Kyrillus Shohdy

The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs) from WES data. Here, we show that UC patients harbor a high prevalence of pDGVs that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these pDGVs in tumor progression. Significant intra-patient heterogeneity in germline-somatic variant interactions results in divergent biological pathway alterations between primary and metastatic tumors. Our results characterize the spectrum of germline variants in UC and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for cancer patients.

© 2018 Background: Since its first description by Otto Werner in 1904, patients with Werner syndrome were subjected to misdiagnosis in part, due to the great mimic with systemic sclerosis and the variable constellation of manifestations including dermatologic, ophthalmic, growth disorders and endocrinopathies. Case presentation: We reported two cases with Werner syndrome. One case of a 31-year-old female presented with six-month history of fever, cough, progressive dyspnea, arthritis affecting all large joints and persistent low back pain. At her age and the presence of sclerotic skin lesions, interstitial lung disease and joint tenderness, it was assumed that this was a case of connective tissue disease. However, her incomplete response to steroids and cyclophosphamide prompted a revision of the diagnosis. She developed metastatic carcinomatous deposits in bone. She had a poor outcome and succumbed to malignancy of unknown primary meanwhile, the 25-year-old sibling had a milder phenotype that without proper family history would have been passed unnoticed. Conclusion: This close mimic with systemic sclerosis might mask cases of Werner syndrome in developing countries where no genetic screening is readily available. The cases are illustrative for the confusion that may arise with systemic sclerosis and the difficulty in making the diagnosis in mild cases. Therefore, these descriptions are of clinical value to clinicians treating such patients.

BACKGROUND Several single chemotherapeutic agents have been evaluated as second line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to previous toxicity of chemotherapy. METHODS This is an open-label, prospective, single center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first line platinum-based regimen for advanced or metastatic disease. RESULTS The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy. CONCLUSION The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to selected group of patients. However, this is a single institute experience in a limited number of patients.

The assessment of motor conduction along the pudendal nerve is an accurate objective measure of pudendal nerve function. Measurement of its latency (that is the time interval between electrical stimulation of the nerve and induced contraction of the external anal sphincter) has been demonstrated to be abnormally long following vaginal delivery, particularly if the delivery was associated with a heavy fetus or a prolonged second stage of labor. The significance of pudendal neuropathy and its relationship to abnormal degrees of descent of the pelvic floor have also been examined in this review.

Background Phase II trials found that tegafur-uracil (UFT) is an effective drug in hepatocellular carcinoma (HCC), while preclinical data suggested that its combination with sorafenib may have a promising activity. Our Phase II randomized trial aimed to evaluate efficacy and tolerability of sorafenib plus UFT vs sorafenib in advanced HCC. Methods Patients with advanced HCC, with no prior systemic therapy, were randomized to receive either UFT at 125 mg/m2 twice daily for 4 out of 5 weeks plus sorafenib at 400 mg twice daily (arm 1) or single agent sorafenib at 400 mg twice daily (arm 2). Primary end point was time to progression (TTP). Results Between March 2012 and March 2014, 76 eligible patients - out of 143 preplanned - were randomized. The study was terminated early because of futility. This is the final analysis of the study, after a median follow-up of 10.2 months and death of 86% of randomized patients (n=64). Median TTP was 7.5 months and 8.2 months in arms 1 and 2 respectively (HR: 1.07; 95% CI, 0.52-2.22; P=0.855), while the median overall survival was 8.2 months and 10.5 months respectively (HR: 1.58; 95% CI: 0.90-2.76, P=0.112). Nine patients (25%) in the combination arm discontinued treatment because of toxicity vs eight patients (21.1%) in the sorafenib monotherapy arm (P=0.899). Conclusion In patients with advanced HCC, adding UFT to sorafenib is feasible, but it did not improve efficacy outcome over sorafenib monotherapy.