Survival Outcomes Following Discontinuation of Ipilimumab and Nivolumab for Advanced Melanoma in a Population-based Cohort.

AIMS: Induction ipilimumab and nivolumab followed by maintenance nivolumab improve overall survival compared with ipilimumab alone in patients with advanced melanoma, but immune-related adverse events (irAE) occur commonly. The need for induction discontinuation because of irAE and the relationship between irAE and survival in non-trials patients are unclear. MATERIALS AND METHODS: Patients with unresectable stage III-IV melanoma receiving first-line combination immunotherapy at one of six centres between December 2017 and February 2020 outside of trials were identified retrospectively. Landmark 12-week Kaplan-Meier analyses and log-rank tests were used to evaluate associations between discontinuation of induction therapy on overall survival and time to treatment failure (TTF). Multivariable analysis of factors influencing overall survival and TTF was undertaken. RESULTS: Among 95 patients, the median age was 62 years, 38.9% had Eastern Cooperative Oncology Group performance status ≥1 and 22.1% had brain metastases. The median follow-up for the whole cohort was 19.8 months by the reverse Kaplan-Meier method. Any grade and grade 3-4 irAE were noted in 78.9% and 44.2% of the cohort, respectively. 44.2% of patients completed induction immunotherapy, whereas 41.1% did not due to irAE. Twelve-week landmark overall survival and TTF were similar in patients who completed induction versus those who did not due to irAE. On multivariable analysis, any grade irAE (versus none) was associated with longer overall survival (hazard ratio = 0.35, 95% confidence interval 0.15-0.82, P = 0.02) and TTF (hazard ratio = 0.38, 95% confidence interval = 0.17-0.81, P = 0.01). Grade 3-4 irAE correlated with longer TTF (hazard ratio = 0.45, 95% confidence interval = 0.20-1.01, P = 0.05). CONCLUSION: In this population-based cohort, discontinuation of induction immunotherapy as a result of irAE did not adversely affect overall survival or TTF. irAE observed during ipilimumab and nivolumab induction were associated with improved survival outcomes.

Treatment of non-small-cell lung cancer after progression on nivolumab or pembrolizumab.

Background: Although PD-1 antibodies (PD1 Ab) are the standard of care for advanced non-small-cell lung cancer (ansclc), most patients will progress. We compared survival outcomes for patients with ansclc who received systemic therapy (st) after progression and for those who did not. Additionally, clinical characteristics that predicted receipt of st after PD1 Ab failure were evaluated. Methods: All patients with ansclc in British Columbia initiated on nivolumab or pembrolizumab between June 2015 and November 2017, with subsequent progression, were identified. Eligibility criteria for additional st included an Eastern Cooperative Oncology Group (ecog) performance status (ps) of 3 or less and survival for more than 30 days from the last PD1 Ab treatment. Post-progression survival (pps) was assessed by landmark analysis. Baseline characteristics associated with pps were identified by multivariable analysis. Results: Of 94 patients meeting the eligibility criteria, 33 received st after progression. In 75.6%, a PD1 Ab was received as first- or second-line treatment. The most common sts were erlotinib (36.4%) and docetaxel (27.3%). No statistically significant difference in median pps was observed between patients who did and did not receive st within 30 days of their last PD1 Ab treatment (6.9 months vs. 3.6 months, log-rank p = 0.15.) In multivariable analysis, factors associated with increased pps included an ecog ps of 0 or 1 compared with 2 or 3 [hazard ratio (hr): 0.42; 95% confidence interval (ci): 0.24 to 0.73; p = 0.002] and any response compared with no response to PD1 Ab (hr: 0.54; 95% ci: 0.33 to 0.90; p = 0.02). Conclusions: In this cohort, only 35.1% of patients eligible for post-PD1 Ab therapy received st. Post-progression survival was not significantly affected by receipt of post-progression therapy. Prospective trials are needed to clarify the benefit of post-PD1 Ab treatments.

Jugular foramen tumour resulting in hypoglossal denervation pseudohypertrophy: a rare and significant cause for tongue asymmetry.

Paragangliomas of the jugular foramen are rare. They may present with symptoms of compression of the glossopharyngeal or vagus nerves, or due to secretion of catecholamines from chromaffin cells within the tumour. This case describes a rare presentation of glomus tumour. A 67-year-old patient presented with a 2-month history of right-sided tongue swelling. She was found to have an obvious swelling on the right side of the tongue but no obvious weakness or fasciculation on initial examination. Ultrasound confirmed diffuse muscle swelling, but no lesion within the tongue. Magnetic resonance imaging of the neck revealed an ipsilateral glomus jugulare tumour that extended to the hypoglossal canal, and had resulted in ipsilateral denervation pseudohypertrophy of the lingual muscles. This paper reviews presentation of glomus jugulare tumours and contributes a novel presentation of a rare entity.

GFP is the way to glow: bioimaging of the plant endomembrane system.

It is less than a decade that the green fluorescent protein (GFP) and its spectral variants have changed the approach to studying the dynamics of the plant secretory pathway. GFP technology has in fact shed new light on secretory events by allowing bioimaging in vivo right to the heart of a plant cell. This review highlights exciting discoveries and the most recent developments in the understanding of morphology and dynamics of the plant secretory pathway achieved with the application of fluorescent proteins.

Hydatid pulmonary emboli.

A case of secondary hydatosis, initially misdiagnosed as pulmonary metastases, is presented. The dissemination of hydatid cysts within the lungs in this case was the consequence of direct rupture of a hepatic hydatid into the inferior vena cava. A brief overview of the pathophysiology of hydatid disease, including a discussion of the types of hydatid rupture (contained, communicating and direct), is presented.

Rat lactase-phlorizin hydrolase/human growth hormone transgene is expressed on small intestinal villi in transgenic mice.

BACKGROUND & AIMS: Lactase-phlorizin hydrolase (LPH) is an absorptive enterocyte-specific gene that is expressed in a well-characterized pattern along the cryptvillus (vertical), proximal-distal (horizontal), and developmental (temporal) gradients. The aim of this study was to characterize the capacity of regulatory elements within the rat LPH gene to direct appropriate cell lineage and topographical patterns of expression in vivo in transgenic mice. METHODS: Transgenic mouse lines were established using a construction containing bases -2038 to +15 of the rat LPH gene fused to a human growth hormone reporter gene. RESULTS: In one line, the transgene was expressed only in small intestine and was localized to absorptive enterocytes on villi. The transgene was not expressed in goblet or enteroendocrine cells or in crypts. Transgene expression along horizontal and developmental gradients was different from that of the native mouse LPH gene. CONCLUSIONS: The results suggest that the region from -2038 to +15 of the rat LPH gene contains regulatory elements that direct correct tissue, cell, and vertical expression but may not contain all the elements necessary for appropriate horizontal and temporal control. This investigation provides further insight into the complexities of the molecular control of intestinal gene expression.

Assay of protein S in systemic lupus erythematosus.

Free protein S:Ag and protein S activity determined by clotting assay are often regarded as synonymous; however, in the study group of patients, abnormal protein S activity (PS:Act) results correlated poorly with abnormal free (PS:Ag(r2 = 0.164). Significantly none of the patients in whom lupus anticoagulant and low free protein S:Ag were detected were found to have low PS:Act. These results could not be explained by activated protein C resistance, suggesting that lupus anticoagulant may cause prolongation of the clotting time within the PS:Act assay and thus give falsely high results. As reduced levels of free protein S:Ag and/or protein S activity are considered risk factors of thrombosis in systemic lupus erythematosus, these findings question the suitability of the protein S activity assay for patients who may have phospholipid antibodies.

Preterm rupture of the membranes associated with recent cocaine use.

OBJECTIVE: We postulated that recent cocaine use is common among patients with preterm (< 37 weeks) rupture of the membranes and that cocaine users have shorter latency periods before the onset of labor and delivery compared with those without recent cocaine use. STUDY DESIGN: A urine toxicologic screen was performed on all patients admitted with preterm rupture of the membranes. Patients were managed expectantly, without tocolytics, antibiotics, or steroids. RESULTS: One hundred three patients were enrolled; 71 had negative screens and 19 were positive for cocaine alone. Cocaine-positive women were significantly older and had more advanced cervical dilatation at admission and a significantly shorter latency period from rupture of membranes to labor and delivery. CONCLUSION: Preterm rupture of the membranes associated with recent cocaine use is characterized by advanced cervical dilatation at admission and a shorter latency period to labor and delivery.

Metabolic fate of 14C-camostat mesylate in man, rat and dog after intravenous administration.

1. The metabolic fate of N,N-dimethylcarbamoylmethyl 4-(4-guanidino[14C]benzoyloxy)phenylacetate methanesulphonate (14C-camostat mesylate) was investigated after i.v. administration to man (12-h infusion), and to rat and dog (bolus injection). 2. Renal excretion (mainly in 24 h) accounted for at least 80% dose in all three species, and the only two important metabolites were identified as 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) and 4-guanidinobenzoic acid (GBA). 3. Parent drug was not detected in human plasma either during or after infusion of 14C-camostat mesylate owing to rapid hydrolysis of the side-chain ester group (t1/2 < 1 min). Steady-state levels of both GBPA and GBA in plasma were apparently attained by the end of the infusion period. Mean terminal half-life, systemic clearance and apparent volume of distribution at steady-state of GBPA in man were 1.0 h, 6.4 ml/min per kg and 0.38 l/kg, respectively, and the corresponding values for GBA were 2.4 h, 4.7 ml/min per kg and 1.01/kg respectively. 4. Radioactivity was rapidly distributed to most tissues after bolus i.v. doses of 14C-camostat mesylate to rats and dogs, with highest levels being associated with the liver and kidney, the two main organs of drug elimination. Concentrations in the pancreas, a possible site for drug action, were generally lower than those in plasma.