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.     

Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

Association Between Patient and Physician Sex and Physician-Estimated Stroke and Bleeding Risks in Atrial Fibrillation

Background

Physicians treating nonvalvular atrial fibrillation (AF) assess stroke and bleeding risks when deciding on anticoagulation. The agreement between empirical and physician-estimated risks is unclear. Furthermore, the association between patient and physician sex and anticoagulation decision-making is uncertain.

Off pump coronary artery bypass (OPCAB) in critical left mainstem stenosis—Our experience

Background Beating heart surgery has now become the commonest technique of doing Coronary Artery Bypass Graft Surgery (CABG) in our country. It is being used even in such high risk situations like diffuse coronary disease and Critical Left Main stem Stenosis (LMCS) with good results. The aim of this study is to retrospectively review our results in Off-Pump Coronary Artery Bypass Surgery (OPCAB) in patients with critical left main stem stenosis. Methods This study is a retrospective analysis of the data of patients who underwent primary coronary artery bypass surgery. During the period from April 2003 to September 2005 a total of 64 patients underwent OPCAB procedure for critical LMCS. During the same period 10 patients underwent CABG on Cardio Pulmonary Bypass (CPB). The age range was 36–77yrs. The sex distribution was M: F 53∶10. Ten patients were done as emergency. 2 of them were on Intra Aortic Balloon Pump (IABP) support preoperatively. 10 patients were high risk with a Euro score of ≥5. Results Left Internal Mammary Artery (LIMA) was used in 78% of cases. Average grafts per patient was 2.96. The median ventilation time was 5.91 hrs. New IABP insertion in postoperative period was required in 1 patient. One patient was reexplored for bleeding. There was one perioperative myocardial infarction. 57% of patients did not need any blood transfusion. There was no conversion to CPB. There was no operative mortality. Inotropes were used in ten cases. Conclusions OPCAB is a safe method of revascularization in patients with critical LMCS. Preoperative IABP is useful in patients with cardiogenic shock. However, there is a place for CPB in patients needing additional procedures like Mitral Valve repair (MV repair) or Dor's procedure or when the vessels are very diffusely diseased. Those patients who are unstable despite IABP support may be managed by Beating heart On Pump (BHOP) technique.     

Pituitary abnormalities in eating disorders: further evidence from MRI studies

1. The frequent occurrence of hypothalamo-pituitary dysfunction in patients with eating disorders as well as prior reports that nutritional and endocrine status influence pituitary morphology, led us to hypothesize that pituitary size and shape may be altered in patients with eating disorders. 2. Magnetic resonance imaging (MRI) does not use ionizing radiation and is currently one of the most feasible modalities available to study the pituitary gland in vivo. Using MRI, we have previously reported in a preliminary study that female patients with eating disorders had significantly smaller pituitary glands than controls. In addition MRI excluded any pituitary mass lesions. 3. In this report, we confirm our previous MRI findings and provide further evidence of pituitary abnormalities in an expanded sample of eating disorder patients. Preliminary data on pituitary volume estimates from MRI scans are provided for a subset of patients and controls.     

Flow requirements for the Bain breathing circuit during anaesthesia for caesarean section

We studied the relationship between arterial carbon dioxide tension (PaCO2) and fresh gas flow (FGF) during use of the Bain breathing circuit for Caesarean section anaesthesia. Thirty-one patients undergoing Caesarean section were anaesthetised using the Bain circuit with intermittent positive pressure ventilation. The PaCO2 were measured at FGF of 70 ml X kg-1 X min-1, 80 ml X kg-1 X min-1, and 100 ml X kg-1 X min-1. The FGF requirement to maintain a given PaCO2 during Caesarean section anaesthesia is the same as the requirements for nonpregnant subjects, despite the increase in carbon dioxide production associated with pregnancy. This is probably because the total FGF determined by body weight and given during Caesarean section anaesthesia is 15-20 per cent higher than nonpregnant levels, due to the weight gain associated with pregnancy. A FGF of 100 ml X kg-1 of pregnant weight/min maintains PaCO2 of 4.44 kPa predelivery, which is in the desirable range of PaCO2 during Caesarean section.     

Primary aspergillosis of the sphenoid sinus with pituitary invasion – a rare differential diagnosis of sellar lesions

Summary Aspergillosis belongs to the group of mycotic diseases of paranasal sinuses. The invasive forms, and particularly the fulminant forms, are potentially fatal. Isolated aspergillosis of the sphenoid sinus or the clivus is a difficult diagnosis, since the often misleading clinical manifestations of this rare disease develop late. These patients become apparent by neurological signs such as cavernous sinus syndrome, pseudotumor of the pituitary or the orbit. Diagnosis is often made intra-operatively or on histological examination. We report a case of invasive aspergillosis uniquely involving the sellar area revealed by clinical features suggesting a pseudotumor of the pituitary. Although such lesions are almost always seen in immune suppressed subjects, in our case, the patient was immune competent and had no past history of sinusitis. The question of whether, and when to perform limited or extensive surgery remains an issue for discussion, owing to the rarity of this disease honed by lack of experience. It depends on several factors: the kind of disease, the immunity, the subtype of invasive fungal sinusitis and the degree of tissue invasion.