Canadian cohort expanded-access program of nivolumab plus ipilimumab in advanced melanoma.

Background: The combination of nivolumab and ipilimumab is approved in several jurisdictions (United States, European Union, Canada) for the first-line treatment of patients with advanced melanoma. CheckMate 218 is a North American expanded-access program (eap) of nivolumab plus ipilimumab in patients with advanced melanoma. Here, we report safety and survival outcomes for the Canadian cohort in the eap. Methods: Eligible patients were those 18 years of age or older with unresectable stage iii or iv melanoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior anti-PD-1 or anti-ctla-4 therapy. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction phase); they then continued with nivolumab 3 mg/kg every 2 weeks (maintenance phase) until progression, unacceptable toxicity, or a maximum of 48 weeks, whichever occurred first. Safety and overall survival (os) data were collected. Results: Of 194 patients enrolled, 174 were treated, and 51% continued on nivolumab maintenance. Median follow-up was 12.9 months. All-grade and grades 3-4 treatment-related adverse events were reported in 98% and 60% of patients respectively and led to treatment discontinuation in 40% and 28% of patients. Two treatment-related deaths were reported. The 12- and 18-month os rates were 80% [95% confidence interval (ci): 73% to 86%] and 76% (95% ci: 67% to 82%) respectively. Conclusions: In this Canadian population, nivolumab plus ipilimumab demonstrated a safety profile and survival outcomes consistent with phase ii and iii clinical trial data.

Diagnosis, monitoring, and management of adverse events from immune checkpoint inhibitor therapy.

Immune checkpoint inhibitor therapy (icit) is now a standard of care for a variety of cancers in both the metastatic and adjuvant settings. As a result, an understanding of the timing, epidemiology, monitoring, diagnosis, and management of immune-related adverse events (iraes) associated with icit is imperative. This article reviews specific iraes by organ system, consolidating recommendations from multiple guidelines and incorporating data from case reports to highlight additional evolving therapeutic options for patients. Managing iraes requires early recognition, early intervention, and education of the patients and the multidisciplinary health care team alike. Given the durable responses observed with icit, and the irreversible nature of some of the iraes, further research into management of the sequelae of icit is required.

Non-Euclidean symmetries of first-order optical systems.

We revisit the basic aspects of first-order optical systems from a geometrical viewpoint. In the paraxial regime, there is a wide family of beams for which the action of these systems can be represented as a Möbius transformation. We examine this action from the perspective of non-Euclidean hyperbolic geometry and resort to the isometric-circle method to decompose it as a reflection followed by an inversion in a circle. We elucidate the physical meaning of these geometrical operations for basic elements, such as free propagation and thin lenses, and link them with physical parameters of the system.

Update and recommendations in decision making referred to limitation of advanced life support treatment. / Puesta al día y recomendaciones en la toma de decisiones de limitación de tratamientos de soporte vital.

The Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC) Bioethics Working Group has developed recommendations on the Limitation of Advanced Life Support Treatment (LLST) decisions, with the aim of reducing variability in clinical practice and of improving end of life care in critically ill patients. The conceptual framework of LLST and futility are explained. Recommendations referred to new forms of LLST encompassing also the adequacy of other treatments and diagnostic methods are developed. In addition, planning of the possible clinical courses following the decision of LLST is commented. The importance of advanced care planning in decision-making is emphasized, and intensive care oriented towards organ donation at end of life in the critically ill patient is described. The integration of palliative care in the critical patient treatment is promoted in end of life stages in the Intensive Care Unit.

An Examination of Lymph Node Sampling as a Predictor of Survival in Resected Node-Negative Small Bowel Adenocarcinoma: a SEER Database Analysis.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare disease. Current recommendations are largely extrapolated from the colorectal literature. For node-negative (N -ve) cases, optimally stratifying cases into high or low risk, may help define optimal management. The objective of this analysis was to determine the importance of lymph node sampling for prognostication and to define what number of lymph nodes sampled is adequate. METHODS: Cases of non-metastatic SBA with complete staging, pathologic, and demographic information were selected from the SEER database and SAS 9.4 software was used. Variables included age, gender, race, grade, TNM staging, and number of lymph nodes were examined. Comparisons were made between N -ve and N +ve cases. Survival analysis using N -ve cases was performed to characterize the impact of nodal sampling on survival and to determine which nodal cut-offs best predict survival. RESULTS: A total of 523 cases from 2004 to 2014 were included in this analysis. Statistically significant differences identified included the median number of nodes sampled between the N -ve and N +ve groups, and the distribution of T stage and grade. Survival analysis in the N -ve cases demonstrated that the strongest predictor of survival was sampling of 16 or more lymph nodes. CONCLUSION: In this analysis, lymph node sampling was shown to be the most important pathologic predictor of survival in cases of N -ve SBA. Replicating these findings in a secondary dataset and determining whether a clinical benefit of adjuvant chemotherapy exists for SBA patients with inadequate sampling are both important next steps.

Clinical outcomes of elderly patients receiving neoadjuvant chemoradiation for locally advanced rectal cancer.

BACKGROUND: Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database. PATIENTS AND METHODS: Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus ≥ 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors. RESULTS: Of 1172 patients included, 295 (25%) were ≥ 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥ 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04). CONCLUSIONS: Elderly patients (≥ 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone.

Assessment of coyote-wolf-dog admixture using ancestry-informative diagnostic SNPs.

The evolutionary importance of hybridization as a source of new adaptive genetic variation is rapidly gaining recognition. Hybridization between coyotes and wolves may have introduced adaptive alleles into the coyote gene pool that facilitated an expansion in their geographic range and dietary niche. Furthermore, hybridization between coyotes and domestic dogs may facilitate adaptation to human-dominated environments. We genotyped 63 ancestry-informative single-nucleotide polymorphisms in 427 canids to examine the prevalence, spatial distribution and the ecology of admixture in eastern coyotes. Using multivariate methods and Bayesian clustering analyses, we estimated the relative contributions of western coyotes, western and eastern wolves, and domestic dogs to the admixed ancestry of Ohio and eastern coyotes. We found that eastern coyotes form an extensive hybrid swarm, with all our samples having varying levels of admixture. Ohio coyotes, previously thought to be free of admixture, are also highly admixed with wolves and dogs. Coyotes in areas of high deer density are genetically more wolf-like, suggesting that natural selection for wolf-like traits may result in local adaptation at a fine geographic scale. Our results, in light of other previously published studies of admixture in Canis, revealed a pattern of sex-biased hybridization, presumably generated by male wolves and dogs mating with female coyotes. This study is the most comprehensive genetic survey of admixture in eastern coyotes and demonstrates that the frequency and scope of hybridization can be quantified with relatively few ancestry-informative markers.

Reporting practices of pharmacodynamic studies involving invasive research procedures in cancer trials.

BACKGROUND: Tumour biopsy for pharmacodynamic (PD) study is increasingly common in early-phase cancer trials. As they are non-diagnostic, the ethical justification for such procedures rests on their knowledge value. On the premise that knowledge value is related to reporting practices and outcome diversity, we assessed in a sample of recent invasive PD studies within cancer trials. METHODS: We assessed reporting practices and outcomes for PD studies in a convenience sample of cancer trials published from 2000 to 2010 that employed invasive, non-diagnostic tissue procurement. Extracted data were used to measure outcome reporting in individual trials. Using a reporting scale we developed for exploratory purposes, we tested whether reporting varied with study characteristics, such as funding source or drug novelty. RESULTS: Reporting varied widely within and across studies. Some practices were sporadically reported, including results of all planned tests (78% trials reporting), use of blinded histopathological assessment (43% trials reporting), biopsy dimensions (38% trials reporting), and description of patient flow through PD analysis (62%). Pharmacodynamic analysis as a primary end point and mandatory biopsy had statistically significant positive relationships with overall quality of reporting. A preponderance of positive results (61% of the studies described positive PD results) suggests possible publication bias. CONCLUSION: Our results highlight the need for PD-reporting guidelines, and suggest several avenues for improving the risk/benefit for studies involving invasive, non-diagnostic tissue procurement.

Cryptococcoma of the brain in an immunocompetent man.

Cryptococcosis is a common opportunistic systemic disease in immunocompromised patients. Pulmonary or brain cryptococcosis is the most common clinical presentation. Immunocompetent patients can also be affected, especially in tropical and subtropical zones where the life cycle of the causal agent, Cryptococcus gattii, is completed. We present a previously healthy man with progressive intracranial hypertension and a right paraventricular mass on CT scan and MRI. Cryptococcus gattii yeasts were isolated from the cerebrospinal fluid. A ventriculoperitoneal shunt was placed and the patient was treated with amphotericin B, fluconazole and dexamethasone. The patient died due to severe intracranial hypertension.

Íleo biliar colónico secundario a fístula colecitocolónica / Colonic gallstone ileus secondary a cholecystocolonic fistula

Presentamos un caso de ileo biliar colónico secundario a fístula colecistocolónica en una mujer de 76 años con clínica de obstrucción intestinal. Se denomina íleo biliar a la obstrucción mecánica del intestino delgado o del colon como consecuencia del paso de una o más litiasis a través de una fístula biliodigestiva. Únicamente entre 1-15 % de estas fístulas producen cuadro de obstrucción intestinal siendo la más frecuente la colecistoduodenal (65-77%) (AU)

We report a case of colonic gallstone ileus secondary a cholecystocolonic fistula. An 76-years-old woman was admitted to the hospital because she had been symptoms of intestinal obstruction. Colonic gallstone ileus is a rare cause of mechanical large bowel obstruction. It occurs most commonly of a passage of one or more stones through biliodigestive fistula. Only between 1-15% of these fistulas pruduce bowel obstruction. The most frequent fistula is cholecystoduodenal (65-77%) (AU)

Conserved peptide sequences bind to actin and enolase on the surface of Plasmodium berghei ookinetes.

The description of Plasmodium ookinete surface proteins and their participation in the complex process of mosquito midgut invasion is still incomplete. In this study, using phage display, a consensus peptide sequence (PWWP) was identified in phages that bound to the Plasmodium berghei ookinete surface and, in selected phages, bound to actin and enolase in overlay assays with ookinete protein extracts. Actin was localized on the surface of fresh live ookinetes by immunofluorescence and electron microscopy using specific antibodies. The overall results indicated that enolase and actin can be located on the surface of ookinetes, and suggest that they could participate in Plasmodium invasion of the mosquito midgut.

Etiología y fisiopatología de la conducta agresiva / Etiology and pathophysiology of aggressive behavior

La conducta agresiva es, en el ser humano, un comportamiento complejo de difícil clasificación y estudio. Participan en ella cuestiones evolutivas, madurativas y de neurodesarrollo, genéticas, bioquímicas, neuroanatómicas y, por supuesto, ambientales, tanto físicas como psicológicas y de crianza y aprendizaje. Pretendemos en la presente revisión realizar una aproximación y repaso (forzosamente parcial por lo extenso de la literatura existente) al fenómeno de la conducta agresiva humana. Su presencia habitual y cada vez más frecuente en las consultas de Psiquiatría Infanto-Juvenil, ya sea como motivo principal de remisión, ya como conducta acompañante, creemos que hace pertinente e importante este repaso (AU)

Human aggressive behavior is a complex behavior hard to classify and investigate. Evolutionary, neurodevelopmental, genetic, biochemical, neuroanatomical and, of course, environmental (physical and psychological) issues are involved in it. In this review we intend to make an approach and review to the phenomenon of human aggressive behavior (necessarily partial due to the large amount of existing literature about it). We believe that its regular and increasingly presence in our Child and Adolescent Psychiatry clinics, either as the main reason for referral, either as a secondary behavior, makes this review relevant and valuable (AU)

[Ethics of the cardiopulmonary resuscitation decisions]. / Ética de las decisiones en resucitación cardiopulmonar.

Cardiopulmonary Resuscitation (CPR) must be attempted if indicated, not done if it is not indicated or if the patient does not accept or has previously rejected it and withdrawn it if it is ineffective. If CPR is considered futile, a Do-Not-Resuscitate Order (DNR) will be recorded. This should be made known to all physicians and nurses involved in patient care. It may be appropriate to limit life-sustaining-treatments for patients with severe anoxic encephalopathy, if the possibility of clinical evolution to brain death is ruled out. After CPR it is necessary to inform and support families and then review the process in order to make future improvements. After limitation of vital support, certain type of non-heart-beating-organ donation can be proposed. In order to acquire CPR skills, it is necessary to practice with simulators and, sometimes, with recently deceased, always with the consent of the family. Research on CPR is essential and must be conducted according to ethical rules and legal frameworks.

Gestión clínica y Psiquiatría Infanto-Juvenil: algunos apuntes / Clinical management and child & adolescent psychiatry: some notes

La respuesta a los nuevos desafíos de la atención médica exige adaptaciones en la organización de los servicios sanitarios asistenciales. En la actualidad, numerosos sectores del colectivo médico buscan nuevas fórmulas organizativas que les permitan enfrentarse mejor al hecho asistencial y sentirse más identificados con su propio trabajo y con la institución en la que lo desarrollan. La evolución de nuestro sistema sanitario hacia la eficiencia, la consideración del paciente como elemento nuclear para la organización, y la mayor implicación de los profesionales, han sentado las bases de lo que hoy día llamamos "Gestión Clínica". Gestión Clínica que es, como todo en Medicina, sentido común a partir de las pruebas científicas (AU)

The response to the new challenges of health care requires adjustments in the organization of health care services. Today, many sectors of the medical seeking new forms of organization that enable them to cope with the health care and feel more identified with their work and their institution. The evolution of our health system toward efficiency, considering the patient as core element for the organization, and the greater involvement of professionals, have laid the groundwork for what today we call "Clinical Management". Clinical Management is, like everything in medicine, common sense from the scientific evidence (AU)

GP35 ANOAL, an abundant acidic glycoprotein of female Anopheles albimanus saliva.

Salivary glands of female mosquitoes produce proteins, not completely described yet, that participate in carbohydrate and blood feeding. Here, we report an acidic glycoprotein of 35 kDa (GP35 ANOAL) secreted in the saliva of the malaria vector mosquito Anopheles albimanus. GP35 ANOAL is produced exclusively in the distal lateral lobes of adult female salivary glands, it has a pI of 4.45 and is negatively stained by regular silver stain. An 888 bp cDNA clone encoding a predicted product of 240 amino acids has a signal peptide, potential post-translational modification sites, and a disintegrin signature RGD. The GP35 ANOAL sequence depicts high similarities with the 30 kDa saliva allergen of Aedes aegypti, 30 kDa allergen-like hypothetical proteins, and GE-rich proteins present in several Anopheles species, as well as in Ae. albopictus and Culex pipiens quinquefasciatus. The function of this protein family is still unknown.

Effects of homeopathic medications Eupatorium perfoliatum and Arsenicum album on parasitemia of Plasmodium berghei-infected mice.

Malaria is one of the most important parasitic diseases in the world and a major public health problem because of emerging drug-resistant strains of Plasmodium. A number of synthetic and natural compounds are now being analysed to develop more effective antimalarial drugs. We investigated the effect of homeopathic preparations of Eupatorium perfoliatum and Arsenicum album on parasitemia using a rodent malaria model. We found significant inhibitory effect on parasite multiplication with both medications with a level of 60% for Eupatorium perfoliatum at a 30 CH potency. Arsenicum album 0/6 gave 70% inhibition but this was less stable than Eupatorium perfoliatum. The number of schizonts was higher in animals treated with homeopathic medications. Although the mechanism of action is unknown, these agents would be good candidates as alternative or complementary medications in the treatment of malaria.

Comparing omnidirectional reflection from periodic and quasiperiodic one-dimensional photonic crystals.

We determine the range of thicknesses and refractive indices for which omnidirectional reflection from quasiperiodic dielectric multilayers occurs. By resorting to the notion of area under the transmittance curve, we assess in a systematic way the performance of the different Fibonacci multilayers.

Treatment of pancreatic pseudoaneurysm with percutaneous transabdominal thrombin injection.

Severe acute pancreatitis is associated with significant morbidity and mortality. Although rare, pancreatic pseudoaneurysm is a serious and often fatal complication of acute pancreatitis. This case report describes an alcoholic male patient with a psuedoaneurysm that was successfully treated with percutaneous transabdominal thrombin injection.

Recomendaciones del grupo de bioética de la SEMICYUC sobre el consentimiento informado en UCI / Recommendations of the Bioethics Group of the Spanish Society of Intensive Care Medicine and Coronary Units regarding informed consent in the intensive care unit

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