratory system, especially the lungs, to absorb too much sodium and water. This causes the normal thin secretions in the lungs to become very thick and hard to remove. The high risk of infection in the respiratory system leads to damage in the lungs, and eventually death of the cells in the lungs. The etiology of chronic inflammation, however, remains unclear. The disorder itself is largely untreatable.
Acute (or Adult) Respiratory Distress Syndrome (ARDS) is severe inflammation in both lungs resulting in an inability of the lungs to function properly, arising from damage to capillary endothelium and alveolar epithelium caused by leukotrienes, oxidants, platelet-activating factor, and/or proteases. ARDS is a devastating, often fatal, inflammatory lung condition that, unlike most lung disorders, usually occurs in conjunction with catastrophic systemic conditions, especially shock, sepsis, and nonpulmonary trauma. No specific pharmaceutical therapies currently exist for ARDS per se. Treatment primarily involves supportive care in an intensive care unit, including use of a mechanical ventilator and supplemental oxygen to help patients breathe, plus in some cases, treatment of the underlying disorder (typically, sepsis) which has triggered the ARDS. Acute Lung Injury is the same clinical disorder, differing only in having a lesser degree of hypoxemia.
Myocarditis is an inflammation of the muscular middle layer of the heart (myocardium) Viruses, bacteria, and noninfectious diseases can cause it. Treatment is primarily supportive e.g. drugs may be used to improve the heart's ability to contract and to remove extra fluids from the body. Unless the underlying infectious agent itself is treatable, this inflammation is not itself treated.
Mucocutaneous lymph node syndrome (MLNS) or Kawasaki syndrome is a potentially fatal inflammatory disease that affects the heart, circulatory system, mucous membranes, skin, and immune system. Its cause is unknown.
Glossitis is inflammation of the tongue. Local causes of glossitis include bacterial or viral infection, mechanical irritation or injury from burns, rough edges of teeth or dental and oral appliances, or other trauma; exposure to irritants (tobacco, alcohol, hot foods, or spices), and sensitization (to e.g. toothpaste, mouthwash, breath fresheners, dyes in candy, plastic in dentures or retainers) anemia and other B vitamin deficiencies, erythema multiform, pemphigus vulgaris, syphilis, and other disorders. It can be inherited. Corticosteroids such as prednisone may be given to reduce the inflammation. Antibiotics, antifungal medications, or other antimicrobials may be prescribed if the cause of glossitis is an infection. Anemia and nutritional deficiencies must be treated, often by dietary changes or other supplements.
Meningitis is the inflammation of the meninges—the surrounding 3-layered membranes of the brain and spinal cord, and the fluid it is bathed in, (CSF). It can be caused by virtually any known infectious agent. Thus, if it is caused by Haemophilus influenzae or Neisseria meningitis, the antibiotic derivative rifampin would be used.
Inflammatory aortic aneurysms can be in the ascending or more commonly descending areas, and these disorders are poorinly understood, but in some cases involve the the presentation of an unknown antigen on the aortic wall.
Myelitis is any inflammation of the spinal cord.
Dactylitis is an inflammatory affection of the fingers.
There is an entire family of Idiopathic Inflammatory Myopathies, generally named as forms of myositis. Polymyositis produices pain, with marked weakness and/or loss of muscle mass in the proximal musculature, particularly in the shoulder and pelvic girdle, and can also include sclerodactyly, dysphagia and other aspects of oesophageal dysmotility, low grade fever and peripheral adenopathy.
Dermatomyositis, considereded a type of autoimmune connective tissue disease, produces skin rash and symmetric proximal muscle weakness which can be as severe as complete paralysis. There is a variant form, juvenile dermatomyositis, with the same general symptoms but also including Calcinosis cutis.
Sporadic inclusion body myositis (s-IBM) and hereditary inclusion body myopathies (h-IBM) encompass a group of disorders sharing the common pathological finding of vacuoles and filamentous inclusions. These constitute an inflammatory slowly progressive proximal myopathy which may cause dysphagia and mild to moderate muscle wasting. Its pathogenesis is unknown, but ubiquitin, prion protein, and tau protein has been found in these inclusions. S-IBM has some evidence of being an autoimmune disorder and some evidence of being a primarily degenerative disorder, But neither theory fits well the complex series of changes seen in this disorder The endomysial infiltrates in patients with s-IBM are composed of CD8+ T cells, macrophages in a 2:1 ratio, myeloid dendritic (antigen-presenting) and CD138+ plasma cells. Myofibers in s-IBM exhibit vacuolization, atrophy, abnormal myonuclei, and deposits of amyloid-β (Aβ), phosphorylated tau (p-tau), apolipoprotein E, presenilin-1, the normal cellular isoform of prion protein (PrPc), and many other characteristic proteins, leading to suspicion of prion involvement.
Hereditary Inclusion Body myositis (HIBM1) is based on the Desmin gene and is a dominant genetic disorder.
Hereditary inclusion body myositis type 2 (HIBM2) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene. It appears to be the same disorder as Nonaka distal myopathy.
A third form, Hereditary inclusion body myopathy with Joint Contractures & Ophthalmoplegia (IBM3), is a Myosin heavy chain IIa disorder.
There are forms of Eosinophilic myositis, including eosinophilic fasciitis, eosinophilic mono/multiplex myositis, esinophilic polymyositis and eosinophilia – myalgia syndrome.
Usually included in this category is Myositis ossificans, including Myositis ossificans circumscripta and progressive myositis ossificans.
Focal myositis seems to be a macrophage and T-cell–rich lesion that changes to B cell and dendritic plasmacytoid cells, and is classified as an inflammatory pseudotumor of skeletal muscle.
There is also a Giant-cell myositis, generally seen in association with giant-cell myocarditis, myasthenia gravis, auto-immune thyroiditis, and thymoma.
There is also the general categories of myositis associated with collagen vascular disease and myositis associated with malignancy.
Behçet's disease is a syndrome of unknown origin, but appears to be an autoimmune disorder. It is characterized primarily by inflammation of the blood vessels. Symptoms include a broad range of problems, which include mouth sores, genital sores, skin sores or lesions, meningoencephalitis, Uveitis, inflammation of the joints, thrombophlebitis, aneurysms, digestive tract ulceration (sometimes called Behçet's colitis)
Encephalitis is inflammation of the brain itself, often caused by a group of arboviruses. Treatment of encephalitis is largely supportive because no specific antiviral agents, except for that which works against herpes simplex virus, are available for therapy.
Inflammation in the brain is a significant component of some important neurodegenerative conditions, including Alzheimer's Disease, AIDS dementia, Pick’s Disease, Parkinson’s Disease, and Huntington’s Disease. The circumstances here are poorly understood because while there does not appear to be lympho-infiltrative processes, there is neuropathological evidence for immune activation. Thus, inflammation may be a disease-aggravating or even a disease-ameliorating factor in pathogenesis, or a non-contributory consequence of the injurious cascade of neurodegeneration and thus incidental.
Hepatitis is an inflammation of the liver, usually caused by viral invasion, notably hepatitis A, B and C, but sometimes Epstein-Barr virus; herpes simplex viruses; measles, mumps, and chicken pox viruses; and cytomegaloviruses. Treatment, when possible, is with antivirals. Inflammation of the liver also take the form of alcoholic hepatitis. Lupoid hepatitis is an autoimmune disorder.
Idiopathic inflammatory trigeminal sensory neuropathy (IITSN) affects the head, producing face numbness, headache, and hemifacial pain attacks.
Hemorrhoids is an enlarged or varicose condition of the hemorrhoidal veins and tissues around the anus, either internal or external. Anything which obstructs the free circulation of the blood in the portal system will give rise to hemorrhoids. Constipation, straining at stool, diarrhea, dysentery, rough toilet paper, uncleanliness, pelvic tumors, displacement of the uterus and pregnancy are among the most common causes.
Rosacea classically presents with patchy flushing and redness and inflammation, particularly on the cheeks, nose, forehead, and around the mouth. Rosacea is persistent and commonly worsens with time, sometimes with the formation of pustules and swelling. Triggers for rosacea are extremely varied and include things not ordinarily associated with inflammation, such as drinking alcohol and hot beverages, or even ordinary social interactions.
There is a series of inflammatory problems directly connected to neutrophil-endothelial cell adhesion (NECA). These include frostbite injury, bacterial meningitis, acute airway inflammation, allograft rejection, hemorrhagic shock, septic shock, ischemia and reperfusion injuries.
Immune reconstitution inflammatory syndrome (IRIS), also known as immune restoration disease and immune restoration inflammatory syndrome is a peculiar syndrome that occurs after a desirable gain in immunocompetence, usually arising from successful treatment of HIV-infected subjects. Although numerous infectious and noninfectious causes have been proposed, its pathogenesis remains unclear. IRIS can present in a variety of ways especially if there is an underlying infections, such as with leprosy or tuberculosis CMV to which the body is suddenly able to (over) react to, but in other cases, the diseases appears to be non-infective, such as with SLE or RA.
Urethritis is an inflammation of the duct that leads from the bladder to the body's exterior. It is often due to fecal contamination or irritation due to physical or chemical substances (e.g. introduction of foreign bodies into the urethra, bubble bath, or soap) or gonorrhea. Treatment may simply involve the withdrawal of the offending chemical agent, or the administration of antibiotics, when Neisseria gonorrhoeae is involved.
Inflammation can arise from the eruption of teeth in a child (teething).
Inflammation of the nails can arise from chronic paronychia, fungus (especially Candida albicans), trauma, impaired circulation, and dermatitis.
Bright's disease (or glomerulonephritis) is inflammation of the glomeruli and the nephrons, the structures in the kidney that produce urine. It usually results from an infection, such as a streptococcal infection, that occurs somewhere else in the body. There is no real treatment beyond relief of the symptoms.
Whipple's disease is a chronic, multisystem, relapsing inflammatory disease that usually affects the small intestine and mesenteric lymph nodes. Its cause is Whipple's bacillus.
Panniculitis is a group of diseases characterized by inflammation of subcutaneous adipose tissue. It occurs in four forms: lobular panniculitis without vasculitis (acute panniculitis, or Weber-Christian disease or systemic nodular panniculitis), lobular panniculitis with vasculitis, and septal panniculitis with or without vasculitis.
Thyroiditis is an inflammation of the thyroid gland, and takes three forms. Hashimoto's Thyroiditis (chronic lymphocytic thyroiditis) is the most common type of thyroiditis. It is an autoimmune disorder, and treatment is to start thyroid hormone replacement. For De Quervain's Thyroiditis (subacute or granulomatous thyroiditis), treatment is usually bed rest and aspirin to reduce inflammation. Occasionally cortisone and thyroid hormone may be used. Silent Thyroiditis usually arises following pregnancy. Treatment is usually bed rest with beta blockers.
Regional enteritis (Crohn's disease or ileitis) is an autoimmune disorder which is associated with the presence of Mycobacterium paratuberculosis. It can affect any part of the gastrointestinal tract but most commonly affects the ileum. The inflammation is controlled primarily by regulation of diet, antibiotics if abscesses and fistulas are present, sometimes Prednisone and other corticosteroids, and surgery.
Proctitis is a form of inflammation of the rectum, and includes Antibiotic-Induced Proctitis, Gonorrheal Proctitis, Herpetic Proctitis, Ischemic Proctitis, Radiation Proctitis, Syphilitic Proctitis and idiopathic proctitis.
Sarcoidosis is a multisystem disorder characterized by a cell-mediated Th1 immune response with formation of noncaseating granulomas. These granulomas generally heal and disappear on their own. However, for those granulomas that do not heal, the tissue can remain inflamed and become scarred, or fibrotic. Pulmonary sarcoidosis can develop into pulmonary fibrosis. Bronchiectasis, a lung disease in which pockets form in the air tubes of the lung and become sites for infection, can also occur. Treatment may include the use of corticosteroids.
Stomatitis, inflammation of the mouth, and mucositis, inflammation of the mucosa can arise from sources as diverse as Candida albicans, dentures, chemotherapy and radiation therapy to the head, neck or mouth ("Radiation mucositis"). It may be secondary to infection, trauma, systemic diseases or autoimmune mechanisms. These come in many forms, such as aphthous ulcers, and Acute Necrotizing Ulcerative Gingivitis i.e. "trench mouth". Herpetiform ulcers treatment has ranged from antibiotics, immunosuppressants and yogurt, to Lactobacillus capsules, tetracycline and systemic steroids. Palliative measures include topical anesthetics, Vitamin E, analgesics, and coating agents. Antiviral agents may be used if viral origin is established.
Allergic rhinitis, a reaction that occurs in the eyes, nose and throat, which exists in two forms, seasonal and perennial, is a Type I Antibody-Antigen reaction to allergens. T Lymphocytes and B Lymphocytes release IgE antibody; mast cells appear in skin and mucosa and degranulate, which is followed by release of histamine and chemotactic factors, prostaglandins and leukotrienes, and a response of intravascular basophils. Histamine causes inflammation and fluid production in the fragile linings of nasal passages, sinuses, and eyelids. The underlying disorder is not itself treated, except possibly via immunotherapy, in which there is administered gradually increasing doses of the allergen. Instead, symptoms are treated with drugs used to block the action of allergic mediators, or to prevent degranulation processes, such as anti-leukotrienes or antihistamines.
Nonallergic Rhinitis (including eosinophilic, rhinitis medicamentosa, vasomotor Rhinitis, neutrophilic rhinosinusitis, and others) also affects the eyes, nose and throat, and comes from fumes, odors, temperature or atmospheric changes, smoke, etc. Treatments for nonallergic rhinitis include oral medications, inhaled medications, immunotherapy, and surgery for some conditions.
Wegener's Granulomatosis is a disease that usually begins as a localized granulomatous inflammation of upper or lower respiratory tract mucosa and may progress into generalized necrotizing granulomatous vasculitis and glomerulonephritis. The cause is unknown. Although the disease resembles an infectious process, no causative agent has been isolated. Treatment is with immunosuppressive cytotoxic drugs.
Pancreatitis is inflammation of the pancreas and can arise from abdominal trauma, or the formation of gallstones that obstruct the common bile duct. It can be associated with excessive ingestion of alcohol; with disorders such as cystic fibrosis or Reye's syndrome; or with scorpion stings. Infectious causes include mycoplasmas, Epstein-Barr viruses, Coxsackie viruses, leptospirosis, hepatitis viruses, mumps, congenital German measles, Ascaris worms, and syphilis. The inflammation per se is generally not treatable. Treatment is usually supportive and consists of the management of pain and intravenous feeding.
Neuroretinitis is a type of inflammation of the retina. It is often idiopathic. It frequently arises secondary to some kind of infection, such as Hepatitis B, HSV, EBV, influenza A, mumps, Coxsackie B, TB, salmonella, Lyme disease, syphilis, leptospirosis, Histoplasmosis, Toxoplasmosis, toxocara, Sarcoidosis and cat-scratch disease. Treatment is thus to the underlying cause. For example, Diffuse unilateral subacute neuroretinitis (DUSN) arises from nematodes deep in the retina or in the subretinal space. Anthelminthic treatment is then used. When the origin is Toxoplasmosis, then anti-Toxoplasma medications such as Pyrimethamine. Vogt-Koyanagi-Harada syndrome (Harada's disease) is an acute inflammatory, immune-mediated disorder that can cause choroidal neovascularization, severe chorioretinal atrophy, and secondary glaucoma.
River blindness arises from inflammation of the eye caused by larvae (microfilaria) of the nematode Onchocerca volvulus, although the Wolbachia bacteria may be involved as well.
Multifocal choroiditis and panuveitis (MCP) is a posterior chorioretinal inflammatory disease of unknown etiology
There are also other forms of choroiditis, inflammation of the middle coat (choroid) of the eyeball, as well as uveitis, which is inflammation of the parts of the eyes that make up the iris. Other eye inflammations include scleritis and episcleritis, inflammation of tissues on the sclera.
Pouchitis is an inflammation of an internal pouch (either the ileoanal pouch or the Koch pouch) created in patients who have part of their colon removed to treat ulcerative colitis or familial adenomatous polyposis (FAP).
Gastritis is inflammation to the stomach lining. Atrophic gastritis is characterized by the loss of the stomach cells that are responsible for manufacturing acid, pepsin, and intrinsic factor. This condition occurs in older people or those suffering from Helicobacter pylori. Erosive (hemorrhagic) gastritis occurs when shallow ulcers or sores develop on the upper layer of the stomach lining, usually because of the excessive ingestion of a stomach irritant such as aspirin or alcohol.
There can also be mentioned appendicitis, which can occur when a hard piece of stool blocks the opening of the appendix, causing swelling and inflammation.
There is an entire family of Idiopathic inflammatory-demyelinating diseases (IIDDs). The most common of these are the various forms of multiple sclerosis. These include relapsing-remitting MS, and secondary progressive multiple sclerosis, as well as
primary progressive MS and progressive relapsing MS as well as the so-called “benign MS” and the Marburg variant of MS. Baló’s concentric sclerosis is generally considered to be a variant of MS.
Acute disseminated encephalomyelitis is usually triggered by viral or bacterial infections or vaccinations and can be quite severe, and can be monophasic or relapsing. Acute hemorrhagic leukoencephalitis (Hurst encephalitis) is now thought to be a hyperacute form of ADEM. Bickerstaff encephalitis is usually included with ADEM as well.
Another IIDD is optic neuritis, either papillitis or retrobulbar neuritis, can occur be monophasic or in recurrent form, the latter of which is more likely to progress to MS. Brainstem inflammatory-demyelinating syndrome.
Acute transverse myelitis resulting in motor, sensory, and autonomic dysfunction can be idiopathic or develop in the context of viral, bacterial, fungal or parasitic infections, as well as in the course of systemic autoimmune diseases, and can be monphaisc or receuurent.
Other IIDDs include Devic’s neuromyelitis optica, and Schilder’s disease.
There are both Tumefactive or pseudotumoral IIDDs.
The great majority of skin problems involve some type of inflammation, such as response to physical injury (e.g. sunburn, ticks, abrasion, or a bee string), acute allergic contact dermatitis (such as poison ivy), and infections (such as boils and cold sores). Ingrowing hairs, or pili incarnati, can cause acute pustular reactions. Cancerous lesions of the skin frequently show some degree of inflammatory response. Acne's inflammation is caused by leakage of sebum and keratin debris outside the distended pilosebaceous duct. The bacillus Propionibacterium acnes, which populates the lesions, may also contribute indirectly to this inflammation by metabolizing the sebum to produce irritant fatty acids. Inflammation in skin problems is usually the result of the release of chemical mediators in the skin, notably histamine, peptides (kinins) and fatty acids (prostaglandins and leukotrienes), which are formed enzymatically in response to e.g. injury. Medications designed to counteract inflammation in the skin may or may not antagonize the effects of the particular type of mediator involved, if that is known. The inflammation can take many different forms, including redness, (from dilation of blood vessels); heat, (from increased blood flow); swelling (from leakage of fluid from the small blood vessels); whealing reactions (hives, nettle rash, urticaria) in which vascular changes predominate, and pain or itching. Blisters (from enzymes released from inflammatory cells, resident cells of the skin, or blood plasma components) can cause the breakdown of proteins responsible for the structural integrity of the skin, leading to serious inflammatory disorders such as pemphigus. In addition, the affected skin may feel indurated (hardened) because of the deposition of the coagulation protein fibrin and the infiltration by inflammatory blood cells (lymphocytes, histiocytes, and polymorphonuclear leukocytes).
Prostatitis, inflammation of the prostate, comes in several different forms, including those of bacterial origins, and those which are not, including chronic abacterial prostatitis and asymptomatic inflammatory prostatitis. Certain types of anti-inflammatory agents, such as non-steroidal anti-inflammatory medications (Ibuprofen and naproxen) along with muscle relaxants can be used in the non-bacterial cases.
There are a number of different forms of vasculitis, including Churg-Strauss vasculitis, consecutive vasculitis, granulomatous vasculitis of central nervous system, hypersensitivity vasculitis, (called also allergic or leukocytoclastic vasculitis or leukocytoclastic angiitis which arises from hypersensitivity to an antigenic stimulus), hypocomplementemic vasculitis, isolated vasculitis of central nervous system, nodular vasculitis, overlap vasculitis (polyangiitis overlap syndrome), pulmonary vasculitis including Wegener's granulomatosis, rheumatoid vasculitis, segmented hyalinizing vasculitis (livedo vasculitis), Polyarteritis nodosa, and urticarial vasculitis. There are also specific forms of arteritis, including coronary arteritis, equine viral arteritis, giant cell arteritis (cranial, granulomatous, or temporal arteritis or Horton's disease), infantile arteritis, infectious arteritis, arteritis obli¢terans (endarteritis obliterans), rheumatic arteritis, syphilitic arteritis, Takayasu's arteritis (aortic arch, or brachiocephalic arteritis or Martorell's syndrome or pulseless disease; it is of unknown origin), tuberculous arteritis, endarteritis obliterans, and verminous mesenteric arteritis.
Angular cheilitis (also called perlèche, cheilosis or angular stomatitis) is an inflammatory lesion at the corner of the mouth. These generally arise from nutritional deficiencies, either from poor diet or malabsorption syndromes, and can because infected with fungus as well.
Seborrhoeic dermatitis, which includes seborrhoea capitis (Cradle cap), seborrhoeic infantile dermatitis and other seborrhoeic forms is a chronic disease characterized by scaling on an erythematous base. Pityriasis simplex capillitii (dandruff) is often included with this category.
Pustular dermatitis is an inflammation of the skin that presents with pustular lesions, and includes eosinophilic pustular folliculitis (Ofuji's disease), Reactive arthritis (Reiter's syndrome), and Subcorneal pustular dermatosis (Sneddon–Wilkinson disease).
Psoriasis is a chronic, and recurrent inflammatory disease of the skin characterized by circumscribed, erythematous, dry, scaling plaques. The psoriasis family includes annular pustular psoriasis, drug-induced psoriasis, generalized pustular psoriasis, guttate psoriasis, inverse psoriasis, keratoderma blennorrhagica (keratoderma blennorrhagicum), localized pustular psoriasis, napkin psoriasis, psoriasis, vulgaris, psoriatic arthritis, psoriatic erythroderma (erythrodermic psoriasis), seborrheic-like psoriasis (sebopsoriasis, seborrhiasis).
Lichenoid eruptions are dermatoses associated with the inflammatory disorder lichen planus and can arise from varied sources. These include annular lichen planus, atrophic lichen planus, bullous lichen planus (vesiculobullous lichen planus), erythema dyschromicum perstans (ashy dermatosis, dermatosis cinecienta), hepatitis-associated lichen planus, hypertrophic lichen planus (lichen planus verrucosus), idiopathic eruptive macular pigmentation, keratosis lichenoides chronica (Nékam's disease), kraurosis vulvae, lichen nitidus, lichen planus actinicus (actinic lichen planus), lichen planus pemphigoides, lichen planus pigmentosus, lichen planus–lichen sclerosus overlap syndrome, lichen planus–lupus erythematosus overlap syndrome, lichen sclerosus (lichen sclerosus et atrophicus), lichen striatus (Blaschko linear acquired inflammatory skin eruption), Lichenoid dermatitis, Lichenoid reaction of graft-versus-host disease, linear lichen planus, peno-gingival syndrome, ulcerative lichen planus, vulvovaginal gingival syndrome, and vulvovaginal lichen planus.
Erysipeloid and erysipelas are both inflammations of the skin due to certain types of bacteria.
Osgood-Schlatter disease is a common form of inflammation of the knee in active adolescents. It has no pharmaceutical treatment per se. Other inflammations of the knee include Sinding-Larsen-Johansson disease, Patellofemoral syndrome, and osteochondritis dissecans.
Pigmented villonodular synovitis (PVNS) is a joint disease characterized by inflammation and overgrowth of the joint lining, typically in the hip, knee, hands or ankle. It is considered to be a neoplastic growth, locally agressive, and comes in two forms, diffuse and nodular.
Adhesive capsulitis is a type of inflammation of the shoulder. Its origin is usually unknown.
There can be a generalized inflammatory response of the entire body. When it arises from a proven source of infection, it is called sepsis. When it does not, it is called systemic inflammatory response syndrome (SIRS). Both of these are characterized by extensive cytokine dysregulation.
The above list is by no means complete, but demonstrates the extraordinary breadth of causes, mechanisms and treatment (or lack thereof) for inflammation.
It should be noted that determining that a disorder is an inflammatory one is sometimes not an easy task. For example, it has taken decades of research to discover that the destruction of the central area of the retina, which is the hallmark of age-related macular degeneration, actually arises out of an inflammatory process, involving the Complement Pathway. This only became well established in 2005. It is entirely possible that a majority of disorders presented considered idiopathic --- including many untreatable disorders --- are in fact inflammatory disorders. An ongoing example of this difficulty is the question of insulin resistance, the underlying disorder in Type II Diabetes Mellitus and Metabolic Syndrome, and possibly a few other disorders as well. The inflammation hypothesis says that the enlarged fat cells drawn in macrophages, which excrete pro-inflammatory cytokines IL-6, α-TNF, and IL1-, which via their receptors activate JNK to block IRS-1. There is significant evidence for this, but no standard anti-inflammatory agents are effective against insulin resistance. The competing lipid overload hypothesis says that the enlarged fat cells leak fatty acids, causing DAGS to accumulate in muscle cells, which inhibit insulin signaling through nPKCs and block IRS-1. At this time, there is no agreement on whether insulin resistance should be best understood as an inflammatory disorder.
It must be finally noted that an inflammatory response is a normal body process and for good reason. A certain level of inflammatory response is needed to protect the body from invading organisms, especially bacteria, viruses, and parasites. An acute inflammatory response is needed to activate the healing process for burns, mediated by a range of MMPs. In sprains or other ligament injuries, some inflammatory response is needed initially to initiate repair of the damage. In mechanical wounds, some inflammatory response is required for satisfactory wound healing and indeed anti-inflammatory drugs such as cortisone can impair healing when administered at the time of wounding. In fact, inflammation is too important to be dependent on a single pathway and so inflammation can be initiated by numerous different systems, and generally, if one fails or is thwarted, another can do some or the entire job.
(2) The nature of the invention and predictability in the art: With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] …anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
(3) Direction or Guidance: That provided is very limited. The dosage range information provided is completely generic. That is, it is the same dosage for all disorders listed in the specification, which is a very substantial range of disorders.
(4) State of the Prior Art: The claimed compounds are, so far as the examiner is aware have not been successfully used as anticancer, anti-inflammatory, etc. agents.
(5) Working Examples:
(6) Skill of those in the art: Many, many mechanisms have been proposed over the decades as methods of treating the assorted cancers generally. Cytotoxic agents could be applied directly to the tumors cells, directly killing them. Immunotherapy involves stimulating the patient's immune system to attack cancer cells generally, either by immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Another approach would be to increase the amount or activity of the body’s tumor suppressor genes, e.g. p53, PTEN, APC and CD95, which can for example activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. The angiogenesis inhibitor strategy was based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells. There is also the cancer stem cell paradigm, which hypothesizes that cancer could be treated generally, either by targeting the cancer stem cells themselves, or by targeting the epithelial-to-mesenchymal transition which supposedly generates the cancer stem cells. Yet another approach is to inhibit one or more of the assorted HSP90 proteins, which will supposedly disrupt the proper folding of signaling proteins that all cancers rely on. Inhibiting telomerase was said to be able to be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. “The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally.” (<http://www.uspto.gov/web/offices/pac/dapp/1pecba.htm#7> ENABLEMENT DECISION TREE, Example F, situation 1). A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environment factors.
Accordingly, there is substantive “reason for one skilled in the art to question the objective truth of the statement of utility or its scope” (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
Similarly, In re Novak, 134 USPQ 335, 337-338, says “unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them.” There is no such evidence in this case. Likewise, In re Cortright, 49 USPQ2d 1464, states: “Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient” does what the specification surmises that it does. That is exactly the case here. Moreover, even if applicants’ assertion that cancer in general could be treated with these compounds were plausible --- which it is not ---, that “plausible” would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.”
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
One skilled in the art knows that chemotherapy of brain tumors is especially difficult. This is because 1) the blood-brain barrier, which is often intact in parts or all of a brain tumor, will block out many drugs, as it is the purpose of the blood-brain barrier to protect the brain from alien chemicals, and 2) CNS tumors are characterized by marked heterogeneity, which greatly decreases vulnerability to chemotherapy. As a result, many categories of CNS tumors simply have no chemotherapy available. These include, generally, hemangioblastomas, meningiomas, craniopharyngiomas, acoustic neuromas, pituitary adenomas, optic nerve gliomas, glomus jugulare tumors and chordomas, to name just some. With regard to gliomas, GBM is considered untreatable; no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is radiation and surgery which are used for low grade gliomas (e.g. pilocytic astrocytoma and diffuse astrocytomas), as no drug has been found effective. There is no drug treatment established as effective for optic nerve gliomas or gangliogliomas. Indeed, very few gliomas of any type are treated with pharmaceuticals; it is one of the categories of cancer that is the least responsive to drugs.
Cartilage tumors do not respond to chemotherapy, nor, generally, do cancerous teratomas.
Of the thyroid cancers, only one (anaplastic thyroid cancer) can be treated with anticancer agents. The other are treated with radioactivity, surgery, or thyroid suppression hormones.
Lymphomas of the stomach are not commonly treated with anti-cancer agents per se, but instead, surgery or radiation and antibiotic therapy (e.g. amoxicillin, metronidazole, bismuth, omeprazole) are the primary treatments.
Neuroendocrine tumors of the cervix generally do not respond to chemotherapy.
A number of sarcomas, including alveolar soft part sarcoma (ASPS), retroperitoneal sarcoma, most liposarcomas, and the assorted chondrosarcomas, are generally considered not to respond to chemotherapy; no chemotherapeutic agent has been established as effective.
Aggressive NK cell leukemia is considered to be untreatable with pharmaceuticals.
Myxoma of the heart (atrial myxoma) is the most common primary cardiac tumor and has no chemotherapy; excision is the only treatment.
Chemotherapy of spleen tumors is rarely even attempted, and no drug has been established as effective for any primary or secondary splenic tumor types.
Many cerebral metastases, such as those from non-small-cell lung cancer and melanoma, are not chemosensitive and will not respond to chemotherapy.
Cancers of the ear canal, middle ear and temporal bone have no established effective chemotherapy. Treatment is via surgery, sometimes combined with radiation. Skin cancers of the outer ear are treated with surgery, sometimes requiring total pinnectomy.
Hepatocellular Carcinoma (HCC or hepatoma) is, in humans, possibly the most prevalent solid tumor and in certain parts of the world is the most common cancer; it has long been understood as a chemotherapy-resistant tumor, with only very recently, some success seen with the Tyrosine protein kinase inhibitor Sorafenib.
Metastatic esophageal cancer, and malignant melanoma of the esophagus do not respond to chemotherapy; there is no chemotherapy for subungual melanoma, which can be treated only with surgery. Indeed, metastatic melanomas as a group are largely unresponsive to chemotherapy; only one drug (dacarbazine, an akylating agent, approved by the FDA in 1975) has been shown effective, although response rates are fairly modest.
Adamantinomas have no chemotherapy. No effective chemotherapy regimens are available for either intraocular or metastatic uveal melanoma.
It is important to note that tumors can need to be treated quite differently even though they are tumors of the same organ. For example, the drugs used most often to treat Wilms tumor, the most common malignant tumor of the kidneys in children, are actinomycin D and vincristine. Such drugs are never used with clear cell renal carcinoma, which is treated, although without much success, with immunotherapy using the cytokines interleukin-2 and interferon-alpha. However, such immunotherapy has never been established as effective in non-clear cell RCC forms such as papillary renal cell carcinoma. Despite strenuous efforts over a period of decades, no chemotherapeutic agent has ever been found effective against this cancer. Cancers of the stomach can be lymphomas, GISTs, carcinoid tumors, carcinomas, or soft tissue sarcomas, and for a single agent to be effective against all or even most of these categories would be contrary to what is known in oncology.
One of ordinary skill in the art knows that there is no common mechanism by which all, or even most, inflammations arise. Mediators include bradykinin, serotonin, histamine, fibrin, some PDE4 isoenzymes, plasmin, thrombin, PAF, Mac-1, VLA-4, VLA-5, VLA-6, VCAM-1, LFA-1, ICAM-1, Prostaglandins and cyclic endoperoxides (particularly prostacycline, prostaglandin E2, and thromboxane A2), leukotrienes (especially LTB4, LTC4, LTD4, and LTE4) and kallikrein, and many, others. Examples of pro-inflammatory cytokines include IL-1-alpha, IL-1beta, IL-6, IL-8, IL-11, IL-12, IL-17A, IL-17E, IL-17F, IL-18, GM-CSF, CNTF, OSM (Oncostatin M), MCP-1, CCL2 (a chemokine), CCL5 (RANTES), TGF-beta, ENA-78, Osteopontin, Cyclophilin A, LIF (leukemia inhibitory factor), leptin, MIP-1, TWEAK, MGSA, keratinocyte-derived chemokine, PF4, MCP-1 (GDCF), IFN-gamma, TNF-α, Abscisic acid, high mobility group box chromosomal protein 1 (HMGB-1), S100A12 (EN-RAGE), TRAIL, sCD40L, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-32, and IL-33. The Complement Pathway, which exists in two separate branches, uses C1, C4a, C4b, C2, C3a, C3b, C5a, C5b, C6, C7, C8 and C9, as well as the membrane attack complex (MAC) and other complexes, C3 and C5 convertase enzymes, PI3K-gamma, Magnesium ions, and Factors B, D, F, H, etc.
One of ordinary skill in the art also knows that mediation of inflammation is among the most pervasive and complex of all body process. There are very complex interactions among just the cytokines. As an example, the Hageman factor (clotting factor XII) is a protein that when activated initiates three different processes: a) the intrinsic clotting process which operates via thrombin and fibrin, b) the fibrinolytic system which produces fibrinolysis via plasmin and 3) the kallikrein/kinin cascade, which produces the kinins, e.g. bradykinin. Bradykinin produces the redness, warmth, and swelling of inflammation by its effects on both arterioles and capillaries. Further, that plasmin can also activate C3 and C5 in the complement cascade (an entirely separate set of vascular events) producing C3a and C5a, respectively, as can thrombin.
One of ordinary skill in the art also knows that there are many paradoxical features in the inflammation system, in which an agent can be either pro- or anti-inflammatory depending on the details of the circumstances. As an example, in lung inflammation, nitric oxide appears to be a pro-inflammatory mediator in acute situations e.g. ARDS but anti-inflammatory in more stable situations. As a second example, the cytokine TGF-beta-1 possesses both pro-inflammatory and anti-inflammatory activities. Virtually all cells have TGF-beta-1 receptors, and the cytokine has many other roles other than in inflammation. As a third example, CRF appears to have both pro-inflammatory and anti-inflammatory activities.
And in fact, there is a tremendous diversity in the combination of mechanisms that produce inflammation. This makes it impossible to imagine a general solution to inflammation. For example, Atherosclerosis, in its four forms, arises from the accumulation of macrophage white blood cells and is promoted by low density (especially small particle) lipoproteins. No other inflammatory disorder has this particular mechanism.
There is no pharmaceutical treatment for COPD per se; no pharmaceutical intervention will slow the progression of the disease. Instead, treatment is supportive and designed to relieve symptoms and improve quality of life. Thus, oxygen is often given to partially compensate for the loss of lung function. Bronchodilators can expand passageways in the lungs, Corticosteroids can reduce inflammation and Antibiotics can ward off bacterial infections, but none of these treat the COPD itself. Asbestosis, perhaps the most important of the most Occupational Lung Diseases, has no pharmacological treatment per se. What treatment there is, is palliative, notably Oxygen therapy to relieve the shortness of breath, respiratory physiotherapy to remove secretions from the lungs by postural drainage, chest percussion, and vibration, and nebulized medications to thin secretions, but these of course do not treat the disorder itself. There is also no pharmacological treatment of ARDS, only for its symptoms, such as pulmonary arterial hypertension, and management of infection with e.g. antibiotics.
Osteoarthritis is characterized by e.g. loss of cartilage, formation of hard bony enlargements (Heberden's nodes and/or Bouchard's nodes), formation of "spurs" or osteophytes, on the margins of the joints, bunions, etc. The pathophysiological process is believed to involve imbalances in many, many factors, including cytokines and growth factors, Prostaglandin E2, Cartilage matrix fragments, assorted neuropeptides, free oxygen radicals, proteolytic enzymes and protease inhibitors. These gives rise to such results as abnormal synovial fluid of reduced viscosity (giving phasic synovial inflammation), remodeling of bone osteophytosis, proteolytic destruction of cartilage matrix and chondrocyte death, peripheral & central sensitization, nociceptor activation, and more. No pharmaceutical has been firmly established as a disease-modifying therapy for osteoarthritis. That is, there are currently no therapeutic agents approved by the US Food and Drug Administration capable of mitigating the changes in cartilage and bone characteristic of OA. This is in large measure because OA usually cannot be diagnosed until it becomes symptomatic decades after it began, at which point structural alterations are already quite advanced, as well as the difficult question of whether question of whether or not biomarkers (and which ones) could serve as surrogate outcome measures in randomized clinical trials. Primary treatment is actually nonpharmacologic, including weight loss, exercise, physical and occupational therapy, assistive devices, joint replacement surgery, acupuncture, and ultrasound. Numerous drugs are used for the palliation of symptoms, including NSAIDs, hyaluronate injections and narcotic analgesics, but these do not affect the disease itself. If the osteoarthritis is secondary to some other disease, such as Wilson's disease, acromegaly, some types of diabetes, then the underlying disease itself could be pharmacologically treated if such treatment exist. However, one of ordinary skill in the art knows that many conditions that osteoarthritis is secondary to, such as leg-length discrepancy, scoliosis, congenital hip dysplasia, congenital dislocation of the hip, etc. themselves do not have pharmacological treatments.
Hallux rigidus itself treated just by surgery, including cheilectomy, involving the excision of irregular bony spurs that limit motion, proximal phalanx osteotomy, silicone arthroplasty, arthrodesis and others. The only drugs used are analgesics and NSAIDs, but these are just for relief of symptoms and do not treat the disorder itself.
Gouty arthritis is a metabolic disorder, in which dysfunction of the purine metabolism results in hyperuricemia, leading to the formation of deposits in the cartilages of the joints, made up chiefly of urates, or uric acid. It is treated directly by the use of uric acid synthesis inhibitors, notably allopurinol and febuxostat, which are inhibitors of xanthine oxidase, which thus inhibit the accumulation of uric acid in the body. A second mode is use of the uricosuric drugs, uric acid excretion promoters, notably Probenecid, sulfinpyrazone and benzbromarone, which act by inhibiting the urate transporter URAT1 at the tubules, and thus accelerate the rapid excretion of uric acid accumulated in the body. A third mode is the use of uricase (rasburicase or pegloticase (PEGylated) form), which mediates the conversion of uric acid into the more soluble molecule allantoin.
Pseudogout and other disorders arising from deposition of calcium pyrophosphate dihydrate is related to other metabolic disorders, such as hemochromatosis, hyperparathyroidism, hypomagnesemia, and hypophosphatasia. The exact cause of CPPD deposition is unknown, although increased breakdown of adenosine triphosphate, the gene ANKH, and magnesium insufficiency have all been fingered as possible causes. Treatments include corticosteroids, NSAIDs, colchicine, methotrexate and magnesium supplementation, but it has not been established that any of these actually affect the disease itself.
Much the same is true for is calcium oxalate associated arthritis, which has no specific treatment, beyond treating the end stage renal failure itself (with increased dialysis) when that is the cause. Otherwise, treatment is just palliation of symptoms, e.g. NSAIDs.
Ochronotic arthritis is caused by alkoptunuria, an inherited autosomal recessive metabolic disorder which is caused by the lack of homogentisic acid-oxidase enzyme, which appears to be responsible for the deposition of homogentisic acid pigment in connective tissues. There is no pharmacological treatment is available for the underlying alkaptonuria; the damage to the joints is approached with physiotherapy, rest, and prosthetic joint replacement; analgesia can be used for relief of pain.
Although Charcot arthropathy can arise from many sources, its exact nature is a matter of some dispute. One theory says it is neurotraumatic, leading to osseous destruction, and the other main theory is it is a neurovascular problem, causing the extremity to receive an increased blood flow, resulting in a mismatch in bone destruction and synthesis, leading to osteopenia. Treatment is via immobilization and reduction of stress via specialized footwear, and assorted surgical procedures. There is no pharmacological treatment.
The pharmaceutical treatment of reactive arthritis is targeted to the underlying infection which caused the infection in the first place, and thus will involve an antibacterial, antiviral, antifungal, etc. The same is true of infectious arthritis.
Lupus arthritis, although difficult to diagnose, is treated by treating the underlying SLE.
Palmar Fasciitis and Polyarthritis Syndrome have no established treatment.
Very few agents have been successfully used to treat rheumatoid arthritis itself, and these, except for penicillamine, have all operated by the mechanism of α-TNF inhibition (the mode action of penicillamine in rheumatoid arthritis is unknown). There has been considerable research on the use of e.g. p38 inhibitors and DPP-IV inhibitors for RA, but none has been clearly established as effective.
Hemorrhagic arthritis in its chronic form arises from a disease process, typically hemophilia, sickle cell disease, and pigmented villonodular synovitis (PVNS). The acute form arises from injury, especially major ligament tear, fracture, meniscus tear, or damage to the joint capsule. For the chronic form, treatment is done via treating the underlying cause. Thus, for example, clotting factors for the particular type of hemophilia involved, although, as with other complications of hemophilia, these are of limited value. For the acute form, treatment of the specific injury, e.g. bone fracture, is required. PVNS has no pharmacological treatment; surgical excision is relied on, although recurrences are common due to the difficulty of complete surgical excision.
Therefore, one of ordinary skill in the art knows that the forms and etiologies of the assorted types of arthritis are so varied that a general treatment of arthritis is contrary to what is known in the art. The skill level is such that many forms have no specific treatment for the arthritis itself, only management of symptoms, such as NSAIDS for pain, hypnotics for sleep, antidepressants for reactive depression, etc.
Furthermore, what specific treatments there are, are not general. Thus, while RA does respond to α-TNF inhibitors which suppress the immune system, such agents would be expected, if anything, to make matters worse for septic arthritis. Antiviral agents used for septic arthritis would be expected to be useless against psoriatic arthritis, clotting factors employed for hemophilic arthritis would be of no value for lupus arthritis, uricosurics used for gouty arthritis would have no value for reactive arthritis or enteropathic arthritis, etc. Similarly, while penicillamine has been established as effective for rheumatoid arthritis, and is apparently effective in treating osteoarthritis secondary to Wilson's disease (by treating the Wilson's disease itself), it has not been established as effective for other forms of arthritis, and indeed, as it appears to do some suppression of the immune system, it would not be used for septic arthritis at all.
The intrinsic form of asthma appears to have unique inflammatory mechanisms that differ from those playing a role in the extrinsic form. There is paucity of research dealing with inflammatory mechanisms unique to intrinsic asthma, in part because there is no animal model for intrinsic asthma, and indeed, the pathogenesis of intrinsic asthma is presently thought to be caused by unknown.
Baló’s concentric sclerosis has no meaningful treatment as it causes death in weeks to months.
No treatment for sporadic inclusion body myositis has been found effective. Steroids such as high-dose prednisone and immunosuppression agenst such as methotrexate have generally been generally ineffective.
As for Hereditary inclusion body myopathy, affected patients have no therapeutic options.
For a compound or genus to be effective against inflammation generally is thus contrary to the present understanding of medical science. Thus, it is not reasonable for any agent to be able to treat inflammation generally. That is, the skill is so low that no compound effective generally against inflammatory disorders has ever been found. In terms of the individual inflammatory disorders, this is completely varied. One of ordinary skill in the art knows that, treatments for inflammation must often be tailored to the particular type of inflammation present, as there is no, and there can be no, "magic bullet" against inflammatory disorders generally.
(7) The quantity of experimentation needed: Given the fact that, historically, the development of new cancers drugs or drugs to treat inflammation disorders, etc. has been difficult and time consuming, and especially in view of factors 1 and 4 and 6, the quantity of experimentation needed is expected to be great.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Conclusion
No claims are allowed.
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/BRIAN E MCDOWELL/Primary Examiner, Art Unit 1624
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