Genome-wide rare copy number variation screening in ulcerative colitis identifies potential susceptibility loci.

BACKGROUND: Ulcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants. METHODS: One thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data. Quantitative PCR and high density custom array-CGH were used for validation of identified CNVs and fine mapping. Two main follow-up panels consisted of an independent cohort of 451 cases and 1274 controls, in which CNVs were assayed through quantitative PCR, and a British cohort of 2396 cases versus 4886 controls with CNV genotypes based on array data. Additional sample sets were assessed for targeted and in silico replication. RESULTS: Twenty-four rare copy number variants (14 deletions and 10 duplications), overrepresented in UC patients were identified in the initial screening panel. Follow-up of these CNV regions in four independent case-control series as well as an additional public in silico control group (totaling 4439 UC patients and 15,961 healthy controls) revealed three copy number variants enriched in UC patients; a 15.8 kb deletion upstream of ABCC4 and CLDN10 at13q32.1 (0.43% cases, 0.11% controls), a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 (0.13% cases, 0.01% controls) and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3 (0.22% carriers among cases, 0.03% carriers among controls). The trend of association with UC was present after the P-values were corrected for combining data from different subpopulations. Break-point mapping of the deleted region suggested non-allelic homologous recombination as the mechanism underlying its formation. CONCLUSION: Our study presents a pragmatic approach for effective rare CNV screening of SNP-array data sets and implicates the potential contribution of rare structural variants in the pathogenesis of UC.

Complications of brain tumors and their treatment.

The diverse medical and neurologic complications of central nervous system (CNS) neoplasms or their treatment cause significant morbidity and mortality. Thus, their recognition and appropriate management by all members of the interdisciplinary team engaged in the care of patients with brain tumors is essential in optimizing quality of life and extending survival. Recognition of the acute, early delayed, and late complications of brain irradiation is essential to optimize management and mitigate their clinical impact.

Clinical vignettes: integrated care of cancer patients by oncologists and cardiologists.

Because of the paucity of large, randomized trials concerning the cardiac care of patients with cancer, treatment and prevention of chemotherapy-induced cardiotoxicity must rely on insights gained from small trials and case reports as well as the application of guidelines developed for the general population. In these clinical vignettes, we present patients referred by their oncologists to a cardiologist for specialized evaluation and management of cardiotoxicity with the goal of emphasizing the importance of identifying risk factors for cardiotoxicity, initiating evidence-based therapy, and establishing a close collaboration between oncologists and cardiologists.

Oxaliplatin-induced pancreatitis: a case series.

BACKGROUND: Drug-induced pancreatitis is less common compared to other causes of acute pancreatitis; the incidence ranges from between 0.1% to 2% of acute pancreatitis cases. Among alkylating agents, oxaliplatin has not been reported to be associated with acute pancreatitis. PATIENTS AND METHODS: This case study presents a series of six cases of acute pancreatitis presumably related to exposure to oxaliplatin which had different gastrointestinal malignancies and were being treated with oxaliplatin in combination with other chemotherapeutic drugs. All other related causes of acute pancreatitis were excluded before implicating oxaliplatin as a possible cause. RESULTS: In all cases, oxaliplatin was stopped and patients had resolution of their signs and symptoms, along with a decrease in serum amylase and lipase levels. CONCLUSION: Knowledge regarding acute pancreatitis related to oxaliplatin is of paramount importance in order to diagnose cases early and institute effective treatment in patients who are undergoing chemotherapy with this drug.

Oxaliplatin-induced hyperexcitability syndrome in a patient with pancreatic cancer.

A recent pooled analysis and a meta-analysis suggested a survival benefit of gemcitabine-platinum doublets when compared with single agent gemcitabine in pancreatic cancer. Sensory neurotoxicity is a potentially limiting toxicity associated with oxaliplatin therapy. In this letter, we describe a case of a patient with metastatic pancreatic cancer who developed acquired neuromyotonia while receiving intravenous oxaliplatin as part of her treatment. It is a condition characterized by cramps, muscle twitching, weakness, myotonia and pseudomyotonia (slow muscle relaxation after forceful contraction). Her symptoms were ameliorated after initiation of pregabalin. We postulate that hyperexcitability syndrome associated with administration of oxaliplatin can be treated with pregabalin. Future studies will be needed to confirm this as well as to determine the long-term adverse effects associated with pregabalin.

Skeletal metastases in pancreatic cancer: a retrospective study and review of the literature.

BACKGROUND: Skeletal metastases represent an underappreciated site of metastasis in patients with pancreatic cancer. Previous reports have estimated the prevalence to range from 5 percent to 20 percent. With the use of gemcitabine and novel targeted agents such as erlotinib, there has been a modest increase in survival in patients with advanced pancreatic cancer. As such, it is anticipated that previously uncommon occurrences such as skeletal metastases will become more frequent. PATIENTS AND METHODS: Retrospective chart review was conducted at two academic institutions to identify pancreatic cancer patients with skeletal metastases over a two-year period. RESULTS: Seven patients were identified from a database of 323 patients (2.2 percent). All patients had advanced disease and had received prior systemic therapy (range: 1-4 lines, median: 2 lines). Approximately half (57.1 percent) of the patients were symptomatic from their skeletal metastases. The most common sites of skeletal metastases were vertebrae (100 percent), hips (57.1 percent), and ribs (57.1 percent). Both blastic and lytic lesions were noted, with a predominance of blastic lesions (71.4 percent). A majority of patients (71.4 percent) received bisphosphonates as part of their care. DISCUSSION: Skeletal metastases are an uncommon but clinically important occurrence in patients with pancreatic cancer. Clinicians caring for patients with pancreatic cancer should be alert regarding skeletal metastases, due to the morbidity it can cause for these patients (e.g., back pain, fractures, etc.).

Role of PTEN gene in progression of prostate cancer.

INTRODUCTION: The aim of this study was to clarify the role of PTEN gene in progression of prostate cancer. MATERIALS AND METHODS: A total of 51 formalin-fixed paraffin-embedded specimens of prostate cancer were analyzed for PTEN mutations. Tissue microdissection and polymerase chain reaction/single-strand conformation polymorphism methods were used. Clinical and pathologic data of the patients were reviewed with regard to PTEN mutation. RESULTS: The Gleason score (GS) was less than 7 in 29 (56.8%), 7 in 11 (21.6%), and greater than 7 in 11 (21.6%). Tumor stage was IIa, IIb, IIc, and IV in 14 (27.4%), 4 (7.8%), 21 (41.2%), and 12 (23.6%) patients, respectively. Eleven of 12 stage IV tumors had metastases at the time of presentation. Six of 51 cases (11.6%) showed mutation in PTEN which had involved exones 1, 2, and 5. Two of these cases had localized and the others had advanced prostate cancer. One case of the tumors with PTEN mutation had a GS of 7 and 5 had GSs greater than 7. Patients with a positive mutation of PTEN had a significantly greater GS (P < .001), lower survival rate (P = .001), higher tendency to metastasis (P = .002), and higher prostate-specific antigen (P = .03). Cox proportional hazard model showed that only GS was significantly correlated with mortality (P = .03). CONCLUSION: Patients with prostate cancer who had PTEN mutation had also a significantly greater GS, poorer prognosis, and higher rate of metastasis. However, this mutation cannot predict the prognosis and the GS is a more precise factor.

AFPep: an anti-breast cancer peptide that is orally active.

BACKGROUND: We have synthesized a cyclic nonapeptide (AFPep) that is effective, after being administered by parenteral routes, for the treatment or the prevention of breast cancer. To test the hypothesis that AFPep remains safe and efficacious after oral administration, three different whole-animal bioassays were utilized, and the mechanism by which AFPep functions was investigated. METHODS: Using a human breast cancer xenograft model in mice for therapeutic activity, a carcinogen-induced breast cancer model in rats for prevention efficacy, and a mouse uterus growth inhibition model of anti-estrogenic activity, AFPep was administered by oral gavage (p.o.) and its effects compared to those following intraperitoneal (i.p.) and subcutaneous (s.c.) administration. Toxicity studies evaluated body weights and organ weights in mice and rats receiving AFPep. Preliminary mechanistic studies were carried out in T47D human breast cancer cells growing in culture and evaluated the effect of AFPep on estrogen-stimulated cell growth, phosphorylation of the estrogen receptor (ER), and on level of ER-related kinases. RESULTS: Orally administered AFPep stopped the growth of human tumor xenografts in mice, decreased the incidence and multiplicity of breast cancers in carcinogen-exposed rats, and inhibited the estrogen-stimulated growth of mouse uteri. In each of these systems, orally administered AFPep produced an effect similar to that obtained for AFPep administered by either i.p or s.c. routes. In rodents, no evidence of toxicity was seen for the peptide, even at very high doses. In culture, AFPep inhibited the estrogen-stimulated growth, but not the basal growth, of T47D cells, and it inhibited the estrogen-stimulated phosphorylation of Serine 118 in the ER of these cells, which was not explainable by early changes in ER-related kinases. CONCLUSIONS: Chronic oral administration of AFPep appears to be safe and effective for the treatment or prevention of breast cancer in animal models.