33 research outputs found
Novel polymorphisms and lack of mutations in the ACD gene in patients with ACTH resistance syndromes
Objective  ACTH resistance is a feature of several human syndromes with known genetic causes, including familial glucocorticoid deficiency (types 1 and 2) and triple A syndrome. However, many patients with ACTH resistance lack an identifiable genetic aetiology. The human homolog of the Acd gene, mutated in a mouse model of adrenal insufficiency, was sequenced in 25 patients with a clinical diagnosis of familial glucocorticoid deficiency or triple A syndrome. Design  A 3·4 kilobase genomic fragment containing the entire ACD gene was analysed for mutations in all 25 patients. Setting  Samples were obtained by three investigators from different institutions. Patients  The primary cohort consisted of 25 unrelated patients, primarily of European or Middle Eastern descent, with a clinical diagnosis of either familial glucocorticoid deficiency (FGD) or triple A syndrome. Patients lacked mutations in other genes known to cause ACTH resistance, including AAAS for patients diagnosed with triple A syndrome and MC2R and MRAP for patients diagnosed with familial glucocorticoid deficiency. Thirty-five additional patients with adrenal disease phenotypes were added to form an expanded cohort of 60 patients. Measurements  Identification of DNA sequence changes in the ACD gene in the primary cohort and analysis of putative ACD haplotypes in the expanded cohort. Results  No disease-causing mutations were found, but several novel single nucleotide polymorphisms (SNPs) and two putative haplotypes were identified. The overall frequency of SNPs in ACD is low compared to other gene families. Conclusions  No mutations were identified in ACD in this collection of patients with ACTH resistance phenotypes. However, the newly identified SNPs in ACD should be more closely examined for possible links to disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73948/1/j.1365-2265.2007.02855.x.pd
Immunotherapy for Prostate Cancer Enters Its Golden Age
In the United States, prostate cancer is the most frequent malignancy in men and ranks second in terms of mortality. Although recurrent or metastatic disease can be managed initially with androgen ablation, most patients eventually develop castration-resistant disease within a number of years, for which conventional treatments (eg, chemotherapy) provide only modest benefits. In the last few years, immunotherapy has emerged as an exciting therapeutic modality for advanced prostate cancer, and this field is evolving rapidly. Encouragingly, the US Food and Drug Administration (FDA) has recently approved two novel immunotherapy agents for patients with advanced cancer: the antigen presenting cell-based product sipuleucel-T and the anti-CTLA4 (cytotoxic T-lymphocyte antigen 4) antibody ipilimumab, based on improvements in overall survival in patients with castration-resistant prostate cancer and metastatic melanoma, respectively. Currently, a number of trials are investigating the role of various immunological approaches for the treatment of prostate cancer, many of them with early indications of success. As immunotherapy for prostate cancer enters its golden age, the challenge of the future will be to design rational combinations of immunotherapy agents with each other or with other standard prostate cancer treatments in an effort to improve patient outcomes further
Advances and Challenges on Management of Gastrointestinal Stromal Tumors
Gastrointestinal stromal tumors (GISTs) originate from interstitial cells of Cajal and account for over 5,000 newly diagnosed cases in the United States. The discovery of activated KIT and PDGFRA mutations and introduction of imatinib revolutionized the treatment strategy and opened up the new era of target therapy for solid tumors. Although surgery remains the primary modality of treatment for curative purpose, almost half of the patients experienced disease recurrence. Tailoring (neo)-adjuvant treatment with imatinib is ongoing to meet the need for an effective therapy. Currently, two drugs (sunitinib and regorafenib) have obtained Food and Drug Administration approval for GISTs after imatinib failure. However, most of the patients eventually progress due to primary or secondary resistance. Deeper understanding of the molecular mechanisms will guide us to develop personalized strategies in the future. Discussion in this review includes current standard management and the most recent advances and multiple ongoing clinical trials with different approaches. This review will provide further steps to be taken to conquer refractory disease
Prognostic factors of malignant paraganglioma and pheochromocytoma: A SEER database review.
Correction: Prognostic Factors of Malignant Pheochromocytoma and Paraganglioma: A Combined SEER and TCGA Databases Review
Intimal sarcoma of the pulmonary artery treated with neoadjuvant radiation prior to pulmonary artery resection and reconstruction
Intimal sarcoma (IS) is a rare malignancy arising in the great vessels or heart, most commonly in the pulmonary artery, primarily treated with surgical intervention. We report a case of IS of the pulmonary artery diagnosed after an endarterectomy to remove a suspected pulmonary embolism. The tumor could not be entirely resected and showed interval growth at post-operative follow up. Neoadjuvant radiotherapy was then delivered to improve resectability. Imaging confirmed decreased tumor size, and a surgical resection with pulmonary artery reconstruction and right upper lobectomy was then successfully performed. Adjuvant gemcitabine and docetaxel was later initiated. Four months post-operatively, the patient is alive without disease recurrence. While prior reports in the literature document use of adjuvant chemotherapy and radiotherapy for treatment of IS of the pulmonary artery, no prior experience has documented utility of neoadjuvant radiotherapy for improvement of resectability. Our experience suggests that neoadjuvant radiation should be considered to improve resectability in cases of borderline resectable IS of the pulmonary artery
Clinical and Genetic Heterogeneity, Overlap with Other Tumor Syndromes, and Atypical Glucocorticoid Hormone Secretion in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Compared with Other Adrenocortical Tumors
Objective: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is often associated with subclinical cortisol secretion or atypical Cushing’s syndrome (CS). We characterized a large series of patients of AIMAH and compared them with patients with other adrenocortical tumors
Association of the M1V PRKAR1A Mutation with Primary Pigmented Nodular Adrenocortical Disease in Two Large Families
Background: Carney complex (CNC) is a familial multiple neoplasia syndrome frequently associated with primary pigmented nodular adrenocortical disease (PPNAD), a bilateral form of micronodular adrenal hyperplasia that leads to Cushing’s syndrome (CS). Germline PRKAR1A mutations cause CNC and only rarely isolated PPNAD