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Concept: Oncology

307

We describe the first definitive case of a fibrous dysplastic neoplasm in a Neandertal rib (120.71) from the site of Krapina in present-day Croatia. The tumor predates other evidence for these kinds of tumor by well over 100,000 years. Tumors of any sort are a rare occurrence in recent archaeological periods or in living primates, but especially in the human fossil record. Several studies have surveyed bone diseases in past human populations and living primates and fibrous dysplasias occur in a low incidence. Within the class of bone tumors of the rib, fibrous dysplasia is present in living humans at a higher frequency than other bone tumors. The bony features leading to our diagnosis are described in detail. In living humans effects of the neoplasm present a broad spectrum of symptoms, from asymptomatic to debilitating. Given the incomplete nature of this rib and the lack of associated skeletal elements, we resist commenting on the health effects the tumor had on the individual. Yet, the occurrence of this neoplasm shows that at least one Neandertal suffered a common bone tumor found in modern humans.

Concepts: Cancer, Human, Oncology, Primate, Chimpanzee, Neanderthal, World population, Human evolution

301

Polybia-MP1 (MP1) is a bioactive host-defense peptide with known anticancer properties. Its activity is attributed to excess serine (phosphatidylserine (PS)) on the outer leaflet of cancer cells. Recently, higher quantities of phosphatidylethanolamine (PE) were also found at these cells' surface. We investigate the interaction of MP1 with model membranes in the presence and absence of POPS (PS) and DOPE (PE) to understand the role of lipid composition in MP1’s anticancer characteristics. Indeed we find that PS lipids significantly enhance the bound concentration of peptide on the membrane by a factor of 7-8. However, through a combination of membrane permeability assays and imaging techniques we find that PE significantly increases the susceptibility of the membrane to disruption by these peptides and causes an order-of-magnitude increase in membrane permeability by facilitating the formation of larger transmembrane pores. Significantly, atomic-force microscopy imaging reveals differences in the pore formation mechanism with and without the presence of PE. Therefore, PS and PE lipids synergistically combine to enhance membrane poration by MP1, implying that the combined enrichment of both these lipids in the outer leaflet of cancer cells is highly significant for MP1’s anticancer action. These mechanistic insights could aid development of novel chemotherapeutics that target pathological changes in the lipid composition of cancerous cells.

Concepts: Protein, Cancer, Breast cancer, Oncology, Cell membrane, Chemotherapy, Leukemia, Lipid bilayer

293

Collectively, lymphoid neoplasms are the fourth most common cancer and the sixth leading cause of cancer death in the United States. The authors provide contemporary lymphoid neoplasm statistics by subtype based on the 2008 World Health Organization classifications, including the most current US incidence and survival data. Presented for the first time are estimates of the total numbers of US lymphoid neoplasm cases by subtype as well as a detailed evaluation of incidence and survival statistics. In 2016, 136,960 new lymphoid neoplasms are expected. Overall lymphoma incidence rates have declined in recent years, but trends vary by subtype. Precursor lymphoid neoplasm incidence rates increased from 2001 to 2012, particularly for B-cell neoplasms. Among the mature lymphoid neoplasms, the fastest increase was for plasma cell neoplasms. Rates also increased for mantle cell lymphoma (males), marginal zone lymphoma, hairy cell leukemia, and mycosis fungoides. Like incidence, survival for both mature T-cell lymphomas and mature B-cell lymphomas varied by subtype and by race. Patients with peripheral T-cell lymphomas had among the worst 5-year relative survival (36%-56%, depending on race/sex), while those with mycosis fungoides had among the best survival (79%-92%). For B-cell lymphomas, 5-year survival ranged from 83% to 91% for patients with marginal zone lymphoma and from 78% to 92% for those with hairy cell leukemia; but the rates were as low as 47% to 63% for patients with Burkitt lymphoma and 44% to 48% for those with plasma cell neoplasms. In general, black men had the lowest survival across lymphoid malignancy subtypes. These contemporary incidence and survival statistics are useful for developing management strategies for these cancers and can offer clues regarding their etiology. CA Cancer J Clin 2016. © 2016 American Cancer Society.

Concepts: AIDS, Cancer, Oncology, B cell, Types of cancer, Neoplasm, Leukemia, Lymphoma

282

Background In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. Methods We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. Results A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. Conclusions In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649 .).

Concepts: Clinical trial, Cancer, Metastasis, Oncology, Lung cancer, Chemotherapy, Normal distribution, Pancreatic cancer

276

Genomic instability is a hallmark of cancer often associated with poor patient outcome and resistance to targeted therapy. Assessment of genomic instability in bulk tumor or biopsy can be complicated due to sample availability, surrounding tissue contamination, or tumor heterogeneity. The Epic Sciences circulating tumor cell (CTC) platform utilizes a non-enrichment based approach for the detection and characterization of rare tumor cells in clinical blood samples. Genomic profiling of individual CTCs could provide a portrait of cancer heterogeneity, identify clonal and sub-clonal drivers, and monitor disease progression. To that end, we developed a single cell Copy Number Variation (CNV) Assay to evaluate genomic instability and CNVs in patient CTCs. For proof of concept, prostate cancer cell lines, LNCaP, PC3 and VCaP, were spiked into healthy donor blood to create mock patient-like samples for downstream single cell genomic analysis. In addition, samples from seven metastatic castration resistant prostate cancer (mCRPC) patients were included to evaluate clinical feasibility. CTCs were enumerated and characterized using the Epic Sciences CTC Platform. Identified single CTCs were recovered, whole genome amplified, and sequenced using an Illumina NextSeq 500. CTCs were then analyzed for genome-wide copy number variations, followed by genomic instability analyses. Large-scale state transitions (LSTs) were measured as surrogates of genomic instability. Genomic instability scores were determined reproducibly for LNCaP, PC3, and VCaP, and were higher than white blood cell (WBC) controls from healthy donors. A wide range of LST scores were observed within and among the seven mCRPC patient samples. On the gene level, loss of the PTEN tumor suppressor was observed in PC3 and 5/7 (71%) patients. Amplification of the androgen receptor (AR) gene was observed in VCaP cells and 5/7 (71%) mCRPC patients. Using an in silico down-sampling approach, we determined that DNA copy number and genomic instability can be detected with as few as 350K sequencing reads. The data shown here demonstrate the feasibility of detecting genomic instabilities at the single cell level using the Epic Sciences CTC Platform. Understanding CTC heterogeneity has great potential for patient stratification prior to treatment with targeted therapies and for monitoring disease evolution during treatment.

Concepts: Gene, Genetics, Cancer, Oncology, Copy number variation, Human genome, Prostate cancer, Tumor

272

Abnormal cancer metabolism creates a glycolytic-dependency which can be exploited by lowering glucose availability to the tumor. The ketogenic diet (KD) is a low carbohydrate, high fat diet which decreases blood glucose and elevates blood ketones and has been shown to slow cancer progression in animals and humans. Abnormal tumor vasculature creates hypoxic pockets which promote cancer progression and further increase the glycolytic-dependency of cancers. Hyperbaric oxygen therapy (HBO2T) saturates tumors with oxygen, reversing the cancer promoting effects of tumor hypoxia. Since these non-toxic therapies exploit overlapping metabolic deficiencies of cancer, we tested their combined effects on cancer progression in a natural model of metastatic disease.

Concepts: Protein, Oxygen, Cancer, Breast cancer, Oncology, Metabolism, Nutrition, Carbohydrate

264

Payment for health care services, including oncology services, is shifting from volume-based fee-for-service to value-based accountable care. The objective of accountable care is to support providers with flexibility and resources to reform care delivery, accompanied by accountability for maintaining or improving outcomes while lowering costs. These changes depend on health care payers, systems, physicians, and patients having meaningful measures to assess care delivery and outcomes and to balance financial incentives for lowering costs while providing greater value. Gaps in accountable care measure sets may cause missed signals of problems in care and missed opportunities for improvement. Measures to balance financial incentives may be particularly important for oncology, where high cost and increasingly targeted diagnostics and therapeutics intersect with the highly complex and heterogeneous needs and preferences of cancer patients. Moreover, the concept of value in cancer care, defined as the measure of outcomes achieved per costs incurred, is rarely incorporated into performance measurement. This article analyzes gaps in oncology measures in accountable care, discusses challenging measurement issues, and offers strategies for improving oncology measurement. Discern Health analyzed gaps in accountable care measure sets for 10 cancer conditions that were selected based on incidence and prevalence; impact on cost and mortality; a diverse range of high-cost diagnostic procedures and treatment modalities (e.g., genomic tumor testing, molecularly targeted therapies, and stereotactic radiotherapy); and disparities or performance gaps in patient care. We identified gaps by comparing accountable care set measures with high-priority measurement opportunities derived from practice guidelines developed by the National Comprehensive Cancer Network and other oncology specialty societies. We found significant gaps in accountable care measure sets across all 10 conditions. For each gap, we searched for available measures not already being used in programs. Where existing measures did not cover gaps, we recommended refinements to existing measures or proposed measures for development. We shared the results of the measure gap analysis with a roundtable of national experts in cancer care and oncology measurement. During a web meeting and an in-person meeting, the roundtable reviewed the gap analysis and identified priority opportunities for improving measurement. The group determined that overreliance on condition-specific process measures is problematic because of rapidly changing evidence and increasing personalization of cancer care. The group’s primary recommendation for enhancing measure sets was to prioritize and develop effective cross-cutting measures that assess clinical and patient-reported outcomes, including shared decision making, care planning, and symptom control. The group also prioritized certain safety and structural measures to complement condition-specific process measures. Further, the group explored strategies for using clinical pathways and devising layered measurement approaches to improve measurement for accountable care. This article presents the roundtable’s conclusions and recommendations for next steps.

Concepts: Health care, Medicine, Health insurance, Cancer, Oncology, Chemotherapy, Tumor, Cancer patient

264

Metastasis through the bloodstream contributes to poor prognosis in many types of cancer. Mounting evidence implicates selectin-based adhesive interactions between cancer cells and the blood vessel wall as facilitating this process, in a manner similar to leukocyte trafficking during inflammation. Here, we describe a unique approach to target and kill colon and prostate cancer cells in the blood that causes circulating leukocytes to present the cancer-specific TNF-related apoptosis inducing ligand (TRAIL) on their surface along with E-selectin adhesion receptor. This approach, demonstrated in vitro with human blood and also in mice, mimics the cytotoxic activity of natural killer cells and increases the surface area available for delivery of the receptor-mediated signal. The resulting “unnatural killer cells” hold promise as an effective means to neutralize circulating tumor cells that enter blood with the potential to form new metastases.

Concepts: Immune system, Lymphocyte, Cancer, Metastasis, Oncology, Blood, Blood vessel, Prostate cancer

262

Background Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). Methods In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. Results Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%). Conclusions In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).

Concepts: Immune system, Cancer, Oncology, Lung cancer, Non-small cell lung carcinoma, Epidermal growth factor receptor, Epidermal growth factor, Monoclonal antibodies

251

The relationship between body size and prostate cancer risk, and in particular risk by tumour characteristics, is not clear because most studies have not differentiated between high-grade or advanced stage tumours, but rather have assessed risk with a combined category of aggressive disease. We investigated the association of height and adiposity with incidence of and death from prostate cancer in 141,896 men in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Concepts: Epidemiology, Cancer, Oncology, Nutrition, Obesity, Prostate cancer, Tumor, Neoplasm