Predictors of responses to immune checkpoint blockade in advanced melanoma.

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

Applying the WHO conceptual framework for the International Classification for Patient Safety to a surgical population.

OBJECTIVE: Efforts to improve patient safety are challenged by the lack of universally agreed upon terms. The International Classification for Patient Safety (ICPS) was developed by the World Health Organization for this purpose. This study aimed to test the applicability of the ICPS to a surgical population. DESIGN: A web-based safety debriefing was sent to clinicians involved in surgical care of abdominal organ transplant patients. A multidisciplinary team of patient safety experts, surgeons and researchers used the data to develop a system of classification based on the ICPS. Disagreements were reconciled via consensus, and a codebook was developed for future use by researchers. RESULTS: A total of 320 debriefing responses were used for the initial review and codebook development. In total, the 320 debriefing responses contained 227 patient safety incidents (range: 0-7 per debriefing) and 156 contributing factors/hazards (0-5 per response). The most common severity classification was 'reportable circumstance,' followed by 'near miss.' The most common incident types were 'resources/organizational management,' followed by 'medical device/equipment.' Several aspects of surgical care were encompassed by more than one classification, including operating room scheduling, delays in care, trainee-related incidents, interruptions and handoffs. CONCLUSIONS: This study demonstrates that a framework for patient safety can be applied to facilitate the organization and analysis of surgical safety data. Several unique aspects of surgical care require consideration, and by using a standardized framework for describing concepts, research findings can be compared and disseminated across surgical specialties. The codebook is intended for use as a framework for other specialties and institutions.

Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation.

The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.

Evaluation of the toxicity of Adonis aestivalis in sheep.

To determine the toxicity of Adonis aestivalis (adonis) in sheep, adult Suffolk ewes were administered 1 per cent bodyweight adonis via surgically placed rumen cannulas in an acute, high-dose toxicity study, and 0.2 per cent bodyweight daily in a two-week, low-dose toxicity study. The ewes received cardiac examinations before dosing, 24 and 48 hours after dosing with 1 per cent bodyweight adonis, and after continuous low-dose administration. All the ewes administered adonis had transient sinus arrhythmias after receiving 1 per cent bodyweight adonis. Two of the three ewes had transient reduced fractional shortening after administration with 1 per cent bodyweight adonis; the same two ewes had reduced fractional shortening after the low-dose treatment regimen. No gross or microscopic lesions were seen when the ewes were examined postmortem at the end of the study.

Puccinia jaceae var. solstitialis teliospore priming on yellow starthistle.

Following the introduction of Puccinia jaceae var. solstitialis to California for biological control of yellow starthistle (Centaurea solstitialis, Asteraceae), teliospores, pycnia, and multiple urediniospore generations have been observed in the field. Because urediniospores have a relatively short life span in the field, functioning teliospores are expected to be necessary for the permanent establishment of P. jaceae var. solstitialis in California. To determine if conditions in California were conducive to this, teliospore emergence and priming were evaluated in the field. A factorial experiment in the laboratory with five incubation times and three incubation temperatures was used to determine teliospore priming requirements. Teliospore production coincided with plant senescence in August and September at two sites in 2 years; fewer teliospores were produced in 2006, suggesting inconsistent teliospore production may limit population growth and contribute to local extinctions in some areas. When teliospores were primed in the field, germination was low through the fall and abruptly peaked in January during both years. In the laboratory, teliospore germination increased as incubation time increased from 2 to 6 weeks and temperatures decreased from 12 to 4 degrees C. A degree-hour model derived from laboratory data accurately predicts when teliospores are primed for germination in the field. Based on the results obtained in this study, it is apparent that teliospore germination can occur over a range of priming conditions. However, lower temperatures and longer incubation periods are superior in breaking teliospore dormancy.

Anatomy of a patient safety event: a pediatric patient safety taxonomy.

BACKGROUND: Idiosyncratic terminology and frameworks in the study of patient safety have been tolerated but are increasingly problematic. Agreement on standard language and frameworks is needed for optimal improvement and dissemination of knowledge about patient safety. METHODS: Patient safety events were assessed using critical incident analysis, a method used to classify risks that has been more recently applied to medicine. Clinician interviews and clinician reports to a web based reporting system were used for analysis of hospital based and ambulatory care events, respectively. Events were classified independently by three investigators. RESULTS: A pediatric patient safety taxonomy, relevant to both hospital based and ambulatory pediatric care, was developed from the analysis of 122 hospital based and 144 ambulatory care events. It is composed of four main categories: (1) problem type; (2) domain of medicine; (3) contributing factors in the patient (child-specific), environment (latent conditions) and care providers (human factors); and (4) outcome or result of the event and level of harm. A classification of preventive mechanisms was also developed. Inter-rater reliability of classifications ranged from 72% to 86% for sub-categories of the taxonomy. CONCLUSIONS: This patient safety taxonomy reflects the nature of events that occur in both pediatric hospital based and ambulatory care settings. It is flexible in its construction, permits analysis to begin at any point, and depicts the relationships and interactions of elements of an event.

First Report of Musk Thistle Rust (Puccinia carduorum) in California and Nevada.

Musk thistle, Carduus nutans L., is an introduced weed of pastures, rangelands, and natural areas in much of North America. Puccinia carduorum Jacky, an autoecious rust fungus from Turkey, has been evaluated for biological control of musk thistle since 1978, including a field study near Blacksburg, VA, from 1987 to 1990. After release of the fungus in Virginia, rusted musk thistle was found in eight eastern states by 1992, in Missouri by 1994 (1), and in Oklahoma by 1997 (2). A rust disease was discovered on musk thistle near Mt. Shasta, CA, on 22 September 1998, and near Mogul, NV, on 12 August 1999. The pathogen was identified as P. carduorum on the basis of pathogenicity on musk thistle and urediniospore morphology (ovate spores, 21 µm diameter, three germ pores equatorial in location, and echinulations over the upper two-thirds to three-quarters of urediniospores). Ribosomal RNA internal transcribed spacer DNA sequences (ITS1 and ITS2) were identical to those from the isolate obtained after the field release in Virginia, verifying that the California isolate is P. carduorum. The initial California infestation was observed on a few plants late in the season, and by September 2000, nearly 100% of plants were infected. The occurrence of P. carduorum in California is apparently the result of natural, unaided spread of the fungus on musk thistle from the East Coast of the United States. References: (1) A. B. A. M. Baudoin and W. L. Bruckart. Plant Dis. 80:1193, 1996. (2) L. J. Littlefield et al. Plant Dis. 82:832, 1998.

Experimental enhancement of drug uptake using short-term flow occlusion: a comparison of balloon and tourniquet techniques.

Three groups of dogs, four per group, were used to examine the safety of short-term arterial flow occlusion and potential benefits of balloon and/or tourniquet occlusion-infusion techniques. In part 1, local plasma gases and pH were monitored during a 1-hr period of vascular occlusion. Tourniquet occlusion was found to significantly (p = 0.01) lower pO2. In part 2, local muscle and venous blood samples were obtained during and after a 30-min intraarterial infusion of floxuridine (FUDR). A tourniquet was added to try to eliminate collateral circulation. Local FUDR concentration was increased by 1.3 times in muscle and 19.6 times (p less than 0.01) in ipsilateral femoral vein serum when a tourniquet was added to arterial balloon occlusion-infusion. In addition, the combination of the two occlusion techniques produced a 4.1-fold reduction (p less than 0.05) in systemic venous FUDR levels during infusion when compared to balloon occlusion.