Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.     

Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2

BackgroundExcessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice.MethodsThe behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured.ResultsEthanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice.ConclusionThe present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.     

What to expect when you're expecting a hepatopancreatobiliary surgeon: self-reported experiences of HPB surgeons from different training pathways

BackgroundHepatopancreatobiliary (HPB) surgery fellowship training has multiple paths. Prospective trainees and employers must understand the differences between training pathways. This study examines self-reported fellowship experiences and current scope of practice across three pathways.MethodsAn online survey was disseminated to 654 surgeons. These included active Americas Hepato-Pancreato-Biliary Association (AHPBA) members and recent graduates of HPB, transplant–HPB and HPB–heavy surgical oncology fellowships.ResultsA total of 416 (64%) surgeons responded. Most respondents were male (89%) and most were practising in an academic setting (83%). 290 (70%) respondents underwent formal fellowship training. Although fellowship experiences varied, current practice was largely similar. Minimally invasive surgery (MIS) and ultrasound were the most commonly identified areas of training deficiencies and were, respectively, cited as such by 47% and 34% of HPB-, 49% and 50% of transplant-, and 52% and 25% of surgical oncology-trained respondents. Non-HPB cases performed in current practice included gastrointestinal (GI) and general surgery cases (56% and 49%, respectively) for HPB-trained respondents, transplant and general surgery cases (87% and 21%, respectively) for transplant-trained respondents, and GI surgery and non-HPB surgical oncology cases (70% and 28%, respectively) for surgical oncology-trained respondents.ConclusionsFellowship training in HPB surgery varies by training pathway. Training in MIS and ultrasound is deficient in each pathway. The ultimate scope of non-transplant HPB practice appears similar across training pathways. Thus, training pathway choice is best guided by the training experience desired and non-HPB components of anticipated practice.     

Death anxiety in patients with epilepsy.

PURPOSE: Whereas the relationship between epilepsy and anxiety has received much attention, less is known about the relationship between death anxiety and this disorder. The objective of this study was to assess death anxiety among epileptic patients who attended the outpatient neurology clinic at the Salmaniya Medical Complex, Kingdom of Bahrain. METHODS: Ninety-two patients (48 males and 44 females) completed a death anxiety scale. The scale items were adopted from already published surveys and adjusted to suit epilepsy patients. RESULTS: Results showed that the mean death anxiety score was moderate (2.75+/-1.35), with 26.09% of patients reporting high levels of death anxiety. Period of illness and educational level were significant predictors of death anxiety. Female patients, generalized type of epilepsy, the short duration of the illness and low level of education were associated with higher death anxiety scores. CONCLUSION: This study highlights the need for developing treatment strategies, counseling therapies and social support for people with epilepsy to decrease their death anxiety and improve their quality of life.     

Ameloblastic carcinoma arising from anterior skull base.

Ameloblastic carcinoma (AC) is an aggressive malignant epithelial odontogenic tumor. It may appear de novo or originate from a pre-existing ameloblastoma or odontogenic cyst. To our knowledge, an AC that originates from the anterior skull base has not been reported before in the English literature. We report a case of an AC that originated from the anterior skull base and invaded the dura of the anterior fossa and discuss its clinical course and treatment.     

Allergen avoidance in the secondary and tertiary prevention of allergic diseases: does it work?

Although allergen avoidance is widely recommended as part of a secondary and tertiary prevention strategy for allergic diseases, a clear-cut demonstration of its effectiveness is still lacking. Ongoing observational secondary prevention cohorts show that sensitisation to mite can be prevented in the short term by allergen avoidance measures, but further follow-up of these children is needed to show if this effect can be sustained, as well as to ascertain its impact on allergic disease. More well-designed trials are still required before we can give any conclusive advice to our patients. Considering the management of allergy, current evidence suggests that interventions in children (either single or multifaceted) may be associated with some beneficial effect on asthma control, but no conclusive evidence exists regarding rhinitis or eczema. Conversely, there is little evidence to support the recommendation of allergen avoidance methods in adults with asthma and rhinitis. There is a need for an adequately designed trial assessing the effects of a multifaceted intervention in this age group.