Dynamics of cancer cell subpopulations in primary and metastatic colorectal tumors

Intratumor heterogeneity—heterogeneity of cancer cells within a single tumor—is considered one of the most problematic factors of treatment. Genetic heterogeneity, such as in somatic mutations and chromosome aberrations, is a common characteristic of human solid tumors and is probably the basis of biological heterogeneity. Using mutations in APC, TP53 and KRAS as markers to identify distinct colorectal cancer subpopulations, we analyzed a total of 42 primary colorectal cancer tissues and six paired liver metastases with multipoint microsampling, which enabled analysis of mutation patterns and allelic imbalances with a resolution of 0.01 mm2 (about 200 cells). There was usually more than one subpopulation in each primary tumor. Only two of 15 (13.3%) cases with three gene mutations and eight of 27 (29.6%) cases with two gene mutations had a single subpopulation. Cells with mutations in all of the examined genes usually constituted the major population. Multipoint microsampling of six primary and metastatic tumor pairs revealed that the majority of discrepancies in mutation patterns found with the bulk tissue analysis were due to loss of subpopulations in the metastatic tissues. In addition, multipoint microsampling uncovered substantial changes in subpopulations that were not detected with bulk tissue analysis. Specifically, the proportion of KRAS mutation-negative subpopulations increased in the metastatic tumors of four cases. Because KRAS mutation status is linked to cetuximab/panitumumab efficacy, subpopulation dynamics could lead to differences in response to cetuximab/panitumumab in primary versus metastatic tumors

Fluropyrimidine single agent or doublet chemotherapy as second line treatment in advanced biliary tract cancer

Fluoropyrimidine (FP) plus platinum chemotherapy has been recently established as a second-line (L2) preferred option in advanced biliary tract cancer (aBTC) (ABC-06 phase III trial). However, the overall survival (OS) benefit was limited and comparison with FP monotherapy was not available. Our aim was to assess the OS of patients treated with a FP monotherapy compared to a doublet with irinotecan or platinum in L2. We performed a retrospective analysis of two large multicenter prospective cohorts: a French cohort (28 centers) and an Italian cohort (9 centers). All consecutive patients with aBTC receiving FP-based L2 after gemcitabine plus cisplatin/gemcitabine plus oxaliplatin L1 between 2003 and 2016 were included. A subgroup analysis according to performance status (PS) and an exploratory analysis according to platinum sensitivity in L1 were planned. In the French cohort (n = 351), no significant OS difference was observed between the FP monotherapy and doublet groups (median OS: 5.6 vs 6.8 months, P =.65). Stratification on Eastern Cooperative Oncology Group (ECOG) PS showed similar results in PS 0-1 and 2. Median OS was not different between FP monotherapy, platinum- and irinotecan-based doublets (5.6 vs 7.1 vs 6.7 months, P =.68). Similar findings were observed in the Italian cohort (n = 174) and in the sensitivity analysis in pooled cohorts (n = 525). No L2 regimen seemed superior over others in the platinum resistant/refractory or sensitive subgroups. Our results suggest that FP monotherapy is as active as FP doublets in aBTC in L2, regardless of the patient PS and country, and could be a therapeutic option in this setting

prediction of overall survival with 2nd line l2os chemotherapy ct in patients with advanced biliary tract cancer abtc ageo ct2bil cohort update and international multicenter external validations

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Completeness of hepatitis, brucellosis, syphilis, measles and HIV/AIDS surveillance in Izmir, Turkey

<p>Abstract</p> <p>Background</p> <p>According to the surveillance system in Turkey, most diseases are notified only by clinicians, without involving laboratory notification. It is assumed that a considerable inadequacy in notifications exists; however, this has not been quantified by any researcher. Our aim was to evaluate the completeness of communicable disease surveillance in the province of Izmir, Turkey for the year of 2003 by means of estimating the incidences of diseases.</p> <p>Methods</p> <p>Data on positive laboratory results for the notifiable and serologically detectable diseases hepatitis A, B, C, brucellosis, syphilis, measles and HIV detected in 2003 in Izmir (population 3.5 million) were collected from serology laboratories according to WHO surveillance standards and compared to the notifications received by the Provincial Health Directorate. Data were checked for duplicates and matched. Incidences were estimated with the capture-recapture method. Sensitivities of both notifications and laboratory data were calculated according to these estimates.</p> <p>Results</p> <p>Among laboratories performing serologic tests (n = 158) in Izmir, 84.2% accepted to participate, from which 23,515 positive results were collected. Following the elimination of duplicate results as well as of cases residing outside of Izmir, the total number was 11,402. The total number of notifications was 1802. Notification rates of cases found in laboratories were 31.6% for hepatitis A, 12.1% for acute hepatitis B, 31.8% for brucellosis, 25.9% for syphilis and 100% for HIV confirmation.</p> <p>Conclusions</p> <p>It was discovered that for hepatitis A, B, C, brucellosis and syphilis, there is a considerable under-notification by clinicians and that laboratory data has the potential of contributing greatly to their surveillance. The inclusion of laboratories in the surveillance system of these diseases could help to achieve completeness of reporting.</p

Development of the Advancing the Patient Experience (APEX) in COPD Registry : A Modified Delphi Study

Funding statement: APEX COPD is conducted by Optimum Patient Care (OPC) Global Limited, and co-funded by OPC Global and Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors received no direct compensation related to the development of the manuscript. Writing, editorial support, and/or formatting assistance was provided by Ms. Audrey Ang of the Observational and Pragmatic Research Institute, Singapore, and Dr. Lisa Buttle of Medscript Ltd, Ireland, which was funded by BIPI. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Acknowledgments The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). We thank Dr. Alvaro Aranda (Hospital Auxilio Mutuo, San Juan, Puerto Rico) for his scientific and clinical contributions during the drafting of this manuscript. We also thank Ms. Audrey Ang for editorial assistance, Ms. Bronte Sawyer for project coordination, and Dr. Lisa Buttle for assistance with drafting the article. Dr. Ruth B. Murray is acknowledged for her substantial contribution to the interpretation, summarization and presentation of data in this article and significant intellectual input to the manuscript. She has provided her final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Ruth B. Murray is the founder and director of Medscript Ltd., a company that provided writing and editorial support for APEX COPD publications.Peer reviewedPostprin

A Perspective on Challenges and Issues in Biomarker Development and Drug and Biomarker Codevelopment

A workshop sponsored by the National Cancer Institute and the US Food and Drug Administration addressed past lessons learned and ongoing challenges faced in biomarker development and drug and biomarker codevelopment. Participants agreed that critical decision points in the product life cycle depend on the level of understanding of the biology of the target and its interaction with the drug, the preanalytical and analytical factors affecting biomarker assay performance, and the clinical disease process. The more known about the biology and the greater the strength of association between an analytical signal and clinical result, the more efficient and less risky the development process will be. Rapid entry into clinical practice will only be achieved by using a rigorous scientific approach, including careful specimen collection and standardized and quality-controlled data collection. Early interaction with appropriate regulatory bodies will ensure studies are appropriately designed and biomarker test performance is well characterized

Variation in Demographic and Clinical Characteristics of COPD Patients Managed in U.S. Primary Care : Data from a Real-Life COPD Registry

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Characterization of COPD in U.S. Primary Care : Data from a Real-Life COPD Registry

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Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy

<p>Abstract</p> <p>Background</p> <p>P53 mutations are an adverse prognostic factor in esophageal cancer. P53 and KRas mutations are involved in chemo-radioresistance. Circulating anti-p53 or anti-KRas antibodies are associated with gene mutations. We studied whether anti-p53 or anti-KRas auto-antibodies were prognostic factors for response to chemoradiotherapy (CRT) or survival in esophageal carcinoma.</p> <p>Methods</p> <p>Serum p53 and KRas antibodies (abs) were measured using an ELISA method in 97 consecutive patients treated at Saint Louis University Hospital between 1999 and 2002 with CRT for esophageal carcinoma (squamous cell carcinoma (SCCE) 57 patients, adenocarcinoma (ACE) 27 patients). Patient and tumor characteristics, response to treatment and the follow-up status of 84 patients were retrospectively collected. The association between antibodies and patient characteristics was studied. Univariate and multivariate survival analyses were conducted.</p> <p>Results</p> <p>Twenty-four patients (28%) had anti-p53 abs. Abs were found predominantly in SCCE (p = 0.003). Anti-p53 abs were associated with a shorter overall survival in the univariate analysis (HR 1.8 [1.03-2.9], p = 0.04). In the multivariate analysis, independent prognostic factors for overall and progression-free survival were an objective response to CRT, the CRT strategy (alone or combined with surgery [preoperative]) and anti-p53 abs. None of the long-term survivors had p53 abs. KRas abs were found in 19 patients (23%, no difference according to the histological type). There was no significant association between anti-KRas abs and survival neither in the univariate nor in the multivariate analysis. Neither anti-p53 nor anti-KRas abs were associated with response to CRT.</p> <p>Conclusions</p> <p>Anti-p53 abs are an independent prognostic factor for esophageal cancer patients treated with CRT. Individualized therapeutic approaches should be evaluated in this population.</p