An Immune Atlas of Clear Cell Renal Cell Carcinoma

Immune cells in the tumor microenvironment modulate cancer progression and are attractive therapeutic targets. Macrophages and T cells are key components of the microenvironment, yet their phenotypes and relationships in this ecosystem and to clinical outcomes are ill defined. We used mass cytometry with extensive antibody panels to perform in-depth immune profiling of samples from 73 clear cell renal cell carcinoma (ccRCC) patients and five healthy controls. In 3.5 million measured cells, we identified 17 tumor-associated macrophage phenotypes, 22 T cell phenotypes, and a distinct immune composition correlated with progression-free survival, thereby presenting an in-depth human atlas of the immune tumor microenvironment in this disease. This study revealed potential biomarkers and targets for immunotherapy development and validated tools that can be used for immune profiling of other tumor types.ISSN:0092-8674ISSN:1097-417

Oral cannabinoid-rich THC/CBD cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting : a study protocol for a pilot and definitive randomised double-blind placebo-controlled trial (CannabisCINV)

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV. METHODS AND ANALYSIS: The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day -1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day -1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients. ETHICS AND DISSEMINATION: The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.Tilray. PROTOCOL VERSION: 2.0, 9 June 2017

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.

BACKGROUND: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older. METHODS: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm. RESULTS: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events. CONCLUSIONS: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Identifying the unmet supportive care needs of people affected by kidney cancer: a systematic review.

Purpose: To synthesize existing evidence on the unmet supportive care needs of people affected by kidney cancer, across the cancer care continuum. Methods: A systematic review was conducted according to the PRISMA Statement Guidelines. Electronic databases (CINAHL, MEDLINE, and PsychINFO) were searched using key search terms. Articles were assessed according to pre-specified eligibility criteria. Data extraction and quality appraisal were conducted. The findings were integrated in a narrative synthesis. Results: One thousand sixty-three publications were screened, and 18 publications met the inclusion criteria. The following domains of unmet needs in order of frequency included psychological/emotional needs (17/18: 94%), physical needs (10/18: 56%), social needs (4/18: 22%), interpersonal/intimacy needs (4/18: 22%), patient-clinician communication needs (3/18: 17%), family-related needs (3/18: 17%), health system/information needs (3/18: 17%), spiritual needs (3/18: 17%), daily living needs (2/18: 11%), practical needs (1/18: 6%), and cognitive needs (1/18: 6%). Conclusions: There was a wide range of unmet supportive care needs experienced by people diagnosed with kidney cancer. A prominent focus was on psychological and physical needs. Further research is needed to understand how clinical (stage/treatment) and demographic (age/socio-economic/ethnicity) variables may moderate or mediate the relationship with unmet needs over time. With many unmet needs identified, this review provides a starting place to inform future work to address the complex unmet supportive care needs of people affected by kidney cancer. Implications for Cancer Survivors: Individuals living with kidney cancer have many unmet supportive care needs, and future research is needed to learn about what are the most pressing needs and how to best address these concerns to ensure holistic person-centered care is delivered

Targeted therapy in melanoma: the era of personalized medicine

Malignant melanoma is the most aggressive of all cutaneous tumours, with over 76, 000 new cases and 9700 deaths estimated for 2014 in the United States.1 In Canada, both the incidence and mortality of melanoma are increasing, with a risk of developing melanoma being 1 in 59 for men and 1 in 73 for women.2 The incidence of melanoma is higher in Australia, with a risk of 1 in 14 for males and 1 in 23 for females to age 85 reported for 2009.3 Although early melanoma can be managed surgically, until recently there have been few advances in the treatment of advanced melanoma. However, with the introduction of molecular targeted therapies, the landscape of melanoma treatment has changed dramatically in the past five years, resulting in improved survival rates for patients with metastatic disease. In this review, we will discuss the molecular basis and implementation for some of these novel treatments with particular emphasis on BRAF and BRAF inhibitors

Stem/progenitor cell marker expression in clear cell renal cell carcinoma: a potential relationship with the immune microenvironment to be explored

Abstract Background Clear cell renal cell carcinoma (ccRCC) is a markedly heterogeneous disease in many aspects, including the tumour microenvironment. Our previous study showed the importance of the tumour microenvironment in ccRCC xeno-transplant success rates. In order to better understand the potential relationship between TICs and the immune microenvironment, we employed a multi-modal approach, examining RNA and protein expression (flow cytometry, immunohistochemistry). Methods We first examined the gene expression pattern of 18 stem/progenitor marker genes in the cancer genome atlas (TCGA) ccRCC cohort. Flow cytometry was next employed to examine lineage-specific expression levels of stem/progenitor markers and immune population makeup in six, disaggregated, primary ccRCC specimens. Immunohistochemistry was performed on a commercial ccRCC tissue microarray (TMA). Results The 18 genes differed with respect to their correlation patterns with one another and to their prognostic significance. By flow cytometry, correlating expression frequency of 12 stem/progenitor markers and CD10 resulted in two clusters—one with CD10 (marker of proximal tubular differentiation), and second cluster containing mostly mesenchymal stem cell (MSC) markers, including CD146. In turn, these clusters differed with respect to their correlation with different CD45+ lineage markers and their expression of immune checkpoint pathway proteins. To confirm these findings, four stem/progenitor marker expression patterns were compared with CD4, CD8 and CD20 in a ccRCC TMA which showed a number of similar trends with respect to frequency of the different tumour-infiltrating leukocytes. Conclusion Taken together, we observed heterogeneous but patterned expression levels of different stem/progenitor markers. Our results suggest a non-random relationship between their expression patterns with the immune microenvironment populations in ccRCC