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154-399: The causes of diffuse large B-cell lymphoma are not well understood. Usually DLBCL arises from normal B cells, but it can also represent a malignant transformation of other types of lymphoma (particularly marginal zone lymphomas ) or, in rare cases termed Richter's transformation , chronic lymphocytic leukemia . An underlying immunodeficiency is a significant risk factor for development of

308-403: A fatty capsule and lie within the renal fascia , which also surrounds the kidneys. A weak septum (wall) of connective tissue separates the glands from the kidneys. The adrenal glands are directly below the diaphragm , and are attached to the crura of the diaphragm by the renal fascia. Each adrenal gland has two distinct parts, each with a unique function, the outer adrenal cortex and

462-438: A pyothorax (i.e. pus in the pleural cavity ). Fibrin-associated large B-cell lymphoma (FA-DLBCL), often considered a sub-type of DLBCL-CI, is an infiltration of large neoplastic B-cells and fibrin affix to a prosthesis (e.g., cardiac valve, orthopaedic device) or accumulate within a hydrocele , pseudocyst , cardiac myxoma , or chronic subdural hematoma . The B-cells in these lesions are often but not always infected with

616-464: A DLBCL in which neoplastic immunoblastic or plasmablastic cells embedded in a background of other cell types infiltrate the oral/nasal cavity or much less often the gastrointestinal tract. Some 70% of individuals with PBL are infected with EBV and/or (particularly those with oral/nasal cavity disease) human immunodeficiency virus (HIV). PBL is an aggressive disease with a median survival time of ~15 months. Intravascular large B-cell lymphoma (IVLBCL)

770-446: A DLBCL in which neoplastic lymphocytes that express the ALK tyrosine kinase receptor protein infiltrate lymph nodes as well as extranodal sites, e.g. the mediastinum , bones, bone marrow , nasopharynx, tongue, stomach, liver, spleen, and skin. About 60% of these individuals present with advanced disease. ALK+ LBCL has an overall 5 year survival rate of ~34%. Plasmablastic lymphoma (PBL) is

924-410: A biologically and clinically diverse set of disease subtypes, many of which are difficult to separate from one another based on well-defined and widely accepted criteria. The World Health Organization , 2008, classification system defined more than a dozen subtypes, each of which was identified based on the location of the tumor, the presence of other cell types such as T cells in the tumor, and whether

1078-514: A chemotherapy regimen (e.g. R-CHOP) and/or, for complicated bulky disease, surgery and/or local radiotherapy. Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in which Epstein–Barr virus-infected B-cells proliferate and cause ulcerations in the mucous membranes and skin of immunosuppressed individuals. Its lesions consist of Epstein–Barr virus-positive, variable-sized, atypical B-cells that by conventional histopathologic criteria indicate

1232-421: A colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker , or passenger, mutations. In contrast, the frequency of epigenetic alterations is much higher. In colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while the corresponding CpG islands are not methylated in

1386-413: A common precursor. Therefore, the first step in steroidogenesis is cholesterol uptake or synthesis. Cells that produce steroid hormones can acquire cholesterol through two paths. The main source is through dietary cholesterol transported via the blood as cholesterol esters within low density lipoproteins (LDL). LDL enters the cells through receptor-mediated endocytosis . The other source of cholesterol

1540-503: A conditioning chemotherapy regimen, usually cyclophosphamide and fludarabine , and then infused with their own T-cells that have been engineered to attack CD19-bearing or, rarely, CD20 -bearing cells. A meta-analysis of 17 studies using this or very similar approaches to treat DLBCL, NOS found the treatments gave complete and partial responses rates of 61% and 43%, respectively. While these studies did not have control groups and were too recent for meaningful estimates of remission durations,

1694-457: A consequence of immunosuppressive therapy generally have a remission after the dosage of the drugs used in their immunosuppressive treatments are reduced. Most of these patients do not relapse. aggressive: Sézary disease Malignant transformation Malignant transformation is the process by which cells acquire the properties of cancer . This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of

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1848-827: A consequence of these gene changes and possibly other changes that have not yet been identified, the neoplastic cells in DLBCL, NOS exhibit pathologically overactive NF-κB, PI3K/AKT/mTOR , JAK-STAT 0, MAPK/ERK , B-cell receptor , toll-like receptor , and NF-κB signaling pathways and thereby uncontrolled pro-malignant behaviors. Microscopic examinations of involved tissues reveal large neoplastic cells that are typically classified as B-cells based on their expression of B-cell marker proteins (e.g. CD20 , CD19 , CD22 , CD79 , PAX5, BOB1 , OCT2 , an immunoglobulin [usually IgM but occasionally IgG or IgA )], CD30 , and in ~20–25% of cases PD-L1 or PD-L2 (PD-L1 and PD-L2 are transmembrane proteins that normally function to suppress attack by

2002-575: A consequence of these studies, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use of the European Medicines Agency recommend granting marketing authorization for tisagenlecleucel (i.e. chimeric antigen receptor T cells directed against CD19) in adult patients with DLBCL, NOS who have relapsed after or are refractory to two or more lines of systemic therapy. The Committee for Orphan Medicinal Products of

2156-562: A frequent step in progression to cancer. As summarized in a review, promoter hypermethylation of DNA repair gene MGMT occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers. In addition, promoter hypermethylation of DNA repair genes LIG4 , NEIL1 , ATM , MLH1 or FANCB occurs at frequencies of between 33% and 82% in one or more of head and neck cancers , non-small-cell lung cancers or non-small-cell lung cancer squamous cell carcinomas. Further,

2310-523: A germ-line mutation in a DNA repair gene, and predisposes the cell and its descendants to progression to cancer. Another review points out that when a gene necessary for DNA repair is epigenetically silenced, DNA repair would tend to be deficient and DNA damages can accumulate. Increased DNA damage can cause increased errors during DNA synthesis, leading to mutations that give rise to cancer. The heavy metals cadmium , arsenic and nickel are all carcinogenic when present above certain levels. Cadmium

2464-497: A good prognoses. Cases with a follicular pattern of tissue infiltrates often have indolent disease and an excellent prognosis following excision and may not need chemotherapy. Cases with a purely diffuse tissue infiltrate pattern, in contrast, often do require chemotherapy. Primary mediastinal large B-cell lymphoma (PMBL), also termed primary mediastinal (thymic) large B-cell lymphoma, is a DLBCL in which neoplastic B-cells infiltrates are commonly located in sclerotic /fibrous tissues of

2618-434: A group of alpha Human papillomaviruses (HPVs). In 1995 epidemiologic evidence indicated that Helicobacter pylori infection increases the risk for gastric carcinoma. More recently, experimental evidence showed that infection with Helicobacter pylori cagA-positive bacterial strains results in severe degrees of inflammation and oxidative DNA damage, leading to progression to gastric cancer. Perera et al. referred to

2772-691: A high frequency of mutations in the noncoding DNA that makes up about 98% of the human genome. The average number of DNA sequence mutations in the entire genome of breast cancer tissue is about 20,000. In an average melanoma (where melanomas have a higher exome mutation frequency ) the total number of DNA sequence mutations is about 80,000. A second underlying commonality in cancers is altered epigenetic regulation of transcription . In cancers, loss of gene expression occurs about 10 times more frequently by epigenetic transcription silencing (caused, for example, by promoter hypermethylation of CpG islands ) than by mutations. As Vogelstein et al. point out, in

2926-700: A highly favorable outcome. Lymphomatoid granulomatosis (LYG) is a DLBCL in which large, atypical B-cells with immunoblastic or Hodgkin disease -like features that are infected by the Epstein-Barr virus center around and destroy the microvasculature . Lymphomatoid granulomatosis almost always involves the lung but may concurrently involve the brain, peripheral nervous system, skin, kidneys, liver, gastrointestinal tract, and/or upper respiratory tract; LYG has an increased incidence in persons with Wiskott–Aldrich syndrome or HIV or who are immunosuppression due to chemotherapy or organ transplantation. The disease's prognosis

3080-408: A long and persistent history of chronic inflammation. The disease's lesions consist of large, mature-appearing B-cells infiltrating the lung's pleura and nearby tissues. Most cases have occurred in patients who were given a pneumothorax (i.e. therapeutic introduction of air into the chest cavity in order to collapse and thereby "rest" the lung) to treat pulmonary tuberculosis that had progressed to

3234-422: A microscope each layer has a distinct appearance, and each has a different function. The adrenal cortex is devoted to production of hormones , namely aldosterone , cortisol , and androgens . The outermost zone of the adrenal cortex is the zona glomerulosa . It lies immediately under the fibrous capsule of the gland. Cells in this layer form oval groups, separated by thin strands of connective tissue from

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3388-455: A network of small arteries within the capsule of the adrenal glands. Thin strands of the capsule enter the glands, carrying blood to them. Venous blood is drained from the glands by the suprarenal veins , usually one for each gland: The central adrenomedullary vein, in the adrenal medulla, is an unusual type of blood vessel. Its structure is different from the other veins in that the smooth muscle in its tunica media (the middle layer of

3542-474: A number of articles pointing to roles of bacteria in other cancers. They pointed to single studies on the role of Chlamydia trachomatis in cervical cancer, Salmonella typhi in gallbladder cancer, and both Bacteroides fragilis and Fusobacterium nucleatum in colon cancer. Meurman has recently summarized evidence connecting oral microbiota with carcinogenesis. Although suggestive, these studies need further confirmation. One underlying commonality in cancers

3696-412: A number of different hormones which are metabolised by enzymes either within the gland or in other parts of the body. These hormones are involved in a number of essential biological functions. Corticosteroids are a group of steroid hormones produced from the cortex of the adrenal gland, from which they are named. The adrenal gland produces aldosterone , a mineralocorticoid , which is important in

3850-406: A patient's neoplastic B-cells by isolating this patient's T-cells ; genetically engineering these cells to express an artificial T-cell receptor designed to bind an antigen expressed on the surface of their neoplastic B-cells; and infusing these cells back into the donor patient. The targeted antigen has usually been CD19 , a surface membrane protein expressed on virtually all B-cells including

4004-607: A previously existing benign tumor . There are many causes of primary malignant transformation, or tumorigenesis . Most human cancers in the United States are caused by external factors, and these factors are largely avoidable. These factors were summarized by Doll and Peto in 1981, and were still considered to be valid in 2015. These factors are listed in the table. Reproductive and sexual behaviors include: number of partners; age at first menstruation; zero versus one or more live births Colon cancer provides one example of

4158-447: A quickening of breathing and heart rate, an increase in blood pressure, and constriction of blood vessels in many parts of the body. Catecholamines are produced in chromaffin cells in the medulla of the adrenal gland, from tyrosine , a non-essential amino acid derived from food or produced from phenylalanine in the liver. The enzyme tyrosine hydroxylase converts tyrosine to L-DOPA in the first step of catecholamine synthesis. L-DOPA

4312-570: A reactive morphology. The World Health Organization, 2016, requires that the neoplastic cells in DLBCL, NOS be further defined based on whether they are derived from germinal center B-cells (i.e. GBC) or activated B-cells (i.e. ABC) as identified by gene expression profiling (GEP) or are GBC or non-GBC as identified by immunohistochemical (IHC) analyses. As identified by GEP, which measures all cellular messenger RNAs , GBC and ABC represent about 50 and ~35% of DLBCL, NOS cases, respectively, with ~15% of cases being unclassifiable. IHC analyses measure

4466-435: A recent advance in treating refractory and relapsed DLBCL, NOS ( tisagenlecleucel , axicabtagene ciloleucel , lisocabtagene maraleucel ). Chimeric antigen receptor T cells are genetically engineered to express: 1) an artificial T-cell receptor consisting of antigen-recognition and attached hinge domains expressed on their surface membranes ; 2) a surface membrane-spanning domain; 3) an intracellular domain which, when

4620-406: A related variant, double expresser lymphoma (i.e. DEL), express the products of MYC and BCL2 genes, i.e. c-Myc and bcl-2 proteins, respectively, but do not have translocations in either of their genes. DEL, which represents about one-third of all DLBCL, NOS cases, has a poorer prognosis than standard DLBCL, NOS but not as poor as DH/THL cases. Cases in which the neoplastic cells have alterations in

4774-446: A result of the dysregulation of hormone production (as in some types of Cushing's syndrome ) leading to an excess or insufficiency of adrenal hormones and the related symptoms. Cushing's syndrome is the manifestation of glucocorticoid excess. It can be the result of a prolonged treatment with glucocorticoids or be caused by an underlying disease which produces alterations in the HPA axis or

Diffuse large B-cell lymphoma - Misplaced Pages Continue

4928-432: A single lesion with a predilection for the supratentorial region of the brain but may involve the eye in 15–25% of cases, the cerebrospinal fluid in 7–42% of cases, and the spinal cord in ~1% of cases. The disease has a 5-year overall survival rate of ~30%. Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is an Epstein–Barr virus-associated lymphoproliferative disease arising in persons with

5082-420: A small amount of circulating noradrenaline. These hormones are released by the adrenal medulla, which contains a dense network of blood vessels. Adrenaline and noradrenaline act by interacting with adrenoreceptors throughout the body, with effects that include an increase in blood pressure and heart rate. Actions of adrenaline and noradrenaline are responsible for the fight or flight response , characterised by

5236-556: A solution to overcome this issue. DLBCL subtypes have been sorted into groups based on their distinctive morphology or immunophenotype , distinctive clinical issues, and distinctive virus-driven etiology. The prognoses and treatment of these subtypes varies with their severity. Most subtypes are aggressive diseases and consequently treated in a manner similar to DLBCL, NOS. Further details on these subtypes, including their treatments, can be found in their respective main article linkages. T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL)

5390-541: A variety of hormones including adrenaline and the steroids aldosterone and cortisol . They are found above the kidneys . Each gland has an outer cortex which produces steroid hormones and an inner medulla . The adrenal cortex itself is divided into three main zones: the zona glomerulosa , the zona fasciculata and the zona reticularis . The adrenal cortex produces three main types of steroid hormones : mineralocorticoids , glucocorticoids , and androgens . Mineralocorticoids (such as aldosterone ) produced in

5544-469: A very poor prognosis with median overall survival times of ~10 months. Patients who have failed or because of health issues are ineligible for autologous stem cell transplantation have been treated with low-dose (i.e. low-intensity) chemotherapy conditioning regimens followed by allogeneic stem cell transplantation . This regimen has achieved 3 year progression-free and overall survival rates of 41% and 52%, respectively. Further studies are underway to determine

5698-598: Is a bispecific monoclonal antibody that was approved for medical use in Canada in March 2023. Neoplastic cell expression of CD30 in DLBCL, NOS is a favorable prognostic indicator; in these cases, brentuximab vedotin may be a useful addition to chemotherapy treatment protocols. This agent is a CD30-targeting antibody that delivers a toxin, monomethyl auristatin E , to CD30-expressing cells, has therapeutic efficacy against other CD30-expressing lymphomas, and may prove useful in treating

5852-430: Is a diagnosis of exclusion . In general, DLBCL, NOS is an aggressive disease with an overall long-term survival rate in patients treated with standard chemotherapy regimens of ~65%. However, this disease has many variants that differ not only in the just cited parameters but also in their aggressiveness and responsiveness to treatment. About 70% of DLBCL, NOS cases present primarily with lymph node disease. In these cases,

6006-661: Is a DLBCL in which medium- to large-sized neoplastic B-cells infiltrate small- to medium-sized blood vessels and sinusoids in the liver, spleen, and/or bone marrow. IVLBCL may be associated with the hemophagic syndrome (i.e. excessive cytokine secretion and systemic inflammation). Patients with the latter syndrome have very short survival times. The poor prognosis of this disease has been significantly improved by rituximab or similar immunochemotherapy drugs but significant proportions of these responding cases relapse, often with central nervous system involvement. Large B-cell lymphoma with IRF4 rearrangement (LBCL with IRF4 rearrangement)

6160-575: Is a DLBCL in which tissue infiltrates containing intermediate- or large-sized neoplastic B-cells strongly express a chromosomal translocation involving the IRF4 gene on the short arm of chromosome 6. These cells form follicular , follicular and diffuse, or entirely diffuse infiltrates in Waldeyer's tonsillar ring or other regions of the head and neck. The disease, which represents ~0.05% of all DLBCL, occurs primarily in children and young adults and typically has

6314-400: Is a DLBCL in which tumors containing small numbers of usually large neoplastic B-cells embedded in a background of reactive T-cells and histiocytes develop in the liver, spleen, bone marrow and/or, rarely other sites. Patients usually present with advanced disease; their overall 3 year survival rates in different studies range between 46% and 72%. ALK+ large B-cell lymphoma (ALK+ LBCL) is

Diffuse large B-cell lymphoma - Misplaced Pages Continue

6468-552: Is a DLBCL, NOS that in >75% of cases involves activated B-cells, i.e. ABC. These cells, which typically have a centroblast -like morphology, infiltrate one or, in ~6% of cases, both testicles . PT-DLBCL is an aggressive disease that often spreads to the central nervous system and has median overall survival and progression-free survival times of 96 and 49 months, respectively. The neoplastic cells in almost all cases of DLBCL, NOS express CD20. Commercially available anti-CD20 antibody agents such as rituximab or Obinutuzumab (which

6622-591: Is a family of congenital diseases in which mutations of enzymes that produce steroid hormones result in a glucocorticoid deficiency and malfunction of the negative feedback loop of the HPA axis . In the HPA axis, cortisol (a glucocorticoid) inhibits the release of CRH and ACTH , hormones that in turn stimulate corticosteroid synthesis. As cortisol cannot be synthesized, these hormones are released in high quantities and stimulate production of other adrenal steroids instead. The most common form of congenital adrenal hyperplasia

6776-639: Is a favorable prognostic indicator. As indicated in the following Treatments and prognoses section, expression of the CD20 and CD30 proteins as well as the CD19, CD20 CD22, CD30, CD79A, CD79B, and D-L1 proteins, expression of the MYC , BCL2 , MYD88nd , and CREBBP genes, and expression of the PI3K/AKT/mTOR, JAK-STAT, B-cell receptor, toll-like receptor, and NF-κB signaling pathways are being studied as potential therapeutic targets for

6930-494: Is also considered to be a borderline DLBCL, NOS is termed high-grade B-cell lymphoma, not otherwise specified (HGBCL, NOS). These two aggressive borderline B-cell lymphomas were previously grouped together as "B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt lymphoma" (i.e. BCLU) but were separated into DH/THL and HGBC, NOS by the World Health Organization, 2016. The neoplastic cells in

7084-611: Is an aggressive disease with an overall 1 year survival rate of ~30%. Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS) is a B-cell lymphoma in which neoplastic B-cells that are infected with the Epstein-Barr virus cause a disease that does not fit into other subtypes of DLBCL. In EBV+ DLBCL, small neoplastic B-cells, other lymphocyte types, plasma cells, histiocytes and epithelioid cells interspersed with Reed–Sternberg-like cells infiltrate, almost exclusively, lymph nodes. Elderly patients with

7238-730: Is an inverse correlation of BRCA1 protein levels with miR-182 expression. Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182. In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation. Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers. Post-transcriptional regulation by microRNA occurs either through translational silencing of

7392-402: Is associated with Addison's disease . Congenital adrenal hyperplasia is a genetic disease produced by dysregulation of endocrine control mechanisms. A variety of tumors can arise from adrenal tissue and are commonly found in medical imaging when searching for other diseases. The adrenal glands are located on both sides of the body in the retroperitoneum , above and slightly medial to

7546-445: Is at the centre of each adrenal gland, and is surrounded by the adrenal cortex. The chromaffin cells of the medulla are the body's main source of the catecholamines , such as adrenaline and noradrenaline, released by the medulla. Approximately 20% noradrenaline (norepinephrine) and 80% adrenaline (epinephrine) are secreted here. The adrenal medulla is driven by the sympathetic nervous system via preganglionic fibers originating in

7700-414: Is called steroidogenesis , and involves a number of reactions and processes that take place in cortical cells. The medulla produces the catecholamines , which function to produce a rapid response throughout the body in stress situations. A number of endocrine diseases involve dysfunctions of the adrenal gland. Overproduction of cortisol leads to Cushing's syndrome , whereas insufficient production

7854-451: Is cleavage of the cholesterol side chain, a reaction that forms pregnenolone as a product and is catalyzed by the enzyme P450scc , also known as cholesterol desmolase . After the production of pregnenolone, specific enzymes of each cortical layer further modify it. Enzymes involved in this process include both mitochondrial and microsomal P450s and hydroxysteroid dehydrogenases . Usually a number of intermediate steps in which pregnenolone

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8008-703: Is due to 21-hydroxylase deficiency. 21-hydroxylase is necessary for production of both mineralocorticoids and glucocorticoids, but not androgens . Therefore, ACTH stimulation of the adrenal cortex induces the release of excessive amounts of adrenal androgens , which can lead to the development of ambiguous genitalia and secondary sex characteristics . Adrenal tumors are commonly found as incidentalomas , unexpected asymptomatic tumors found during medical imaging . They are seen in around 3.4% of CT scans , and in most cases they are benign adenomas . Adrenal carcinomas are very rare, with an incidence of 1 case per million per year. Pheochromocytomas are tumors of

8162-497: Is genetic mutation, acquired either by inheritance, or, more commonly, by mutations in one's somatic DNA over time. The mutations considered important in cancers are those that alter protein coding genes (the exome ). As Vogelstein et al. point out, a typical tumor contains two to eight exome "driver gene" mutations, and a larger number of exome mutations that are "passengers" that confer no selective growth advantage. Cancers also generally have genome instability , that includes

8316-474: Is highly variable: patients with low grade disease often require no therapy except watchful waiting while patients with high grade disease usually require chemotherapy. Primary effusion lymphoma (PEL) is a DLBCL in which neoplastic B cells that resemble immunoblasts, plasmablasts, or Reed–Sternberg cells infiltrate the pleural , pericardial , or peritoneal membranes that surround the lungs, heart, and abdominal organs, respectively. This infiltration leads to

8470-586: Is involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double-strand breaks. BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers. Only about 3–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2. BRCA1 promoter hypermethylation was present in only 13% of unselected primary breast carcinomas. However, breast cancers were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue. In breast cancer cell lines, there

8624-461: Is known to be carcinogenic, possibly due to reduction of DNA repair. Lei et al. evaluated five DNA repair genes in rats after exposure of the rats to low levels of cadmium. They found that cadmium caused repression of three of the DNA repair genes: XRCC1 needed for base excision repair , OGG1 needed for base excision repair, and ERCC1 needed for nucleotide excision repair . Repression of these genes

8778-402: Is modified several times are required to form the functional hormones. Enzymes that catalyze reactions in these metabolic pathways are involved in a number of endocrine diseases. For example, the most common form of congenital adrenal hyperplasia develops as a result of deficiency of 21-hydroxylase , an enzyme involved in an intermediate step of cortisol production. Glucocorticoids are under

8932-479: Is not evenly released during the day – its concentrations in the blood are highest in the early morning and lowest in the evening as a result of the circadian rhythm of ACTH secretion. Cortisone is an inactive product of the action of the enzyme 11β-HSD on cortisol. The reaction catalyzed by 11β-HSD is reversible, which means that it can turn administered cortisone into cortisol, the biologically active hormone. All corticosteroid hormones share cholesterol as

9086-469: Is regulated mainly by the renin–angiotensin–aldosterone system (RAAS), the concentration of potassium , and to a lesser extent the concentration of ACTH. Sensors of blood pressure in the juxtaglomerular apparatus of the kidneys release the enzyme renin into the blood, which starts a cascade of reactions that lead to formation of angiotensin II . Angiotensin receptors in cells of the zona glomerulosa recognize

9240-417: Is sometimes used in place of rituximab) kill cells that express high levels of CD20 by binding to this cell-surface protein and thereby targeting them for attack by the hosts adaptive immune system . The addition of one of these immunotherapy agents to chemotherapy protocols has greatly improved the prognosis of most DLBCL, NOS variants. Neoplastic cell expression of CD30, found in 10–15% of DLBCL, NOS cases

9394-400: Is synthesis in the cell's endoplasmic reticulum . Synthesis can compensate when LDL levels are abnormally low. In the lysosome , cholesterol esters are converted to free cholesterol, which is then used for steroidogenesis or stored in the cell. The initial part of conversion of cholesterol into steroid hormones involves a number of enzymes of the cytochrome P450 family that are located in

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9548-500: Is the DA-R-EPOCH regimen (dose-adjusted rituximab, etoposide , prednisolone, oncovin, cyclophosphamide, and hydroxydaunorubicin). S-R-EPOCH achieves 2 year survival rates of 40–67% compared to a ~25% survival rate for R-CHOP in these cases. DA-R-EPOCH has also been recommended for patients with double expresser lymphoma although some experts recommend treating this variant more like a typical DLCBL, NOS. First-line therapy for patients with

9702-462: Is the adrenal crisis , a medical emergency in which low glucocorticoid and mineralocorticoid levels result in hypovolemic shock and symptoms such as vomiting and fever. An adrenal crisis can progressively lead to stupor and coma . The management of adrenal crises includes the application of hydrocortisone injections. In secondary adrenal insufficiency, a dysfunction of the hypothalamic–pituitary–adrenal axis leads to decreased stimulation of

9856-800: Is the largest of the three layers, accounting for nearly 80% of the volume of the cortex. In the zona fasciculata, cells are arranged in columns radially oriented towards the medulla. Cells contain numerous lipid droplets, abundant mitochondria and a complex smooth endoplasmic reticulum . The innermost cortical layer, the zona reticularis , lies directly adjacent to the medulla. It produces androgens , mainly dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione (the precursor to testosterone ) in humans. Its small cells form irregular cords and clusters, separated by capillaries and connective tissue. The cells contain relatively small quantities of cytoplasm and lipid droplets, and sometimes display brown lipofuscin pigment. The adrenal medulla

10010-407: Is the main responsible for this, and that glucocorticoids only play a role in the subsequent development of the cells. The normal function of the adrenal gland may be impaired by conditions such as infections, tumors, genetic disorders and autoimmune diseases , or as a side effect of medical therapy. These disorders affect the gland either directly (as with infections or autoimmune diseases) or as

10164-412: Is then converted to dopamine before it can be turned into noradrenaline. In the cytosol , noradrenaline is converted to epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) and stored in granules. Glucocorticoids produced in the adrenal cortex stimulate the synthesis of catecholamines by increasing the levels of tyrosine hydroxylase and PNMT. Catecholamine release is stimulated by

10318-426: Is usually observed for protein coding genes. Other microRNA promoters are hypomethylated in breast cancers, and, as a result, these microRNAs are over-expressed. Several of these over-expressed microRNAs have a major influence in progression to breast cancer. BRCA1 is normally expressed in the cells of breast and other tissue, where it helps repair damaged DNA , or destroy cells if DNA cannot be repaired. BRCA1

10472-484: The MYC gene or its expression without changes in BLC2 or BLC6 also have a poor prognosis, particularly in cases where the MYC gene translocates (i.e. rearranges) with one of the immunoglobulin gene loci . DLBCL that begin in the testicles are a variant of DLBCL, NOS that some authors suggest should be classified as a distinct DLBCL subtype. This variant, termed Primary testicular diffuse large B-cell lymphoma (PT-DLBCL),

10626-404: The gonads , acting in this way as a metabolic intermediate . Primarily referred to in the United States as epinephrine and norepinephrine , adrenaline and noradrenaline are catecholamines , water-soluble compounds that have a structure made of a catechol group and an amine group . The adrenal glands are responsible for most of the adrenaline that circulates in the body, but only for

10780-405: The kidneys . In humans, the right adrenal gland is pyramidal in shape, whereas the left is semilunar or crescent shaped and somewhat larger. The adrenal glands measure approximately 5 cm in length, 3 cm in width, and up to 1 cm in thickness. Their combined weight in an adult human ranges from 7 to 10 grams. The glands are yellowish in colour. The adrenal glands are surrounded by

10934-407: The maturation , proliferation , survival, spread, evasion of the immune system , and other malignant behaviors of the cells in which they occur. While scores of genes have been reported to be altered in DLBCL, NOS many of these may not contribute to DLBCL, NOS. Changes in the following genes occur frequently in, and are suspected of contributing to, this disease's development and/or progression. As

11088-538: The medical history examination, can find that there have been changes in size or patient sensation and, upon direct examination, that there has been a change in the lesion itself. Risk assessments can be done and are known for certain types of benign tumor which are known to undergo malignant transformation. One of the better-known examples of this phenomenon is the progression of a nevus to melanoma . Adrenal gland The adrenal glands (also known as suprarenal glands ) are endocrine glands that produce

11242-537: The placenta for estrogen biosynthesis. Cortical development of the adrenal gland is regulated mostly by ACTH , a hormone produced by the pituitary gland that stimulates cortisol synthesis. During midgestation, the fetal zone occupies most of the cortical volume and produces 100–200 mg/day of DHEA-S , an androgen and precursor of both androgens and estrogens (female sex hormones). Adrenal hormones, especially glucocorticoids such as cortisol, are essential for prenatal development of organs, particularly for

11396-556: The thoracic spinal cord , from vertebrae T5–T11. Because it is innervated by preganglionic nerve fibers , the adrenal medulla can be considered as a specialized sympathetic ganglion . Unlike other sympathetic ganglia, however, the adrenal medulla lacks distinct synapses and releases its secretions directly into the blood. The adrenal glands have one of the greatest blood supply rates per gram of tissue of any organ: up to 60 small arteries may enter each gland. Three arteries usually supply each adrenal gland: These blood vessels supply

11550-445: The thymus and mediastinal lymph nodes. The disease represents 6–10% of all DLBCL cases, presents with early stage disease in ~80% of cases, and has an overall survival rate at 5 years of 75–85%. Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a DLBCL in which diffuse patterns of immunoblastic and/or centroblastic B-cells infiltrate the dermis and/or subcutaneous tissue principally, but not exclusively, of

11704-466: The transcriptional activity of protein-encoding genes. Epigenetic silencing or epigenetic over-expression of miRNA genes, caused by aberrant DNA methylation of the promoter regions controlling their expression, is a frequent event in cancer cells. Almost one third of miRNA promoters active in normal mammary cells were found to be hypermethylated in breast cancer cells, and that is a several fold greater proportion of promoters with altered methylation than

11858-761: The 10–15% of DLBCL, NOS cases expressing this protein. The neoplastic cells in the GBC variant of DLBCL, NOS often have mutations in the EZH2, BCL2 and CREBBP genes and overactive PI3K/AKT/mTOR and JAK-STAT signaling pathways while neoplastic cells in the ABC variant often have mutations in the MYD88, CD79A and CD79B ( polatuzumab vedotin ) genes and overactive B-cell receptor , toll-like receptor , and NF-κB signaling pathways. These different gene mutations and dysregulated signaling pathways are also being studied as potential therapeutic targets for

12012-461: The 2016 World Health Organization's classification, are clearly associated with, and caused by, chronic infection by the bacterium , Helicobacter pylori . DLBCL cases that do not fit the distinctive clinical presentation, tissue morphology, neoplastic cell phenotype , and/or pathogen-associated criteria of other DLBCL subtypes are termed Diffuse large B-cell lymphoma, not otherwise specified: DLBCL, NOS, while representing 80–85% of all DLBCL cases,

12166-424: The ABC variants. Gene and protein markers in the neoplastic cells of DLBCL, NOS that have clinical significance include CD5 , MYC , BCL2 , BCL6, CD20, CD19, CD22, CD30, PD-L1, and PD-L2. The 5–10% of DLBCL, NOS cases in which the neoplastic cells express CD5 have a very poor prognosis that is not improved by even aggressive treatment regimens. Cases in which fluorescence in situ hybridization analysis show that

12320-478: The ABC, unclassifiable, and non-GBC variants have significantly worse prognoses than individuals with the GBC variant: respective 5 year progression-free and overall survival rates have been reported to be 73–80% for GBC variants and 31–56% for ABC variants. Clinically, however, most DLBCL, NOS cases are analyzed by IHC and therefore classified as either GBC or non-GBC variants with non-GBC variants having progression-free and overall survival rates similar to those of

12474-807: The ABC, undetermined, or non-GBC variants has been the DA-R-EPOCH regimen. Patients with these variants (including those with double expresser lymphoma) have had a ~40% cure rate when treated with it. A randomized clinical trial conducted in France reported that a R-ACVBP chemotherapy regimen (rituximab, adriamycin , cyclophosphamide, vindesine , bleomycin , and cytarabine followed by sequential consolidation therapy with systemic methotrexate , ifosfamide , and etoposide , and then cytarabine) achieved significantly better response rates than R-CHOP in ABC/NGC variant cases lymphoma. In DLBCL, NOS variants which trend to spread or to

12628-558: The Epstein–Barr virus. DLBCL-CI occurring in cases of pleural empyema (sometimes termed pyothorax-associated lymphoma , i.e. PAL) is an aggressive lymphoma with a five-year overall survival rate of 20–35%; FA-DLBCL, when involving the heart (e.g. occurring on myxomata or prosthetic valves) or vasculature structures (e.g. on thrombus-laden vascular grafts), may involve life-threatening cardiovascular complications, particularly strokes. Outside of these complications, however, DLBCL-CI usually has

12782-570: The European Medicines Agency recommends tisagenlecleucel retain its orphan drug designation. The USA Food and Drug Administration (FDA) has also approved the use of this drug for relapsed or refractory DLBCL of the large B-cell lymphoma subtype in patients who have failed after two or more lines of systemic therapy. Monoclonal antibodies directed against CD19, CD22, CD30, and PD-L1 have been developed for use as immunotherapeutic agents in other hematological malignancies and are being or plan to be tested for their usefulness in DLBCL, NOS. In August 2020,

12936-523: The FDA approved the humanized Fc-modified cytolytic CD19 targeting monoclonal antibody tafasitamab in combination with lenalidomide as a treatment for adult patients with relapsed or refractory DLBCL. In April 2021, the FDA approved the CD19-directed antibody-drug conjugate loncastuximab tesirine as a treatment for adult patients with relapsed or refractory DLBCL after systemic therapy. Glofitamab (Columvi)

13090-472: The Index's age-adjusted variant use age >60 years, elevated serum lactate dehydrogenase levels, low performance status , and involvement in more than one extranodal site as contributors to a poor prognosis in patients with DLBCL, NOS. In addition, disease that initially involves the testes, breast, or uterus has a relatively high rate of spreading to the central nervous system while disease initially involving

13244-742: The R-CHOP regimen produce an ~80% complete response rate in GBC as well as non- GBC DLBCL, NOS variants. Two phase III clinical research trials are underway to confirm these results and determine if the R-CHOP + lenalidomide regimen is superior to R-CHOP in the up-front treatment of GBC and/or non-GBC variants. Patients with DLBCL, NOS who relapse or progress following first-line therapy have been treated with "salvage regimens" consisting of high-dose (also termed high-intensity) chemotherapy conditioning drugs followed by autologous stem cell transplantation . This regimen has attained 3-year progression-free survival rates of 21–37%. Relapse following this treatment carries

13398-439: The activation of the sympathetic nervous system . Splanchnic nerves of the sympathetic nervous system innervate the medulla of the adrenal gland. When activated, it evokes the release of catecholamines from the storage granules by stimulating the opening of calcium channels in the cell membrane. The  human genome  includes approximately 20,000 protein coding genes and 70% of these  genes are expressed  in

13552-592: The adjacent mucosa. Such methylation turns off expression of a gene as completely as a mutation would. Around 60–70% of human genes have a CpG island in their promoter region. In colon cancers, in addition to hypermethylated genes, several hundred other genes have hypomethylated (under-methylated) promoters, thereby causing these genes to be turned on when they ordinarily would be turned off. Epigenetic alterations are also carried out by another major regulatory element, that of microRNAs (miRNAs). In mammals, these small non-coding RNA molecules regulate about 60% of

13706-447: The adrenal cortex. Apart from suppression of the axis by glucocorticoid therapy, the most common cause of secondary adrenal insufficiency are tumors that affect the production of adrenocorticotropic hormone (ACTH) by the pituitary gland . This type of adrenal insufficiency usually does not affect the production of mineralocorticoids , which are under regulation of the renin–angiotensin system instead. Congenital adrenal hyperplasia

13860-414: The adrenal gland is derived from mesoderm , whereas the medulla is derived from the neural crest , which is of ectodermal origin. The adrenal glands in a newborn baby are much larger as a proportion of the body size than in an adult. For example, at age three months the glands are four times the size of the kidneys. The size of the glands decreases relatively after birth, mainly because of shrinkage of

14014-570: The adrenal gland. In the Western world, Addison's disease is most commonly an autoimmune condition, in which the body produces antibodies against cells of the adrenal cortex. Worldwide, the disease is more frequently caused by infection, especially from tuberculosis . A distinctive feature of Addison's disease is hyperpigmentation of the skin, which presents with other nonspecific symptoms such as fatigue. A complication seen in untreated Addison's disease and other types of primary adrenal insufficiency

14168-416: The adrenal medulla that arise from chromaffin cells . They can produce a variety of nonspecific symptoms, which include headaches, sweating, anxiety and palpitations . Common signs include hypertension and tachycardia . Surgery, especially adrenal laparoscopy , is the most common treatment for small pheochromocytomas. Bartolomeo Eustachi , an Italian anatomist, is credited with the first description of

14322-509: The antigen-recognition domain binds its targeted antigen, activates signaling pathways that cause the T-cell to attack and kill cells that bear the recognized antigen on their surface membranes; and 4) , in more recently devised second generation CAR-T strategies, an associated intracellular co-stimulating molecule (e.g. CD28 or 4-1BB ) which augments activation of the cell-killing signaling pathways. CAR-T therapy, as it pertains to DLBCL, NOS, kills

14476-401: The article Werner syndrome ATP-dependent helicase indicates the DNA repair gene WRN has a promoter that is often hypermethylated in a variety of cancers, with WRN hypermethylation occurring in 11% to 38% of colorectal , head and neck , stomach , prostate , breast , thyroid , non-Hodgkin lymphoma , chondrosarcoma and osteosarcoma cancers. Such silencing likely acts similarly to

14630-607: The bacterium. Perhaps because of these features of the disease, H. pylori + DLBCL has not been classified as a DLBCL by the World Health Organization, 2016. Recent studies suggest that localized, early-stage H. pylori + DLBCL, when limited to the stomach, is successfully treated with H. pylori eradication protocols consisting of two or more antibiotics plus a proton pump inhibitor. However, these studies also agree that patients treated with one of these H. pylori eradication regimes need to be carefully followed: those unresponsive to, or worsening on, these regimens should be switched to

14784-419: The beginning of puberty. The adrenal medulla is derived from neural crest cells , which come from the ectoderm layer of the embryo . These cells migrate from their initial position and aggregate in the vicinity of the dorsal aorta , a primitive blood vessel, which activates the differentiation of these cells through the release of proteins known as BMPs . These cells then undergo a second migration from

14938-478: The best treatment regimens for these cases. Patients refractory to first-line therapy or who relapse within 12 months of receiving salvage therapy (including bone marrow transplant) for recurrent disease have had poor prognoses with median overall survival rates of 3.3 and 6.3 months, respectively. The prognosis of these patients appears to be improved by using CAR-T therapy. Chimeric antigen receptor T cell (i.e. CAR-T) adoptive cellular immunotherapy has emerged as

15092-463: The cellular expression of specific proteins using a panel of fluorescent antibodies that bind to and therefore stain a set of key proteins. For example, one commercially available panel uses three antibodies to detect CD10, BCL6, and MUM1 proteins; GBC express whereas ABC and unidentified cells do not express these proteins; accordingly, this as well as other IHC panels classify ABC and undetermined neoplastic cell types together as non-GBC. Individuals with

15246-428: The central nervous system, methotrexate has been recommended to be added to regimens not containing it for use as prophylaxis to reduce the incidence of this complication. The role of Autologous stem-cell transplantation as an addition to first-line therapy in the treatment of DLBCL, NOS, including cases with a poor prognosis, is unclear. A phase I clinical research trial found that the addition of lenalidomide to

15400-425: The circulating level of glucose . This is the result of an increase in the mobilization of amino acids from protein and the stimulation of synthesis of glucose from these amino acids in the liver. In addition, they increase the levels of free fatty acids , which cells can use as an alternative to glucose to obtain energy. Glucocorticoids also have effects unrelated to the regulation of blood sugar levels, including

15554-469: The colonic microbiota. Evidence reviewed by Sun and Kato indicates that differences in human colonic microbiota play an important role in the progression of colon cancer. A second example, relating a dietary component to a cancer, is illustrated by lung cancer. Two large population-based studies were performed, one in Italy and one in the United States. In Italy, the study population consisted of two cohorts:

15708-455: The cortex. The cortex, which almost completely disappears by age 1, develops again from age 4–5. The glands weigh about 1 gram at birth and develop to an adult weight of about 4 grams each. In a fetus the glands are first detectable after the sixth week of development. Adrenal cortex tissue is derived from the intermediate mesoderm . It first appears 33 days after fertilisation , shows steroid hormone production capabilities by

15862-510: The disease have median survival times of ~2 years while young patients have long-term treatment-related remissions in >80% of cases. HHV8-positive diffuse large B-cell lymphoma, NOS (HHV8+ DLBCL, NOS; also termed HHV8-positive diffuse large B-cell lymphoma [HHV8+ DLBCL]) is a DLBCL in which Kaposi's sarcoma-associated herpesvirus -infected, medium- to large-size neoplastic B-cells that resemble lymphocytes or immunoblasts infiltrate lymph nodes (~80% of cases) and, when disseminated (20% of cases),

16016-596: The disease. Infections with the Epstein–Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus , human immunodeficiency virus (i.e. HIV), and the Helicobacter pylori bacterium are also associated with the development of certain subtypes of diffuse large B-cell lymphoma. However, most cases of this disease are associated with the unexplained step-wise acquisition of increasing numbers of gene mutations and changes in gene expression that occur in, and progressively promote

16170-478: The dorsal aorta to form the adrenal medulla and other organs of the sympathetic nervous system . Cells of the adrenal medulla are called chromaffin cells because they contain granules that stain with chromium salts, a characteristic not present in all sympathetic organs. Glucocorticoids produced in the adrenal cortex were once thought to be responsible for the differentiation of chromaffin cells. More recent research suggests that BMP-4 secreted in adrenal tissue

16324-436: The eighth week and undergoes rapid growth during the first trimester of pregnancy. The fetal adrenal cortex is different from its adult counterpart, as it is composed of two distinct zones: the inner "fetal" zone, which carries most of the hormone-producing activity, and the outer "definitive" zone, which is in a proliferative phase. The fetal zone produces large amounts of adrenal androgens (male sex hormones) that are used by

16478-469: The fibrous capsule of the gland and carry wide capillaries . This layer is the main site for production of aldosterone , a mineralocorticoid , by the action of the enzyme aldosterone synthase . Aldosterone plays an important role in the long-term regulation of blood pressure . The zona fasciculata is situated between the zona glomerulosa and zona reticularis. Cells in this layer are responsible for producing glucocorticoids such as cortisol . It

16632-469: The first 3 years of diagnosis with few cases doing so after 5 years. Patients who are refractory to, relapse within 1 year of diagnosis before starting, relapse within 6 months after completing, or progress within 2 years of starting R-CHOP have poorer prognoses. R-CHOP is less effective and not recommended for patients who have MYC, BL2, and/or BL6 rearrangements regardless of their GBC, ABC, or non-GBC type. One recommendation for treating these DH/THL cases

16786-637: The first, 1721 individuals diagnosed with lung cancer and no severe disease, and the second, 1918 control individuals with absence of lung cancer history or any advanced diseases. All individuals filled out a food frequency questionnaire including consumption of walnuts, hazelnuts, almonds, and peanuts, and indicating smoking status. In the United States, 495,785 members of AARP were questioned on consumption of peanuts, walnuts, seeds, or other nuts in addition to other foods and smoking status. In this U.S. study 18,533 incident lung cancer cases were identified during up to 16 years of follow-up. Overall, individuals in

16940-433: The general population. Diseases classified as primary adrenal insufficiency (including Addison's disease and genetic causes) directly affect the adrenal cortex. If a problem that affects the hypothalamic–pituitary–adrenal axis arises outside the gland, it is a secondary adrenal insufficiency . Addison's disease refers to primary hypoadrenalism, which is a deficiency in glucocorticoid and mineralocorticoid production by

17094-499: The highest quintile of frequency of nut consumption had a 26% lower risk of lung cancer in the Italian study and a 14% lower risk of lung cancer in the U.S. study. Similar results were obtained among individuals who were smokers. The most important chemical compounds in smoked tobacco that are carcinogenic are those that produce DNA damage since such damage appears to be the primary underlying cause of cancer. Cunningham et al. combined

17248-830: The immune system). These cells arrange in a diffuse pattern, efface the tissues' architecture, and resemble Centroblast cells (80% of cases), Immunoblast cells (8–10% of cases), or anaplastic cells (9% of cases; anaplastic cells have bizarre nuclei and other features that may mimic the Reed–Sternberg cells of Hodgkin disease or the neoplastic cells of anaplastic large cell lymphoma ). Rarely, these neoplastic cells are characterized as having signet ring or spindle shaped nuclei, prominent cytoplasmic granules, multiple microvillus projections, or, when viewed by electron microscopy , tight junctions with other cells . These neoplastic tissue infiltrates are often accompanied by small non-malignant T-cell lymphocytes and histiocytes that have

17402-503: The individualized treatment of GBC and ABC/non-GBC DLBCL, NOS cases. First-line therapy for patients with the GBC variant of DLBCL, NOS is R-CHOP . R-CHOP consists of rituximab, three chemotherapy drugs ( cyclophosphamide , doxorubicin , and vincristine ) and a glucocorticoid (either prednisone or prednisolone ). The regimen achieves cure, relapse following remission, and unresponsive rates of 60–70%, 30–40% and <10%, respectively, in GBC variant cases. Relapses generally occur within

17556-475: The individualized treatment of GBC and ABC/non-GBC cases. CUDC-907 , an inhibitor of PI3K and histone deacetylases , is being evaluated in two separate clinical trials for the treatment of refractory and/or relapsed DLBCL, NOS including cases with alterations in the MYC gene . GSK525762 , an inhibitor of the BET family of proteins , suppresses expression of the MYC gene and is undergoing a phase I clinical trial for

17710-432: The inner medulla , both of which produce hormones. The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. The adrenal cortex is the outermost layer of the adrenal gland. Within the cortex are three layers, called "zones". When viewed under

17864-430: The inner membrane of mitochondria . Transport of cholesterol from the outer to the inner membrane is facilitated by steroidogenic acute regulatory protein and is the rate-limiting step of steroid synthesis. The layers of the adrenal gland differ by function, with each layer having distinct enzymes that produce different hormones from a common precursor. The first enzymatic step in the production of all steroid hormones

18018-434: The kidneys, adrenal glands , ovaries, or bone marrow has a high rate of spreading to other organs, including the central nervous system. All of these cases as well as cases initially involving the central nervous system have relatively poor to very poor prognoses. Cases initially involving the stomach, thyroid, or a single bone site have relatively good prognoses. Most cases of DLBCL, NOS appear to result at least in part from

18172-429: The legs. This disease's 5-year overall survival rate is 50–60%. Primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS, also termed primary central nervous system lymphoma [PCNSL]) is a DLBCL in which diffuse patterns of neoplastic B-cells with centroblastic, immunoblastic, or poorly differentiated features infiltrate the brain, spinal cord, leptomeninges , or eye. The disease usually presents as

18326-488: The lesions are a form of DLBCL. Since these lesions regress spontaneously without anti-cancer treatment, EBVMCU is now considered a pseudo-malignant disorder. Elderly individuals that evidence the disease but have no other cause for immunosuppression may exhibit a relapsing and remitting course with their ulcers worsening but then regressing spontaneously. Persistent and/or severely symptomatic cases have had excellent responses to rituximab . Individuals developing these ulcers as

18480-411: The levels of StAR within the cells, and then of all steroidogenic P450 enzymes. The HPA axis is an example of a negative feedback system, in which cortisol itself acts as a direct inhibitor of both CRH and ACTH synthesis. The HPA axis also interacts with the immune system through increased secretion of ACTH at the presence of certain molecules of the inflammatory response . Mineralocorticoid secretion

18634-484: The liver and spleen. This infiltration usually disrupts the normal architecture of the involved tissues. HHV8+ DLBCL develops in HIV -infected individuals in ~50% of cases, in individuals with multicentric Castleman disease, plasma cell variant in uncommon cases, and in individuals with Kaposi sarcoma in rare cases. HHV8+ DLBCL commonly takes an aggressive course and has a poor prognosis. Rare cases of DLBCL are associated with

18788-475: The malignant behavior of, certain B-cell types. Diagnosis of DLBCL is made by removing a portion of the tumor through a biopsy , and then examining this tissue using a microscope. Usually a hematopathologist makes this diagnosis. Numerous subtypes of DLBCL have been identified which differ in their clinical presentations, biopsy findings, aggressive characteristics, prognoses , and recommended treatments. However,

18942-437: The maturation of the lungs . The adrenal gland decreases in size after birth because of the rapid disappearance of the fetal zone, with a corresponding decrease in androgen secretion. During early childhood androgen synthesis and secretion remain low, but several years before puberty (from 6–8 years of age) changes occur in both anatomical and functional aspects of cortical androgen production that lead to increased secretion of

19096-601: The mechanisms by which diet, the top factor listed in the table, is an external factor in cancer. The Western diet of African Americans in the United States is associated with a yearly colon cancer rate of 65 per 100,000 individuals, while the high fiber/low fat diet of rural Native Africans in South Africa is associated with a yearly colon cancer rate of <5 per 100,000. Feeding the Western diet for two weeks to Native Africans increased their secondary bile acids, including carcinogenic deoxycholic acid , by 400%, and also changed

19250-469: The medulla. The adrenal glands are composed of two heterogenous types of tissue. In the center is the adrenal medulla , which produces adrenaline and noradrenaline and releases them into the bloodstream, as part of the sympathetic nervous system . Surrounding the medulla is the cortex , which produces a variety of steroid hormones . These tissues come from different embryological precursors and have distinct prenatal development paths. The cortex of

19404-894: The microgram weight of the compound in the smoke of one cigarette with the known genotoxic effect per microgram to identify the most carcinogenic compounds in cigarette smoke. These compounds and their genotoxic effects are listed in the article Cigarette . The top three compounds are acrolein , formaldehyde and acrylonitrile , all known carcinogens . In 2002 the World Health Organizations International Agency for Research on Cancer estimated that 11.9% of human cancers are caused by one of seven viruses (see Oncovirus overview table ). These are Epstein-Barr virus (EBV or HHV4); Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8); Hepatitis B and Hepatitis C viruses (HBV and HCV); Human T-lymphotrophic virus 1 (HTLV-1); Merkel cell polyomavirus (MCPyV); and

19558-499: The most typical presenting symptom at the time of diagnosis is a mass that is rapidly enlarging and located in a part of the body with multiple lymph nodes such as the groin, arm pits, or neck. In the remaining ~30% of other cases, the disease begins as an extranodal lymphoma, most commonly in the stomach, or, less commonly, in other sites such as the testicles, breasts, uterus, ovaries, kidneys, adrenal glands , thyroid gland, or bone. The presenting signs and symptoms in these cases reflect

19712-439: The neoplastic cells in DLBCL, NOS. However, design of CARs as well as the antigens chosen to be their targets are constantly being changed in order to improve the efficacy of this therapeutic strategy. CAR-T therapy for DLBCL, NOS has been used on patients who are refractory to and/or have progressed on first-line as well as salvage (including autologous stem cell transplantation) treatment regimens. Patients are treated first with

19866-575: The neoplastic cells' in this disease bear translocations in both the MYC and BCL2 genes or MYC and BCL6 genes (termed double hit lymphomas) or in all three genes (termed triple hit lymphomas) are associated with advanced disease that spreads to the central nervous system . These lymphomas, termed high-grade B-cell lymphoma with MYC, BL2, and/or BL6 rearrangements or, more simply, DH/THL, are regarded as borderline DLBCL, NOS. They represent 6–14% of all DLBCL, NOS and have had long-term survival rates of only 20–25%. Another variant B-cell lymphoma that

20020-436: The nickel-refinery workers and two over-expressed. The alterations in gene expression appear to be due to epigenetic alterations of histones, methylations of gene promoters, and hypermethylation of at least microRNA miR-152. Malignant transformation of cells in a benign tumor may be detected by pathologic examination of tissues. Often the clinical signs and symptoms are suggestive of a malignant tumor. The physician, during

20174-591: The normal adult adrenal glands.  Only some 250 genes are more specifically expressed in the adrenal glands compared to other organs and tissues. The adrenal-gland-specific genes with the highest level of expression include members of the cytochrome P450 superfamily of enzymes. Corresponding proteins are expressed in the different compartments of the adrenal gland, such as CYP11A1 , HSD3B2 and FDX1 involved in steroid hormone synthesis and expressed in cortical cell layers, and PNMT and DBH involved in noradrenaline and adrenaline synthesis and expressed in

20328-609: The patient had certain other illnesses related to DLBCL. Based on further research, the World Health Organization, 2016, reclassified DLBCL into its most common subtype, diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). DLBCL, NOS represents 80–85% of all DLBCL. The remaining DLBCL cases consist of relatively rare subtypes that are distinguished by their morphology , (i.e. microscopic appearance), immunophenotype , (i.e. expression of certain marker proteins), clinical findings, and/or association with certain pathogenic viruses . Some cases of DLBCL, NOS, while not included in

20482-623: The presence of a rapidly expanding tumor or infiltrate that produces symptoms specific to the organ of involvement such as increased size, pain, and/or dysfunction. Individuals with nodal or extranodal disease also present with: systemic B symptoms such as weight loss, night sweats, fevers, and/or fatigue in ~33% of cases; unexplained elevations in their blood levels of lactic acid dehydrogenase and beta-2 microglobulin in many cases; malignant cells infiltrating their bone marrow in 10–20% of cases; and/or localized Stage I or II disease in up to 50% of cases and disseminated Stage III or IV disease in

20636-463: The presence of the bacterium, Helicobacter pylori , in the neoplastic B-cells. While the histology of Helicobactor pylori -associated diffuse large B-cell lymphoma ( H. pylori + DLBCL) is typical of DLBCL, the disease is sometimes a progression of mantle cell lymphoma , is often restricted to the stomach, is less aggressive that most DLBCL cases, and may respond to a drug regimen consisting of antibiotics and proton pump inhibitors directed at killing

20790-454: The production of cortisol. Causes can be further classified into ACTH -dependent or ACTH-independent. The most common cause of endogenous Cushing's syndrome is a pituitary adenoma which causes an excessive production of ACTH. The disease produces a wide variety of signs and symptoms which include obesity, diabetes, increased blood pressure, excessive body hair ( hirsutism ), osteoporosis , depression, and most distinctively, stretch marks in

20944-513: The regulation of salt ("mineral") balance and blood volume . In the kidneys, aldosterone acts on the distal convoluted tubules and the collecting ducts by increasing the reabsorption of sodium and the excretion of both potassium and hydrogen ions. Aldosterone is responsible for the reabsorption of about 2% of filtered glomerular filtrate . Sodium retention is also a response of the distal colon and sweat glands to aldosterone receptor stimulation. Angiotensin II and extracellular potassium are

21098-435: The regulatory influence of the hypothalamic–pituitary–adrenal axis (HPA) axis . Glucocorticoid synthesis is stimulated by adrenocorticotropic hormone (ACTH), a hormone released into the bloodstream by the anterior pituitary . In turn, production of ACTH is stimulated by the presence of corticotropin-releasing hormone (CRH), which is released by neurons of the hypothalamus . ACTH acts on the adrenal cells first by increasing

21252-407: The remaining cases. Bone marrow involvement may be due to DLBCL, NOS cells or low grade lymphoma cells; only DLBCL, NOS cell infiltrates indicate a worse prognosis. Uncommonly, DLBCL may arise as a transformation of marginal zone lymphoma (MZL) in individuals who have been diagnosed with this indolent cancer 4–5 years (median times) previously. The International Prognostic Index and more recently,

21406-684: The remission rates were higher than expected using other treatment approaches. Significant and potentially lethal therapeutic complications of this therapy included development of the cytokine release syndrome (21% of cases), neurotoxicity, i.e. the CAR-T cell-related encephalopathy syndrome (9% of cases), and the hemophagocytic lymphohistiocytosis/macrophage-activation syndrome (i.e. a form of Hemophagocytic lymphohistiocytosis ). Individual studies within and outside of this meta-analysis have reported remissions lasting >2 years but also lethal cytokine release syndrome and neurotoxicity responses to this therapy. As

21560-446: The role of arsenic in causing telomere dysfunction, mitotic arrest, defective apoptosis, as well as altered promoter methylation and miRNA expression. Each of these alterations could contribute to arsenic-induced carcinogenesis. Nickel compounds are carcinogenic and occupational exposure to nickel is associated with an increased risk of lung and nasal cancers. Nickel compounds exhibit weak mutagenic activity, but they considerably alter

21714-417: The seeping of fluid into the cavities which are encased by these membranes, i.e. it leads to pleural effusions , pericardial effusions , and abdominal ascites . Some cases of PEL also involve the gastrointestinal tract and lymph nodes. The disease occurs primarily in people who are immunosuppressed or test positive for HIV and are also latently infected with Kaposi's sarcoma-associated herpesvirus ; PEL

21868-534: The skin, caused by its progressive thinning. When the zona glomerulosa produces excess aldosterone , the result is primary aldosteronism . Causes for this condition are bilateral hyperplasia (excessive tissue growth) of the glands, or aldosterone-producing adenomas (a condition called Conn's syndrome ). Primary aldosteronism produces hypertension and electrolyte imbalance, increasing potassium depletion sodium retention. Adrenal insufficiency (the deficiency of glucocorticoids ) occurs in about 5 in 10,000 in

22022-406: The step-wise development of gene changes such as mutations , altered expressions , amplifications (i.e. increases in the number of copies of specific genes), and translocations from normal sites to other chromosomal sites. These changes often result in gains or loses in the production or function of the product of these genes and thereby the activity of cell signaling pathways that regulate

22176-412: The steroids DHEA and DHEA-S . These changes are part of a process called adrenarche , which has only been described in humans and some other primates. Adrenarche is independent of ACTH or gonadotropins and correlates with a progressive thickening of the zona reticularis layer of the cortex. Functionally, adrenarche provides a source of androgens for the development of axillary and pubic hair before

22330-405: The substance, and upon binding they stimulate the release of aldosterone . Cells in zona reticularis of the adrenal glands produce male sex hormones, or androgens , the most important of which is DHEA . In general, these hormones do not have an overall effect in the male body, and are converted to more potent androgens such as testosterone and DHT or to estrogens (female sex hormones) in

22484-415: The suppression of the immune system and a potent anti-inflammatory effect. Cortisol reduces the capacity of osteoblasts to produce new bone tissue and decreases the absorption of calcium in the gastrointestinal tract . The adrenal gland secretes a basal level of cortisol but can also produce bursts of the hormone in response to adrenocorticotropic hormone (ACTH) from the anterior pituitary . Cortisol

22638-478: The target mRNA or through degradation of the target mRNA, via complementary binding, mostly to specific sequences in the three prime untranslated region of the target gene's mRNA. The mechanism of translational silencing or degradation of target mRNA is implemented through the RNA-induced silencing complex (RISC). Silencing of a DNA repair gene by hypermethylation or other epigenetic alteration appears to be

22792-434: The transcriptional landscape of the DNA of exposed individuals. Arita et al. examined the peripheral blood mononuclear cells of eight nickel-refinery workers and ten non-exposed workers. They found 2756 differentially expressed genes with 770 up-regulated genes and 1986 down-regulated genes. DNA repair genes were significantly over-represented among the differentially expressed genes, with 29 DNA repair genes repressed in

22946-651: The treatment of high-grade B-cell lymphoma with MYC, BL2, and/or BL6 rearrangements (i.e. DH/THL). RO6870810, another BET inhibitor, in combination with Venetoclax , an inhibitor of the Bcl-2 protein, is likewise in a phase I clinical trial for the treatment of DH/THL. Pharmacological inhibition of BCL-2 is effective in most B cell lymphomas, but often leads to acquired resistance due to the expression of other major anti-apoptotic BCL-2 family proteins like BCL-XL and MCL-1 . Combined therapy using MCL-1 inhibitor (S63845) or BCL-XL inhibitor (A-1331852) in addition to Venetoclax can be

23100-511: The two main regulators of aldosterone production. The amount of sodium present in the body affects the extracellular volume, which in turn influences blood pressure . Therefore, the effects of aldosterone in sodium retention are important for the regulation of blood pressure. Cortisol is the main glucocorticoid in humans. In species that do not create cortisol, this role is played by corticosterone instead. Glucocorticoids have many effects on metabolism . As their name suggests, they increase

23254-414: The usual treatment for most subtypes of DLBCL is chemotherapy combined with a monoclonal antibody drug that targets the disease's cancerous B-cells , usually rituximab . Through these treatments, more than half of all patients with DLBCL can be cured; the overall cure rate for older adults is less than this but their five-year survival rate has been around 58%. Diffuse large B-cell lymphoma encompasses

23408-433: The vessel) is arranged in conspicuous, longitudinally oriented bundles. The adrenal glands may not develop at all, or may be fused in the midline behind the aorta . These are associated with other congenital abnormalities , such as failure of the kidneys to develop, or fused kidneys. The gland may develop with a partial or complete absence of the cortex, or may develop in an unusual location. The adrenal gland secretes

23562-469: The zona glomerulosa help in the regulation of blood pressure and electrolyte balance . The glucocorticoids cortisol and cortisone are synthesized in the zona fasciculata; their functions include the regulation of metabolism and immune system suppression. The innermost layer of the cortex, the zona reticularis, produces androgens that are converted to fully functional sex hormones in the gonads and other target organs. The production of steroid hormones

23716-447: Was not due to methylation of their promoters. Arsenic carcinogenicity was reviewed by Bhattacharjee et al. They summarized the role of arsenic and its metabolites in generating oxidative stress, resulting in DNA damage. In addition to causing DNA damage, arsenic also causes repression of several DNA repair enzymes in both the base excision repair pathway and the nucleotide excision repair pathway. Bhattacharjee et al. further reviewed

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