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M H Greene

Publications and source records attributed to M H Greene.

At least 19 recordsLinked to original sources
PubMed2005

Hereditary breast/ovarian and colorectal cancer genetics knowledge in a national sample of US physicians.

BACKGROUND: Clinically relevant genetics knowledge is essential for appropriate assessment and management of inherited cancer risk, and for effective communication with patients. This national physician survey assessed knowledge regarding basic cancer genetics concepts early in the process of introduction of predictive genetic testing for breast/ovarian and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. METHODS: A stratified random sample was selected from the American Medical Association Masterfile of all licensed physicians. In total, 1251 physicians (820 in primary care, 431 in selected subspecialties) responded to a 15 minute questionnaire (response rate 71%) in 1999-2000. Multivariate logistic regression analyses were conducted to identify demographic and practice characteristics associated with accurate response to three knowledge questions. RESULTS: Of the study population, 37.5% was aware of paternal inheritance of BRCA1/2 mutations, and 33.8% recognised that these mutations occur in <10% of breast cancer patients. Only 13.1% accurately identified HNPCC gene penetrance as >or=50%. Obstetrics/gynaecology physicians, oncologists, and general surgeons were significantly more likely than general and family practitioners to respond accurately to the breast/ovarian questions, as were gastroenterologists to the HNPCC question. CONCLUSIONS: These nationally representative data indicate limited physician knowledge about key cancer genetics concepts in 1999-2000, particularly among general primary care physicians. Specialists were more knowledgeable about syndromes they might treat or refer elsewhere. Recent dissemination of practice guidelines and continued expansion of relevant clinical literature may enhance knowledge over time. In addition to educational efforts to assist physicians with the growing knowledge base, more research is needed to characterise the organisational changes required within the healthcare system to provide effective cancer genetics services.

Adult↗
PubMed2004

Somatic mutations of KIT in familial testicular germ cell tumours.

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.

DNA Mutational Analysis↗
PubMed2003

Desmoid tumors in familial adenomatous polyposis: a pilot project evaluating efficacy of treatment with pirfenidone.

OBJECTIVES: Pirfenidone (Deskar, Marnac Inc., Dallas, TX), 5-methyl-1-phenyl-2-(1H)-pyridone, is a broad-spectrum, noncytotoxic, oral antifibrotic agent that is reported to inhibit or block the action of cytokine growth factors: transforming growth factor beta1, platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor, and to prevent formation of new fibrotic lesions. METHODS: We enrolled 10 women and four men with extensive familial adenomatous polyposis (FAP)-associated desmoid disease in a 2-yr open-label treatment trial with oral pirfenidone. Imaging of desmoids was conducted at baseline and 6, 12, and 24 months. RESULTS: No drug toxicity or drug intolerance was encountered. Seven patients dropped out (three because of progressive disease), and seven continued for at least 18 months. Of those that continued, two had partial but significant reduction in the size of all desmoids beginning in the first 6 months of treatment, and two others experienced relief of symptoms without change in desmoid size. Three patients experienced no change in tumor size or symptoms. CONCLUSIONS: Pirfenidone is well tolerated by patients with FAP-associated desmoid tumors. Some patients with FAP/desmoid tumors treated with pirfenidone had regression of tumors, some had progression, and some had no response. Patients with rapidly growing tumors did not respond to pirfenidone. A placebo-controlled trial is needed to determine whether there is a subset of patients for whom pirfenidone may result in partial shrinkage of desmoid tumors, because the natural history of desmoid tumors is not predictable or understood.

Adenomatous Polyposis Coli↗
PubMed2001

Solid tumors after chronic lymphocytic leukemia.

Prior reports indicate that patients with chronic lymphocytic leukemia (CLL) may be at increased risk of subsequent neoplasms. This study quantified the risk of second cancers among 16 367 patients with CLL in the population-based Surveillance, Epidemiology and End Results Program. Overall, the observed/expected ratio (O/E) was 1.20 (95% confidence interval [CI], 1.15-1.26). Second cancer risks for patients who received chemotherapy only as the first course of treatment (O/E = 1.21) were similar to risks for those who received no treatment initially (O/E = 1.19). Significant excesses were found for Kaposi sarcoma (O/E = 5.09), malignant melanoma (O/E = 3.18), and cancers of the larynx (O/E = 1.72) and the lung (O/E = 1.66). Increased risks were also found for brain cancer among men (O/E =1.91) and for cancers of the stomach (O/E = 1.76) and bladder (O/E = 1.52) among women. Additional investigations of cancers after CLL are needed to explore the role of immunologic impairment and/or other etiologic influences.

Aged↗
PubMed2001

Papillary renal cell carcinoma: analysis of germline mutations in the MET proto-oncogene in a clinic-based population.

Approximately 10% of all renal cell carcinomas (RCCs) present a distinctive papillary histology. Familial papillary RCC (PRCC) has been described, but the majority of cases appear to be sporadic. Recently, germline mutations in the MET proto-oncogene on chromosome 7 have been identified in families with hereditary PRCC. We evaluated 59 patients with PRCC for the frequency of MET germline mutations to determine the value of genetic screening of this patient population. Between 1976 and 1997, 165 patients were identified with PRCC by retrospective chart review. Fifty-nine of 133 surviving patients agreed to provide a family history, a blood specimen, and informed consent for genetic research. DNA was isolated from peripheral blood leukocytes. Denaturing high-performance liquid chromatography (DHPLC) followed by genomic sequencing was performed on eight exons of the MET proto-oncogene, including exons 5-7 of the extracellular domain, exon 14, and exons 16-19 of the tyrosine kinase domain. The 59 patients in this study included 49 men and 10 women with a mean age at diagnosis of 61 years. Bilateral and/or multifocal disease was present in 13 cases (22%). No germline mutations were detected in the studied exons of the MET proto-oncogene (exons previously reported to contain deleterious mutations in familial PRCC). No pathological MET proto-oncogene germline mutations were identified in 59 patients with PRCC. The germline mutation rate in this clinic-based population of individuals with PRCC approaches 0% (CI = 0-6.18). MET proto-oncogene germline mutation screening does not appear to be clinically indicated in patients with PRCC without additional evidence for a genetic predisposition (positive family history, unusual age at onset, bilateral disease).

Aged↗
PubMed1999

The genetics of hereditary melanoma and nevi. 1998 update.

Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, it was 1983 before formal genetic analysis suggested an autosomal dominant mode of inheritance for both melanoma and the then newly described melanoma precursor, dysplastic nevi (DN). Subsequent genetic studies have assumed this model to be correct, although when viewed in aggregate, the data are inconsistent. The first proposed melanoma gene (CMM1) was mapped to chromosome 1p36. This gene assignment has not been confirmed. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed, and the cell cycle regulator CDKN2A has been proposed as the candidate gene. Germline mutations in this gene have been identified in about 20% of melanoma-prone families that have been studied to date. Pancreatic cancer occurs excessively in melanoma families with germline mutations in CDKN2A. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have been described in three melanoma families. This finding represents a third melanoma gene but one that accounts for only a tiny fraction of all hereditary melanoma. Recently, a familial melanoma-astrocytoma syndrome has been reported. Large germline deletions of 9p21 occur in these families, with the p19 gene implicated in its pathogenesis. At present, clinical predictive genetic testing for mutations in the CDKN2A gene is available commercially, but its use has been limited by uncertainty as to how test results would affect the management of melanoma-prone family members. Currently, management recommendations include monthly skin self-examination, clinical skin examination once or twice yearly, a low threshold for simple excision of changing pigmented lesions, moderation of sun exposure, and appropriate use of sunscreens. A heritable determinant for total nevus number has been suggested by twin studies. Other data suggest the presence of a major gene responsible for "total nevus density" in melanoma-prone families. Approximately 55% of the mole phenotype in multiplex melanoma families was explained by this proposed gene. An autosomal dominant mode of inheritance has been proposed for DN, and data exist to suggest that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. However, there clearly are melanoma-prone families that do not express the dysplastic nevus trait, and some of the families linked to CDKN2A also present with dysplastic nevi. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk of melanoma, these family studies suggest that relatives of persons with DN should be examined for both DN and melanoma. Genetic determinants play a major role in the pathogenesis of normal nevi, DN, and melanoma. Identifying the molecular basis of these genetic events promises to enhance melanoma risk-reduction strategies and, ultimately, reduce melanoma-associated mortality.

Adult↗
PubMed1997

Genetics of breast cancer.

Familial breast cancer is characterized by young age at diagnosis, an increased risk of bilateral breast cancer, an increasing risk in conjunction with increasing numbers of affected family members, and a strong association with ovarian cancer. At least eight candidate breast cancer susceptibility genes have been identified. Mutations in BRCA1, BRCA2, p53, and the Cowden disease gene are relatively uncommon, are highly penetrant, and produce striking familial clusters of breast cancer. BRCA1 and BRCA2 are the most important of these, accounting for an estimated 80% of hereditary breast cancer and 5 to 6% of all breast cancers. Specific BRCA1 and BRCA2 mutations are of particular importance in population subgroups, such as those identified among Jewish women of central European (Ashkenazi) origin. Mutations in the ataxia-telangiectasia gene and the rare HRAS1 variable number of tandem repeats polymorphisms are much more common but also much less penetrant. They do not produce dramatic familial aggregations of breast cancer but may prove to be responsible for a substantial proportion of all breast cancers if their epidemiologic association with breast cancer is confirmed. Predictive genetic testing for breast cancer risk is under way. Oncologists and primary-care physicians must become familiar with these genetic disorders and the issues surrounding predictive testing in order to make appropriate management decisions about women thought to have a high genetic risk of breast cancer.

Ataxia Telangiectasia↗
PubMed1997

Genetics of cutaneous melanoma and nevi.

To provide a state-of-the-art summary of currently available data about the genetics of cutaneous melanoma and nevi, we reviewed the pertinent literature and outlined the important findings on genetic analyses. Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, seminal studies by investigators at the National Cancer Institute and the University of Pennsylvania identified dysplastic nevi (DN) as an important melanoma precursor, suggested an autosomal dominant mode of inheritance for both melanoma and DN, and proposed that a melanoma-susceptibility gene (CMM1) was located on chromosome 1p36. This gene assignment has not yet been confirmed by independent investigators. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed independently, and the cell cycle regulator p16INK4a has been proposed as a candidate gene; germline mutations in this gene have been identified in about half of melanoma-prone families. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have recently been described in two melanoma kindreds; this finding likely represents a third melanoma gene. A heritable determinant for total nevus number has been suggested, as has the presence of a major gene responsible for total nevus density in melanoma-prone families. An autosomal dominant mode of inheritance for DN has been proposed, and evidence suggests that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk for melanoma, these family studies suggest that relatives of persons with DN should be examined for DN and for melanoma. Overall, genetic determinants have a major role in the pathogenesis of normal nevi, DN, and melanoma. Elucidating the molecular basis of these genetic events promises to enhance melanoma risk reduction strategies and thereby reduce melanoma-associated mortality.

Case-Control Studies↗
PubMed1992

Emphysematous cystitis due to Clostridium perfringens and Candida albicans in two patients with hematologic malignant conditions.

BACKGROUND: Fever, abdominal pain, and hematuria developed in two patients with hematologic malignant conditions (multiple myeloma and agnogenic myeloid metaplasia). Each patient was found to have emphysematous cystitis (EC), secondary to Clostridium perfringens and Candida albicans, respectively. Both patients had debilitated general medical conditions, compromised immune function, prior treatment with broad-spectrum antibiotics and corticosteroids, bladder outlet obstruction, and indwelling Foley catheters as predisposing factors to EC. Neither was diabetic. METHODS: These cases provide an opportunity to review the related medical literature on the pathophysiology and management of this uncommon entity. RESULTS: Treatment consists of control of underlying diabetes (if present), administration of appropriate antibiotics, establishment of urinary drainage, provision of supportive general medical care, exclusion of the presence of a bladder fistula, and surgical debridement only when unavoidable. CONCLUSIONS: EC should be part of the differential diagnosis in patients with cancer who have fever, abdominal pain, and hematuria.

Aged↗
PubMed1992

Is cisplatin a human carcinogen?

Traditionally, cisplatin has not been regarded among chemotherapeutic drugs as a carcinogenic risk to humans because it is not a classical alkylating agent. A review of recently published experimental data indicates that cisplatin is mutagenic, clastogenic, capable of inducing cell transformation, able to act as an initiator in classical mouse skin initiation/promotion experiments, and carcinogenic in laboratory animals. Notably, it causes myeloid leukemia in BD IX rats. These observations demonstrate that cisplatin should be considered a potent carcinogen in experimental settings. A review of the literature identified 65 instances of subsequent cancer in patients receiving cisplatin-based chemotherapy for an initial malignancy. The majority of second cancers were acute nonlymphocytic leukemias or myelodysplasia. In only one instance was cisplatin the sole antineoplastic drug given to patients. The routine use of cisplatin in conjunction with other known or suspected human carcinogens makes it impossible to use these anecdotal reports as a basis for assessing cisplatin's carcinogenicity in humans. Two quantitative epidemiologic studies have addressed this question: One suggested that the combination of cisplatin and doxorubicin is leukemogenic in humans, while the other implicated etoposide rather than cisplatin as the leukemogen. Formal epidemiologic studies of appropriate cohorts of cisplatin-treated patients are needed to resolve the question of its carcinogenicity in humans.

Animals↗