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.

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.

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.

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.

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.

Lipolysis in adipocytes isolated from deep and superficial subcutaneous adipose tissue.

OBJECTIVE: Abdominal subcutaneous adipose tissue (SAT) occurs in two depots separated by a fascial plane: deep SAT and superficial SAT. In a recent study it was demonstrated that the amount of deep SAT has a much stronger relationship to insulin resistance than does superficial SAT. Because insulin resistance may be related to fatty acid release from adipose tissue, we hypothesized that the two SAT depots may have a different lipolytic activity. RESEARCH METHODS AND PROCEDURES: To test this hypothesis, we obtained samples of deep and superficial SAT from patients undergoing elective abdominal surgery. The rate of lipolysis was determined in the collagenase-digested adipocytes obtained from the two fat depots by measuring glycerol release in the presence and absence of isoproterenol. In addition, the relative concentration of hormone-sensitive lipase was determined in both SAT depots by Western blot analysis. RESULTS: Our results showed that the rate of isoproterenol-stimulated lipolysis was approximately 20% higher in cells from deep SAT compared with those from superficial SAT, indicating that the deep SAT is more lipolytically active. The concentration of hormone-sensitive lipase did not differ between the two adipose tissue depots. DISCUSSION: These findings suggest that the higher lipolytic activity of deep SAT may account for its stronger association with insulin resistance. The mechanism seems to be independent of differences in hormone-sensitive lipase concentration.

Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma.

Approximately 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families. CDKN2A (also known as P16, INK4, p16INK4A and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point. Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers. We show here that a subset of these kindreds possess a G-->T transversion at base -34 of CDKN2A, designated G-34T. This mutation gives rise to a novel AUG translation initiation codon that decreases translation from the wild-type AUG. The G-34T mutation is not seen in controls, segregates with melanoma in families and, on the basis of haplotyping studies, probably arose from a common founder in the United Kingdom. Characterization of this and other CDKN2A non-coding mutations should have an impact on current efforts to identify susceptible melanoma-prone families and individuals.

Role of the cyclin-dependent kinase inhibitor CDKN2A in familial melanoma.

BACKGROUND: Approximately 8 to 12% of melanoma appears to be inherited in an autosomal dominant form. Although most early stage melanomas can be treated successfully by simple surgical excision, patients with advanced disease are rarely cured even with aggressive chemotherapy and/or immunotherapy. OBJECTIVE: There is now compelling evidence that germline mutations of the CDKN2A gene on chromosome 9p21 predispose to melanoma in a subset of melanoma-prone families. In this article the evidence for the role of CDKN2A in the genesis of familial melanoma is reviewed and the implications of genetic testing in families with this disease are discussed. CONCLUSION: The identification and subsequent surveillance of unaffected individuals who have a genetic predisposition to melanoma may lead to the detection of early (curable) melanomas and to a reduction in mortality.

CDKN2A mutations in multiple primary melanomas.

BACKGROUND: Germ-line mutations in the CDKN2A tumor-suppressor gene (also known as p16, p16INK4a, and MTS1) have been linked to the development of melanoma in some families with inherited melanoma. Whether mutations in CDKN2A confer a predisposition to sporadic (nonfamilial) melanoma is not known. In some patients with sporadic melanoma, one or more additional primary lesions develop, suggesting that some of these patients have an underlying genetic susceptibility to the cancer. We hypothesized that this predisposition might be due to germ-line CDKN2A mutations. METHODS: We used the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct DNA sequencing to identify germ-line mutations in the CDKN2A gene in patients with multiple primary melanomas who did not have family histories of the disease. A quantitative yeast two-hybrid assay was used to evaluate the functional importance of the CDKN2A variants. RESULTS: Of 33 patients with multiple primary melanomas, 5 (15 percent; 95 percent confidence interval, 4 percent to 27 percent) had germ-line CDKN2A mutations. These included a 24-bp insertion at the 5' end of the coding sequence, three missense mutations (Arg24Pro, Met53Ile, and Ser56Ile), and a 2-bp deletion at position 307 to 308 (resulting in a truncated CDKN2A protein). In three families, CDKN2A mutations identical to those in the probands were found in other family members. In two families with mutations, we uncovered previously unknown evidence of family histories of melanoma. CONCLUSIONS: Some patients with multiple primary melanomas but without family histories of the disease have germ-line mutations of the CDKN2A gene. The presence of multiple primary melanomas may signal a genetic susceptibility to melanoma not only in the index patient but also in family members, who may benefit from melanoma-surveillance programs.

[Relation of spondylarthropathies and HLA-B27 antigen in patients from the state of Zulia, Venezuela]. / Estudio de la relación existente entre las espondiloartropatías y el antígeno HLA-B27 en pacientes del estado Zulia de Venezuela.

HLA-B27 and associate antigens incidence were studied in 620 cases of seronegative spondiloarthropathies (SNS) and 262 controls of a Venezuelan mestizo population from Zulla state between 1985 and 1995. The incidence of HLA-B27 was 20.96% of all cases of SNS. It was increased in patients with ankilosing spondylitis (AS) 33.33% and Relter's syndrome (RS) 30%, but not in uveitis (Uv) 20% an psoriatic arthropathy (PsA) 0%. The incidence in the control group was 4.2%. This results are lower than the previous description in Venezuelan mestizo and caucasic population but are close to the incidence described in population of West Africa with important contribution to admixture of the occidental part of Venezuela.