Prognostic value of primary tumour resection in synchronous metastatic colorectal cancer: Individual patient data analysis of first-line randomised trials from the ARCAD database

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): K.L. van Rooijen, Q. Shi, K.K.H. Goey, J. Meyers, V. Heinemann, E. Diaz-Rubio, E. Aranda, A. Falcone, E. Green, A. de Gramont, D.J. Sargent, C.J.A. Punt, M. Koopman
Indication for primary tumour resection (PTR) in asymptomatic metastatic colorectal cancer (mCRC) patients is unclear. Previous retrospective analyses suggest a survival benefit for patients who underwent PTR. The aim was to evaluate the prognostic value of PTR in patients with synchronous mCRC by analysis of recent large RCTs including systemic therapy with modern targeted agents.Individual patient data (IPD) of 3423 patients enrolled into 8 randomised controlled trials (RCTs) with first-line systemic therapy in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analysed.The number of patients with unresected synchronous mCRC, resected synchronous mCRC and metachronous mCRC was 710 (21%), 1705 (50%) and 1008 (29%), respectively. Adjusting for age, gender, performance status (PS) and prior chemotherapy, the unresected group had a significantly worse median overall survival (16.4 m) compared with the synchronous resected (22.2 m; hazard ratio [HR] 1.60, 95% CI 1.43–1.78) and metachronous (22.4 m; HR 1.81, 95% CI 1.58–2.07) groups. Similarly, median progression-free survival was significantly worse for the unresected group compared with the synchronous resected (HR 1.31, 95% CI 1.19–1.44) and metachronous (HR 1.47, 95% CI 1.30–1.66) groups. In a multivariate analysis, the observed associations remained significant.This largest IPD analysis of mCRC trials to date demonstrates an improved survival in synchronous mCRC patients after PTR. These results may be subject to bias since reasons for (non)resection were not available. Until results of ongoing RCTs are available, both upfront PTR followed by systemic treatment and upfront systemic treatment are considered appropriate treatment strategies.



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Fast growing melanoma following treatment with vismodegib for locally advanced basal cell carcinomas: report of two cases

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): Roberta Giuffrida, Karl Kashofer, Emi Dika, Annalisa Patrizi, Carlotta Baraldi, Nicola Di Meo, Iris Zalaudek




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Integrative expression quantitative trait locus–based analysis of colorectal cancer identified a functional polymorphism regulating SLC22A5 expression

Publication date: April 2018
Source:European Journal of Cancer, Volume 93
Author(s): Danyi Zou, Jiao Lou, Juntao Ke, Shufang Mei, Jiaoyuan Li, Yajie Gong, Yang Yang, Ying Zhu, Jianbo Tian, Jiang Chang, Rong Zhong, Jing Gong, Xiaoping Miao
Multiple single nucleotide polymorphisms (SNPs) have been found to be highly correlated with colorectal cancer (CRC) risk. However, the variants identified thus far only explain a small part of the cases, suggesting the existence of many uncharacterised genetic determinants. In this study, using the multilevel 'omics' data provided in The Cancer Genome Atlas, we systematically performed expression quantitative trait locus (eQTL) analysis for CRC and identified nine SNPs with significant effects on mRNA expression (correlation |r| > 0.3 and FDR < 0.01). Then we conducted a two-stage case–control study consisting of 1528 cases and 1528 controls to examine the associations between candidate SNPs and CRC risk. We found that rs27437 in SLC22A5 was significantly correlated with CRC risk in both stages and the combined study (additive model, OR = 1.31, 95%CI = 1.17–1.47, P = 1.97 × 10⁻⁶). eQTL analysis showed that rs27437 GG and GA genotypes were associated with lower expression of SLC22A5 compared with the AA genotype. Dual-luciferase reporter assays confirmed that the G risk allele could decrease the expression of luciferase. SLC22A5 was significantly decreased in CRC tumour tissues compared with adjacent normal tissues, indicating that SLC22A5 may play important roles in CRC, and rs27437 in SLC22A5 might serve as a novel biomarker for early detection and prevention of CRC.



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Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): Adriana María Belén Abiuso, María Luisa Varela, Luis Haro Durand, Marcos Besio Moreno, Alejandra Marcos, Roberto Ponzio, Marco Aurelio Rivarola, Alicia Belgorosky, Omar Pedro Pignataro, Esperanza Berensztein, Carolina Mondillo
Leydig-cell tumours (LCTs) are rare endocrine tumours of the testicular interstitium, with recent increased incidence. Symptoms include precocious puberty in children; and erectile dysfunction, infertility and/or gynaecomastia, in adults. So far, scientific evidence points to aromatase (CYP19) overexpression and excessive oestrogen and insulin-like growth factor (IGF) –1 production as responsible for Leydig-cell tumourigenesis. LCTs are usually benign; however, malignant LCTs respond poorly to chemo/radiotherapy, highlighting the need to identify novel targets for treatment. Herein, we investigated the potential role of the histamine receptor H4 (HRH4) as a therapeutic target for LCTs using R2C rat Leydig tumour cells, a well-documented in vitro model for Leydigioma. Also, we studied for the first time the expression of CYP19, IGF-1R, oestrogen receptor (ER) α, ERβ, androgen receptor (AR) and HRH4 in human prepubertal LCTs versus normal prepubertal testes (NPTs). HRH4 agonist treatment inhibited steroidogenesis and proliferation in R2C cells and also negatively affected their pro-angiogenic capacity in vitro and in vivo, as assessed by evaluating the proliferative activity of human umbilical vein endothelial cells and by means of the quail chorioallantoic membrane assay, respectively. Moreover, E2 and IGF-1 inhibited HRH4 mRNA and protein levels. In human prepubertal LCTs, CYP19, IGF-1R, ERα and ERβ were overexpressed compared with NPTs. In contrast, HRH4 staining was weak in LCTs, but moderate/strong and confined to the interstitium in NPTs. Importantly, HRH4 was absent or barely detectable in seminiferous tubules or germ cells. Overall, our results point to HRH4 as a novel therapeutic target in LCTs.



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Hallmarks of cancer: The CRISPR generation

Publication date: April 2018
Source:European Journal of Cancer, Volume 93
Author(s): Colette Moses, Benjamin Garcia-Bloj, Alan R. Harvey, Pilar Blancafort
The hallmarks of cancer were proposed as a logical framework to guide research efforts that aim to understand the molecular mechanisms and derive treatments for this highly complex disease. Recent technological advances, including comprehensive sequencing of different cancer subtypes, have illuminated how genetic and epigenetic alterations are associated with specific hallmarks of cancer. However, as these associations are purely descriptive, one particularly exciting development is the emergence of genome editing technologies, which enable rapid generation of precise genetic and epigenetic modifications to assess the consequences of these perturbations on the cancer phenotype. The most recently developed of these tools, the system of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), consists of an RNA-guided endonuclease that can be repurposed to edit both genome and epigenome with high specificity, and facilitates the functional interrogation of multiple loci in parallel. This system has the potential to dramatically accelerate progress in cancer research, whether by modelling the genesis and progression of cancer in vitro and in vivo, screening for novel therapeutic targets, conducting functional genomics/epigenomics, or generating targeted cancer therapies. Here, we discuss CRISPR research on each of the ten hallmarks of cancer, outline potential barriers for its clinical implementation and speculate on the advances it may allow in cancer research in the near future.



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Current perspective: Osimertinib-induced QT prolongation: new drugs with new side-effects need careful patient monitoring

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): Mart Schiefer, Lizza E.L. Hendriks, Trang Dinh, Ulrich Lalji, Anne-Marie C. Dingemans
An increasing number of tyrosine kinase inhibitors (TKIs) are available for the treatment of non–small cell lung cancer (NSCLC). QT prolongation is one of the known, but relatively rare, adverse events of several TKIs (e.g. osimertinib, crizotinib, ceritinib). Screening for QT prolongation in (high risk) patients is advised for these TKIs. When a QT prolongation develops, the physician is challenged with the question whether to (permanently) discontinue the TKI. In this perspective, we report on a patient who developed a grade III QT prolongation during osimertinib (a third-generation epidermal growth factor receptor [EGFR]-TKI) treatment. On discontinuation of osimertinib, she developed a symptomatic disease flare, not responding to subsequent systemic treatment. The main aim of this perspective is to describe the management of QT prolongation in stage IV EGFR driver mutation NSCLC patients. We also discuss the ethical question of how to weigh the risk of a disease flare due to therapy cessation against the risk of sudden cardiac death. A family history of sudden death and a prolonged QT interval might indicate a familiar long QT syndrome. We have summarised the current monitoring advice for TKIs used in the treatment of lung cancer and the most common drug–TKI interactions to consider and to optimise TKI treatment in lung cancer patients.



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Diversity of brain metastases screening and management in non-small cell lung cancer in Europe: Results of the European Organisation for Research and Treatment of Cancer Lung Cancer Group survey

Publication date: April 2018
Source:European Journal of Cancer, Volume 93
Author(s): Antonin Levy, Corinne Faivre-Finn, Baktiar Hasan, Eleonora De Maio, Anna S. Berghoff, Nicolas Girard, Laurent Greillier, Sylvie Lantuéjoul, Mary O'Brien, Martin Reck, Anne-Marie C. Dingemans, Silvia Novello, Thierry Berghmans, Benjamin Besse, Lizza Hendriks
BackgroundBrain metastases (BM) are frequent in non-small cell lung cancer (NSCLC) patients, but there is a lack of evidence-based management of this patient group. We aimed to capture a snapshot of routine BM management in Europe to identify relevant research questions for future clinical trials.MethodsAn EORTC Lung Cancer Group (LCG) online survey containing questions on NSCLC BM screening and treatment was distributed between 16/02/17 and 15/06/17 to worldwide EORTC LCG members, and through several European scientific societies in the thoracic oncology field.ResultsA total of 462 European physician responses (394 institutions) were analysed (radiation oncologist: 53% [n = 247], pulmonologist: 26% [n = 119], medical oncologist: 18% [n = 84]; 84% with >5 years' experience in NSCLC). Italy (18%, n = 85), Netherlands (15%, n = 68), UK (14%, n = 66), and France (12%, n = 55) contributed most. 393 physicians (85%) screened neurologically asymptomatic patients for BM at diagnosis (52% using magnetic resonance imaging). Most often screened patients were those with a driver mutation (MUT+; 51%, n = 234), stage III (63%, n = 289), and IV (43%, n = 199). 158 physicians (34%) used a prognostic classification to guide initial treatment decisions, and in 50%, lowest prognostic-score threshold to receive treatment differed between MUT+ and non-driver mutation (MUT−) patients. MUT+ patients with >4 BM were more likely to receive stereotactic radiosurgery (SRS) compared with MUT− (27% versus. 21%; p < 0.01). Most physicians (90%) had access to SRS. After single BM surgery, 50% systematically prescribed SRS or WBRT, and 45% only in case of incomplete resection. The preferred treatment in neurologically asymptomatic treatment-naive patients diagnosed with >5 BM was systemic treatment (79%). Of all, 45%/49% physicians stated that all tyrosine kinase inhibitors and immune checkpoint blockers were discontinued (timing varied) during SRS/WBRT, respectively. Drugs most often continued during SRS/WBRT were erlotinib (44%/40%), gefitinib (39%/34%), afatinib (29%/25%), crizotinib (33%/26%) and anti-PD-(L)-1 (28%/22%).ConclusionBM management is highly variable in Europe: screening is not uniform, prognostic classifications are not often used and MUT+ NSCLC patients generally receive more intensive local treatment. Prospective assessment of BM management in MUT+ NSCLC patients is required.



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Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): Sara Valpione, Matteo S. Carlino, Johanna Mangana, Meghan J. Mooradian, Grant McArthur, Dirk Schadendorf, Axel Hauschild, Alexander M. Menzies, Ana Arance, Paolo A. Ascierto, AnnaMaria Di Giacomo, Francesco de Rosa, James Larkin, John J. Park, Simone M. Goldinger, Ryan J. Sullivan, Wen Xu, Elisabeth Livingstone, Michael Weichenthal, Rajat Rai, Lydia Gaba, Georgina V. Long, Paul Lorigan
BackgroundMost metastatic melanoma patients treated with BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) eventually progress on treatment. Along with acquired resistance due to genetic changes, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse retrospectively outcomes for patients retreated with BRAF-directed therapy.Patients and methodsOne hundred sixteen metastatic melanoma patients who received BRAFi-based therapy and, after a break, were rechallenged with BRAFi ± MEKi at 14 centres in Europe, US and Australia were studied, respectively. Response rate (RR), overall survival (OS) and progression-free survival (PFS) from the start of retreatment were calculated.ResultsThe median duration of treatment was 9.4 months for first BRAFi ± MEKi treatment and 7.7 months for the subsequent treatment (immunotherapy 72%, other 17%, drug holiday 11%) after BRAFi discontinuation. Brain metastases were present in 51 (44%) patients at BRAFi retreatment. The RR to rechallenge with BRAFi ± MEKi was 43%: complete response (CR) 3%, partial response (PR) 39%, stable disease (SD) 24% and progressive disease 30%, 4% missing. Of 83 patients who previously discontinued BRAFi due to disease progression, 31 (37.3%) responded (30 PR and 1 CR) to retreatment. The median OS from retreatment was 9.8 months, and PFS was 5 months. Independent prognostic factors for survival at rechallenge included number of metastatic sites (hazard ratio [HR] = 1.32 for each additional organ with metastases, P < .001), lactic dehydrogenase (HR = 1.37 for each multiple of the upper normal limit, P < .001), while rechallenge with combination BRAFi + MEKi conferred a better OS versus BRAFi alone (HR = 0.5, P = .006).ConclusionRechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients.



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High-risk soft tissue sarcomas treated with perioperative chemotherapy: Improving prognostic classification in a randomised clinical trial

Publication date: April 2018
Source:European Journal of Cancer, Volume 93
Author(s): Sandro Pasquali, Chiara Colombo, Sara Pizzamiglio, Paolo Verderio, Dario Callegaro, Silvia Stacchiotti, Javier Martin Broto, Antonio Lopez-Pousa, Stefano Ferrari, Andres Poveda, Antonino De Paoli, Vittorio Quagliuolo, Josefina Cruz Jurado, Alessandro Comandone, Giovanni Grignani, Rita De Sanctis, Elena Palassini, Antonio Llomboart-Bosch, Angelo Paolo Dei Tos, Paolo G. Casali, Piero Picci, Alessandro Gronchi
BackgroundPatients with extremity and trunk wall soft tissue sarcoma (STS) with high malignancy grade and size >5 cm are at high-risk of death. This risk varies depending also on other patient and tumour features, including histologic subtype. This study investigated whether a prognostic nomogram can improve risk assessment of these patients.MethodsData from high-risk STS patients enrolled in a randomised controlled trial investigating different perioperative chemotherapy regimens were analysed. Ten-year probability of overall survival (OS) and incidence of distant metastasis (DM) were computed using the prognostic nomogram Sarculator (pr-OS and inc-DM, respectively). Tumour response according to RECIST and Choi criteria was also investigated.FindingsVariation in pr-OS and inc-DM were observed and patients stratified in three prognostic groups. The 10-year OS in the low, intermediate, and high pr-OS categories were 0·42 (95%CI 0·32–0·52), 0·63 (95%CI 0·53–0·72), and 0·78 (95%CI 0·68–0·85), respectively. Patients in the intermediate (HR 0·51, P = 0·002) and high (HR 0·28, P < 0·001) pr-OS categories were at statistically significant lower risk of death compared with those in the low pr-OS category. Higher rate of Choi partial tumour responses were detected in intermediate pr-OS category. Tumour response according to Choi but not to RECIST criteria stratified patient survival of pr-OS categories, particularly for patients with intermediate to low pr-OS. Analyses conducted for 10-year inc-DM were consistent with results for pr-OS for prognostic value of Sarculator predictions and Choi tumour response.InterpretationSarculator identifies variations in outcomes of high-risk STS treated with perioperative chemotherapy and improve prognostic classification, which is also associated with different patterns of tumour response, an outcome that further stratifies survival particularly for patients predicted at higher risk. Future trials investigating neoadjuvant chemotherapy should consider prognostic tool for selecting patients to be enrolled.Trial registration numberEuropean Union Drug Regulating Authorities Clinical Trials No. 2004-003979-36.



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Blood classification and blood response criteria in mycosis fungoides and Sézary syndrome using flow cytometry: recommendations from the EORTC cutaneous lymphoma task force

Publication date: April 2018
Source:European Journal of Cancer, Volume 93
Author(s): Julia J. Scarisbrick, Emmilia Hodak, Martine Bagot, Rene Stranzenbach, Rudolf Stadler, Pablo L. Ortiz-Romero, Evangelia Papadavid, Felicity Evison, Robert Knobler, Pietro Quaglino, Maarten H. Vermeer
Our current mycosis fungoides (MF) and Sézary Syndrome (SS) staging system includes blood-classification from B0-B2 for patch/plaque/tumour or erythroderma based on manual Sézary counts but results from our EORTC survey confirm these are rarely performed in patch/plaque/tumour MF, and there is a trend towards using flow cytometry to measure blood-class. Accurately assigning blood-class effects overall stage and the 'global response' used to measure treatment responses in MF/SS and hence impacts management. The EORTC Cutaneous Lymphoma Task Force Committee have reviewed the literature and held a Workshop (June 2017) to agree a definition of blood-class according to flow cytometry.No large study comparing blood-class as defined by Sézary count with flow cytometry has been performed in MF/SS. The definition of blood-class by flow cytometry varies between publications. Low-level blood involvement occurs in patch/plaque/tumour much less than erythroderma (p < 0.001). The prognostic relevance of blood involvement (B1 or B2) in patch/plaque/tumour is not known. Studies have not shown a statistically worse difference in prognosis in erythrodermic MF patients with low-level blood involvement (IIIB) versus those without (IIIA), but Sezary patients who by definition have a leukaemic blood picture (staged IVA1 or higher) have a worse prognosis.For consistency flow, definition for blood-class must be an objective measurement. We propose absolute counts of either CD4+CD7-or CD4+CD26-where B0<250/μL, B1 = 250/μl–<1000/μL and B2≥1000/μL plus a T-cell blood clone. Fluctuations between B0 and B1 should not be considered in the treatment response criteria until further prognostic information is known.



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A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: Final safety, immunogenicity and survival results

Publication date: April 2018
Source:European Journal of Cancer, Volume 93
Author(s): X. Pivot, I. Bondarenko, Z. Nowecki, M. Dvorkin, E. Trishkina, J.-H. Ahn, S.-A. Im, T. Sarosiek, S. Chatterjee, M.Z. Wojtukiewicz, Y. Shparyk, V. Moiseyenko, M. Bello, V. Semiglazov, Y. Lee, J. Lim
BackgroundThe equivalent efficacy between SB3, a proposed trastuzumab biosimilar, and the trastuzumab reference product (TRZ) in terms of the breast pathologic complete response rate after neoadjuvant therapy in patients with early or locally advanced human epidermal growth factor receptor 2-positive breast cancer was demonstrated in the previous report. Here, we report the final safety, immunogenicity and survival results after neoadjuvant-adjuvant treatment.Patients and methodsPatients were randomised 1:1 to receive neoadjuvant SB3 or TRZ for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery, followed by 10 cycles of adjuvant SB3 or TRZ as randomised. End-points included safety, immunogenicity, event-free survival (EFS) and overall survival through the adjuvant period.ResultsOf 875 patients randomised, 764 (SB3, n = 380; TRZ, n = 384) completed the study. The median follow-up duration was 437 days in the SB3 group and 438 days in the TRZ group. The incidence of treatment-emergent adverse events was comparable between groups (SB3, 97.5%; TRZ, 96.1%) during the overall study period. Up to the end of study, the overall incidence of antidrug antibody was low in both treatment groups (3 patients each). EFS was comparable between groups with a hazard ratio (SB3/TRZ) of 0.94 (95% confidence interval, 0.59–1.51) and EFS rates at 12 months of 93.7% for SB3 and 93.4% for TRZ.ConclusionsFinal safety, immunogenicity and survival results of this study further support the biosimilarity established between SB3 and TRZ.Trial registrationClinicalTrials.gov (NCT02149524); EudraCT (2013-004172-35).



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Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma

Publication date: April 2018
Source:European Journal of Cancer, Volume 93
Author(s): Tarec Christoffer El-Galaly, Chan Yoon Cheah, Mette Dahl Bendtsen, Grzegorz S. Nowakowski, Roopesh Kansara, Kerry J. Savage, Joseph M. Connors, Laurie H. Sehn, Neta Goldschmidt, Adir Shaulov, Umar Farooq, Brian K. Link, Andrés J.M. Ferreri, Teresa Calimeri, Caterina Cecchetti, Eldad J. Dann, Carrie A. Thompson, Tsofia Inbar, Matthew J. Maurer, Inger Lise Gade, Maja Bech Juul, Jakob W. Hansen, Staffan Holmberg, Thomas S. Larsen, Sabrina Cordua, N. George Mikhaeel, Martin Hutchings, John F. Seymour, Michael Roost Clausen, Daniel Smith, Stephen Opat, Michael Gilbertson, Gita Thanarajasingam, Diego Villa
PurposeSecondary CNS involvement (SCNS) is a profoundly adverse complication of diffuse large B-cell lymphoma. Evidence from older series indicated a median overall survival (OS) < 6 months; however, data from the immunochemotherapy era are limited.MethodsPatients diagnosed with SCNS during or after first-line immunochemotherapy were identified from databases and/or regional/national registries from three continents. Clinical information was retrospectively collected from medical records.ResultsIn total, 291 patients with SCNS were included. SCNS occurred as part of first relapse in 254 (87%) patients and 113 (39%) had concurrent systemic relapse. With a median post-SCNS follow-up of 48 months, the median post-SCNS OS was 3.9 months and 2-year OS rate was 20% (95% CI: 15–25). In multivariable analysis of 173 patients treated with curative/intensive therapy (such as high-dose methotrexate [HDMTX] or platinum-containing regimens), age ≤60 years, performance status 0–1, absence of combined leptomeningeal and parenchymal involvement, and SCNS occurring after completion of first-line therapy were associated with superior outcomes. Patients ≤60 years with performance status 0–1 and treated with HDMTX-based regimens for isolated parenchymal SCNS had a 2-year OS of 62% (95% CI: 36–80). In patients with isolated SCNS, the addition of rituximab to HDMTX-based regimens was associated with improved OS. Amongst patients with isolated SCNS in CR following intensive treatment, high-dose chemotherapy and autologous stem cell transplantation did not improve OS (P = 0.9).ConclusionsIn this large international cohort of patients treated with first-line immunochemotherapy, outcomes following SCNS remain poor. However, a moderate proportion of patients with isolated SCNS who received intensive therapies achieved durable remissions.



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Time interval between neoadjuvant chemoradiotherapy and surgery for oesophageal or junctional cancer: A nationwide study

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): L.R. van der Werf, J.L. Dikken, E.M. van der Willik, M.I. van Berge Henegouwen, G.A.P. Nieuwenhuijzen, B.P.L. Wijnhoven
IntroductionThe optimal time between end of neoadjuvant chemoradiotherapy (nCRT) and oesophagectomy is unknown. The aim of this study was to assess the association between this interval and pathologic complete response rate (pCR), morbidity and 30-day/in-hospital mortality.MethodsPatients with oesophageal cancer treated with nCRT and surgery between 2011 and 2016 were selected from a national database: the Dutch Upper Gastrointestinal Cancer Audit (DUCA). The interval between end of nCRT and surgery was divided into six periods: 0–5 weeks (n = 157;A), 6–7 weeks (n = 878;B), 8–9 weeks (n = 972;C), 10–12 weeks (n = 720;D), 13–14 weeks (n = 195;E) and 15 or more weeks (n = 180;F). The association between these interval groups and outcomes was investigated using univariable and multivariable analysis with group C (8–9 weeks) as reference.ResultsIn total, 3102 patients were included. The pCR rate for the groups A to F was 31%, 28%, 26%, 31%, 40% and 37%, respectively. A longer interval was associated with a higher probability of pCR (≥10 weeks for adenocarcinoma: odds ratio [95% confidence interval]: 1.35 [1.00–1.83], 1.95 [1.24–3.07], 1.64 [0.99–2.71] and ≥13 weeks for squamous cell carcinoma: 2.86 [1.23–6.65], 2.67 [1.29–5.55]. Patients operated ≥10 weeks after nCRT had the same probability for intraoperative/postoperative complications. Patients from groups D and F had a higher 30-day/in-hospital mortality (1.80 [1.08–3.00], 3.19 [1.66–6.14]).ConclusionAn interval of ≥10 weeks for adenocarcinoma and ≥13 weeks for squamous cell carcinoma between nCRT and oesophagectomy was associated with a higher probability of having a pCR. Longer intervals were not associated with intraoperative/postoperative complications. The 30-day/in-hospital mortality was higher in patients with extended intervals (10–12 and ≥15 weeks); however, this might have been due to residual confounding.



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Heterogeneity of mismatch repair defect in colorectal cancer and its implications in clinical practice

Publication date: Available online 5 March 2018
Source:European Journal of Cancer
Author(s): Gaelle Tachon, Eric Frouin, Lucie Karayan-Tapon, Marie-Luce Auriault, Julie Godet, Valerie Moulin, Qing Wang, David Tougeron




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Comprehensive genomic profiling of head and neck squamous cell carcinoma reveals FGFR1 amplifications and tumour genomic alterations burden as prognostic biomarkers of survival

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): C. Dubot, V. Bernard, M.P. Sablin, S. Vacher, W. Chemlali, A. Schnitzler, G. Pierron, K. Ait Rais, N. Bessoltane, E. Jeannot, J. Klijanienko, O. Mariani, T. Jouffroy, V. Calugaru, C. Hoffmann, M. Lesnik, N. Badois, F. Berger, C. Le Tourneau, M. Kamal, I. Bieche
BackgroundWe aimed at identifying deleterious genomic alterations from untreated head and neck squamous cell carcinoma (HNSCC) patients, and assessing their prognostic value.Patients and methodsWe retrieved 122 HNSCC patients who underwent primary surgery. Targeted NGS was used to analyse a panel of 100 genes selected among the most frequently altered genes in HNSCC and potential therapeutic targets. We selected only deleterious (activating or inactivating) single nucleotide variations, and copy number variations for analysis. Univariate and multivariate analyses were performed to assess the prognostic value of altered genes.ResultsA median of 2 (range: 0–10) genomic alterations per sample was observed. Most frequently altered genes involved the cell cycle pathway (TP53 [60%], CCND1 [30%], CDKN2A [25%]), the PI3K/AKT/MTOR pathway (PIK3CA [12%]), tyrosine kinase receptors (EGFR [9%], FGFR1 [5%]) and cell differentiation (FAT1 [7%], NOTCH1 [4%]). TP53 mutations (p = 0.003), CCND1 amplifications (p = 0.04), CDKN2A alterations (p = 0.02) and FGFR1 amplifications (p = 0.003), correlated with shorter overall survival (OS). The number of genomic alterations was significantly higher in the HPV-negative population (p = 0.029) and correlated with a shorter OS (p < 0.0001). Only TP53 mutation and FGFR1 amplification status remained statistically significant in the multivariate analysis.ConclusionThese results suggest that genomic alterations involving the cell cycle (TP53, CCND1, CDKN2A), as well as FGFR1 amplifications and tumour genomic alterations burden are prognostic biomarkers and might be therapeutic targets for patients with HNSCC.



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When and how to use carboplatin in metastatic castration-resistant prostate cancer?

Publication date: March 2018
Source:European Journal of Cancer, Volume 92
Author(s): A. Omlin, S. Gillessen




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Paediatric dysgerminoma: Results of three consecutive French germ cell tumours clinical studies (TGM-85/90/95) with late effects study

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): Gwénaëlle Duhil de Bénazé, Hélène Pacquement, Cécile Faure-Conter, Catherine Patte, Daniel Orbach, Nadège Corradini, Claire Berger, Hélène Sudour-Bonnange, Cécile Vérité, Hélène Martelli, Brice Fresneau
MethodsFrench patients (≤18years) treated for dysgerminoma between 1985 and 2005 in TGM-85, 90, 95 protocols were included. Treatment was based on primary unilateral oophorectomy followed by prophylactic lymph node irradiation (1985–1998) or a wait-and-see strategy (1998–2005) for localised completely resected tumours (pS1) or by platinum-based chemotherapy for advanced diseases.ResultsForty-eight patients (median age 12.8 years) were included. Six patients had gonadal dysgenesis. Two had bilateral dysgerminoma. Twenty-eight patients had loco-regional dissemination, seven with para-aortic lymph nodes. None had distant metastases. Primary surgery was performed in 47/48 patients. Among the 15 patients with pS1 tumour: seven did not receive adjuvant treatment, six had lymph node irradiation and two received chemotherapy. Among the 32 patients with advanced tumour, 31 received cisplatinum-based (n = 25) or carboplatin-based (n = 8) regimen with lymph node irradiation for one of them and one did not receive adjuvant treatment. With a median follow-up of 14 years, all patients are alive in complete remission. Five events occurred: 2 contralateral dysgerminomas, 1 peritoneal relapse and 2 second neoplasms (teratoma and melanoma). Bilateral oophorectomy was necessary for 12 patients. Desire of pregnancy was expressed for 17/36 patients with unilateral oophorectomy, which succeeded in 13 cases (5 medically assisted). 2/17 had ovarian failure. The renal function was normal in 24/25 evaluated patients treated with platinum, ifosfamide or irradiation. The hearing function was evaluated on 17/36 patients treated with platinum: 12 Brock grade-0, 3 brock grade-1 and 2 grade-4.ConclusionDysgerminoma has an excellent prognosis even in advanced cases with conservative surgery and platinum-based chemotherapy. However the disease and/or treatment resulted in a high rate of bilateral oophorectomies and a significant impact on future fertility.



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The future of blood-based biomarkers for the early detection of breast cancer

Publication date: March 2018
Source:European Journal of Cancer, Volume 92
Author(s): Sau Yeen Loke, Ann Siew Gek Lee
Breast cancer (BC) is the most frequently diagnosed cancer and the most common cause of cancer-related mortality among women worldwide. Despite the extensive use of mammography as the gold standard for BC screening, the occurrences of false-positive and false-negative mammograms, as well as overdiagnosis, remain a concern in breast oncology. Thus, there is a need to identify reliable biomarkers from an easily accessible source that could generate cost-effective assays feasible for routine screening. Blood-based biomarkers may offer an alternative non-invasive strategy to improve cancer screening. Although none of the currently used blood-based biomarkers are sensitive enough for the early detection of BC, a plethora of significant findings pertaining to the development of screening tools using blood-based biomarkers have emerged in recent years. Promising candidate biomarkers such as proteins, autoantibodies, miRNAs, nucleic acid methylation, metabolites and lipids have shown great potential for detecting BC, including detection at the pre-invasive and early stages of the disease. Nevertheless, blood-based biomarkers for BC screening are still at the early phases of development, and various clinical and preclinical issues need to be addressed before these biomarkers can be used clinically. This review summarises the latest discoveries for harnessing blood-based biomarkers as novel BC screening tools, as well as discusses the limitations and challenges that need to be overcome before the translation of their use from the bench to the bedside.



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Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): François-Xavier Danlos, Anne-Laure Voisin, Valérie Dyevre, Jean-Marie Michot, Emilie Routier, Laurent Taillade, Stéphane Champiat, Sandrine Aspeslagh, Julien Haroche, Laurence Albiges, Christophe Massard, Nicolas Girard, Stéphane Dalle, Benjamin Besse, Salim Laghouati, Jean-Charles Soria, Christine Mateus, Caroline Robert, Emilie Lanoy, Aurélien Marabelle, Olivier Lambotte
ObjectivePatients with autoimmune or inflammatory disease (AID) are susceptible to immune-related adverse events (irAEs) when treated with immune check-point inhibitors (ICIs). We decided to analyse the safety and effectiveness of anti-PD-1 antibodies in AID patients and look for an association between the presence of pre-existing AID and the clinical outcome.MethodsIn a prospective study of the REISAMIC registry of grade ≥2 irAEs occurring in ICI-treated patients, we studied the associations between pre-existing AID on one hand and irAE-free survival, overall survival and best objective response rate on the other.ResultsWe identified 45 patients with 53 AIDs in REISAMIC. The cancer diagnoses included melanoma (n = 36), non–small-cell lung cancer (n = 6) and others (n = 3). The most frequent pre-existing AIDs were vitiligo (n = 17), psoriasis (n = 12), thyroiditis (n = 7), Sjögren syndrome (n = 4) and rheumatoid arthritis (n = 2). Twenty patients (44.4%) presented with at least one irAE: eleven of these were associated with a pre-existing AID ('AID flare'). Treatment with anti-PD-1 antibodies was maintained in 15 of the 20 patients with an irAE. The IrAE-free survival time was significantly shorter in AID patients (median: 5.4 months) than in AID-free patients (median: 13 months, p = 2.1 × 10⁻⁴). The AID and AID-free groups did not differ significantly with regard to the overall survival time and objective response rate (p = 0.38 and 0.098, respectively).ConclusionIn patients treated with anti-PD-1 antibody, pre-existing AID was associated with a significantly increased risk of irAEs. Our results indicate that cancer treatments with anti-PD-1 antibodies are just as effective in AID patients as they are in AID-free patients.



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PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer—a randomised biomarker-driven clinical phase II AIO study

Publication date: March 2018
Source:European Journal of Cancer, Volume 92
Author(s): Arndt Vogel, Stefan Kasper, Michael Bitzer, Andreas Block, Marianne Sinn, Henning Schulze-Bergkamen, Markus Moehler, Nicole Pfarr, Volker Endris, Benjamin Goeppert, Kirsten Merx, Elisabeth Schnoy, Jens T. Siveke, Patrick Michl, Dirk Waldschmidt, Jan Kuhlmann, Michael Geissler, Christoph Kahl, Ralph Evenkamp, Torben Schmidt, Alexander Kuhlmann, Wilko Weichert, Stefan Kubicka
BackgroundCombination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer.Patients and methodsPatients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m² and gemcitabine 1000 mg/m² on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.v q3w). The primary end-point was the evaluation of progression-free survival (PFS) at 6 months. Secondary end-points included objective response rate (ORR), overall survival (OS), and toxicity. In addition, a post hoc assessment of genetic alterations was performed. Finally, we performed a meta-analysis of trials with chemotherapy with and without EGFR antibodies.ResultsSixty-two patients were randomised in arm A and 28 patients in arm B. Patients received 7 treatment cycles in median (1–35) with a median treatment duration of 4.7 months (141 days, 8–765). PFS rate at 6 months was 54% in patients treated with cisplatin/gemcitabine and panitumumab but was 73% in patients treated with cisplatin/gemcitabine without antibody, respectively. Secondary end-points were an ORR of 45% in treatment arm A compared with 39% receiving treatment B and a median OS of 12.8 months (arm A) and of 20.1 months (arm B), respectively. In contrast to the p53-status, genetic alterations in IDH1/2 were linked to a high response after chemotherapy and prolonged survival. In accordance with our results, the meta-analysis of 12 trials did not reveal a survival advantage for patients treated with EGFR antibodies compared with chemotherapy alone.ConclusionsPanitumumab in combination with chemotherapy does not improve ORR, PFS and OS in patients with KRAS wild-type, advanced biliary cancer. Genetic profiling should be included in CCA trials to identify and validate predictive and prognostic biomarkers.Clinical Trials NumberThe trial was registered with NCT01320254.



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Meta-analysis of whole-brain radiotherapy plus temozolomide compared with whole-brain radiotherapy for the treatment of brain metastases from non-small-cell lung cancer

Abstract

The aim of this meta-analysis was to compare the efficiency of whole-brain radiotherapy (WBRT) plus temozolomide (TMZ) with WBRT for the treatment of brain metastases from non-small-cell lung cancer (NSCLC). For dichotomous variables, outcomes were reported as relative risk ratio (RR) and 95% confidence interval (CI) was used to investigate the following outcome measures: overall response rate, headache, gastrointestinal adverse reactions, and hematological adverse reactions. Twelve randomized controlled trials involving 925 participants (480 received WBRT plus TMZ; 445 received WBRT) were included in the meta-analysis. There was a significant difference between the overall response rate (RR = 1.40, 95% CI 1.24–1.57; Z = 5.51; P < 0.00001), gastrointestinal adverse reactions (RR = 1.46, 95% CI 1.05–2.04; Z = 2.27; P = 0.02), and hematological adverse reactions (RR = 1.45, 95% CI 1.04–2.02; Z = 2.21; P = 0.03) of patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. There was no significant difference between headaches (RR = 1.11, 95% CI 0.93–1.02; Z = 1.13; P = 0.26) in patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. In conclusion, the currently available evidence shows that WBRT plus TMZ increases the overall response rate in patients with brain metastases of NSCLC compared with WBRT alone.

The currently available evidence shows that whole-brain radiotherapy (WBRT) plus temozolomide increases the overall response rate in patients with brain metastases of non-small-cell lung cancer compared with WBRT alone.

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Meta-analysis of whole-brain radiotherapy plus temozolomide compared with whole-brain radiotherapy for the treatment of brain metastases from non-small-cell lung cancer

Abstract

The aim of this meta-analysis was to compare the efficiency of whole-brain radiotherapy (WBRT) plus temozolomide (TMZ) with WBRT for the treatment of brain metastases from non-small-cell lung cancer (NSCLC). For dichotomous variables, outcomes were reported as relative risk ratio (RR) and 95% confidence interval (CI) was used to investigate the following outcome measures: overall response rate, headache, gastrointestinal adverse reactions, and hematological adverse reactions. Twelve randomized controlled trials involving 925 participants (480 received WBRT plus TMZ; 445 received WBRT) were included in the meta-analysis. There was a significant difference between the overall response rate (RR = 1.40, 95% CI 1.24–1.57; Z = 5.51; P < 0.00001), gastrointestinal adverse reactions (RR = 1.46, 95% CI 1.05–2.04; Z = 2.27; P = 0.02), and hematological adverse reactions (RR = 1.45, 95% CI 1.04–2.02; Z = 2.21; P = 0.03) of patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. There was no significant difference between headaches (RR = 1.11, 95% CI 0.93–1.02; Z = 1.13; P = 0.26) in patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. In conclusion, the currently available evidence shows that WBRT plus TMZ increases the overall response rate in patients with brain metastases of NSCLC compared with WBRT alone.

The currently available evidence shows that whole-brain radiotherapy (WBRT) plus temozolomide increases the overall response rate in patients with brain metastases of non-small-cell lung cancer compared with WBRT alone.

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PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity

Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DCs). DC signals can be bypassed by CD27 agonists and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb).Experimental Design: The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow-cytometry analysis were used to delineate mechanisms underpinning the observed synergy. Results: PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8+ T-cell expansion and effector function, exemplified by enhanced IFN-, TNF-α, granzyme B and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL-2 and Myc. However, division of labor was also apparent such that anti-PD-1/L1 activates a cytotoxicity-gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8+ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for anti-tumor immunity. Finally, we show that a clinically-relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD-L1 blockade for protection against lymphoma in human-CD27 transgenic mice. Conclusions: Our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches co-operate for CD8+ T-cell activation.

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Identification and Validation of Stromal Immunotype Predict Survival and Benefit from Adjuvant Chemotherapy in Patients with Muscle Invasive Bladder Cancer

Purpose: This study aims to construct the stromal immunotype which could improve prediction of postsurgical survival and adjuvant platinum-based chemotherapy in muscle-invasive bladder cancer (MIBC). Patients and Methods: A total of 118 MIBC patients from Shanghai Cancer Center, 140 MIBC patients from Zhongshan hospital and 287 MIBC patients from TCGA cohort were included in the study. Immune cell infiltration was evaluated by immunohistochemical staining or CIBERSORT method. Five immune features were selected out of 22 immune features to construct immunotype based on LASSO Cox regression model. Result: Using the LASSO model, we classified MIBC patients into stromal immunotype A subgroup (CTL high NK high Treg low Macrophage low MC low) and stromal immunotype B subgroup (CTL low NK low Treg high Macrophage high MC high). Significant differences were found between immunotype A and immunotype B in the combined cohort with 5-year overall survival (76.0% vs. 44.0%; P<0.001) and 5-year disease-free survival (62.8% vs. 48.3%; P<0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately. Either overall survival or disease-free survival was not improved by adjuvant chemotherapy (ACT) in pT2 stage patients or pT3+pT4 patients. But further analysis revealed that overall survival and disease-free was significantly improved by ACT in pT3+pT4 patients. (P=0.016 and P=0.006, respectively). Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, CTLA-4) expression. Conclusion: The stromal immunotypes could predict survival and recurrence of MIBC effectively. Furthermore, the immunotypes might be a practical predictive tool to identify pT3+pT4 patients who would benefit from ACT.

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The Magnitude of Androgen Receptor Positivity in Breast Cancer is Critical for Reliable Prediction of Disease Outcome

Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically-validated primary breast cancer cohorts (training cohort n=219; validation cohort n=418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively). The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22/46 (48%) of previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1 nor 10% cut-points were robustly prognostic. ROC analysis revealed a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR 0.41, P=0.015) and validation (HR 0.50, P=0.014) cohorts. Ten-fold cross validation confirmed the robustness of this AR cut-point. Patients with ERα positive tumors and AR positivity >78% had the best survival in both cohorts (P<0.0001). Among the combined ERα positive cases, those with comparable or higher levels of AR (AR:ERα positivity ratio >0.87) had the best outcomes (P<0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.

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Enhanced Intratumoral Delivery of SN38 as a Tocopherol Oxyacetate Prodrug Using Nanoparticles in a Neuroblastoma Xenograft Model

Purpose: Currently, <50% of high-risk pediatric solid tumors like neuroblastoma (NB), can be cured, and many survivors experience serious or life-threatening toxicities, so more effective, less toxic therapy is needed. One approach is to target drugs to tumors using nanoparticles, which take advantage of the enhanced permeability of tumor vasculature. Experimental Design: SN38, the active metabolite of irinotecan (CPT-11), is a potent therapeutic agent that is readily encapsulated in polymeric nanoparticles (NPs). Tocopherol oxyacetate (TOA) is a hydrophobic mitocan that was linked to SN38 to significantly increase hydrophobicity and enhance NP retention. We treated NBs with SN38-TOA NPs and compared the efficacy to the parent prodrug CPT-11 using a mouse xenograft model. Results. NP treatment induced prolonged event-free survival (EFS) in most mice, compared to CPT-11. This was shown for both SH-SY5Y and IMR-32 NB xenografts. Enhanced efficacy was likely due to increased and sustained drug levels of SN38 in the tumor compared to conventional CPT-11 delivery. Interestingly, when recurrent CPT-11-treated tumors were retreated with SN38-TOA NPs, the tumors transformed from undifferentiated NBs to maturing ganglioneuroblastomas. Furthermore, these tumors were infiltrated with Schwann cells of mouse origin, which may have contributed to the differentiated histology. Conclusion. NP delivery of SN38-TOA produced increased drug delivery and prolonged EFS compared to conventional delivery of CPT-11. Also, lower total dose and drug entrapment in NPs during circulation should decrease toxicity. We propose that NP-based delivery of a rationally designed prodrug is an attractive approach to enhance chemotherapeutic efficacy in pediatric and adult tumors.

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COX-2/PGE2 Axis Regulates HIF-2{alpha} Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

Purpose: Hypoxia-inducible factor (HIF)-2α is regarded as a preferential target for individualized HCC treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF-2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF-2α activity and of sorafenib resistance in hypoxic HCC cells. Experimental Design: The cell viability, migration and invasion abilities were measured to analyze the effects of HIF-2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF-2α level and activity, which then reduce the sensitivity of sorafenib treatment in hypoxic HCC cells. Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF-2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF-2α activity by promoting HIF-2α nuclear translocation via MAPK pathway. The activation of HIF-2α then led to the enhanced activation of VEGF, cyclin D1, and TGF-α/EGFR pathway to mediate HCC progression and reduce the sensitivity of sorafenib. More importantly, COX-2 specific inhibitors synergistically enhanced the antitumour activity of sorafenib treatment. Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF-2α expression and activity to promote HCC progression and attenuate sorafenib sensitivity by constitutively activating the TGF-α/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment.

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Genome-wide discovery and identification of a novel miRNA signature for recurrence prediction in stage II and III colorectal cancer

Purpose The current TNM (Tumor Node Metastasis) staging system is inadequate at identifying high-risk colorectal cancer (CRC) patients. Using a systematic and comprehensive-biomarker discovery and validation approach, we aimed to identify a miRNA-recurrence classifier (MRC) that can improve upon the current TNM-staging as well as superior to currently offered molecular assays. Experimental Design Three independent genome-wide miRNA-expression profiling datasets were used for biomarker discovery (N=158) and in-silico validation (N=109 and N=40) to identify a miRNA signature for predicting tumor recurrence in CRC patients. Subsequently, this signature was analytically trained and validated in retrospectively collected independent patient cohorts of fresh frozen (N=127, cohort 1) and FFPE (N=165, cohort 2 and N=139, cohort 3) specimens. Results We identified an 8-miRNA signature that significantly predicted recurrence free interval (RFI) in the discovery (p=0.002) and two independent publicly available datasets (p=0.00006 and p=0.002). The RT-PCR based validation in independent clinical cohorts revealed that MRC-derived high-risk patients succumb to significantly poor RFI in stage II and III CRC patients [cohort 1: HR: 3.44 (1.56-7.45), P=0.001, cohort 2: HR: 6.15 (3.33-11.35), P=0.001 and cohort 3: HR: 4.23 (2.26-7.92), P=0.0003]. In multivariate analyses, MRC emerged as an independent predictor of tumor recurrence, and achieved superior predictive accuracy than the currently available molecular assays. Conclusions This novel miRNA-recurrence classifier works superior to currently used clinicopathological features, as well as NCCN criteria, and works independent of adjuvant chemotherapy status in identifying high-risk stage II and III CRC patients. This can be deployed in clinical practice with FFPE specimens.

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The transcriptional co-activator TAZ is a potent mediator of alveolar rhabdomyosarcoma tumorigenesis

Purpose: Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature PAX3-FOXO1 (P3F) fusion gene. 5-year survival for aRMS is <50%, with no improvement in over four decades. Although the transcriptional co-activator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis. Experimental Design: After determining from public datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays. Using constitutive and inducible RNAi, we examined the impact of TAZ loss-of-function on aRMS oncogenic phenotypes in vitro and tumorigenesis in vivo. Last, we performed pharmacological studies in aRMS cell lines using porphyrin compounds, which interfere with TAZ-TEAD transcriptional activity. Results: TAZ is upregulated in our P3F-initiated aRMS model, and aRMS cells and tumors have high nuclear TAZ expression. In vitro, TAZ suppression inhibits aRMS cell proliferation, induces apoptosis, supports myogenic differentiation, and reduces aRMS cell stemness. TAZ-deficient aRMS cells are enriched in G2/M. In vivo, TAZ suppression attenuates aRMS xenograft tumor growth. Preclinical studies show decreased aRMS xenograft tumor growth with porphyrin compounds alone and in combination with vincristine. Conclusions: TAZ is oncogenic in aRMS sarcomagenesis. While P3F is currently not therapeutically tractable, targeting TAZ could be a promising novel approach in aRMS.

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PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity

Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DCs). DC signals can be bypassed by CD27 agonists and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb).Experimental Design: The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow-cytometry analysis were used to delineate mechanisms underpinning the observed synergy. Results: PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8+ T-cell expansion and effector function, exemplified by enhanced IFN-, TNF-α, granzyme B and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL-2 and Myc. However, division of labor was also apparent such that anti-PD-1/L1 activates a cytotoxicity-gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8+ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for anti-tumor immunity. Finally, we show that a clinically-relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD-L1 blockade for protection against lymphoma in human-CD27 transgenic mice. Conclusions: Our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches co-operate for CD8+ T-cell activation.

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Identification and Validation of Stromal Immunotype Predict Survival and Benefit from Adjuvant Chemotherapy in Patients with Muscle Invasive Bladder Cancer

Purpose: This study aims to construct the stromal immunotype which could improve prediction of postsurgical survival and adjuvant platinum-based chemotherapy in muscle-invasive bladder cancer (MIBC). Patients and Methods: A total of 118 MIBC patients from Shanghai Cancer Center, 140 MIBC patients from Zhongshan hospital and 287 MIBC patients from TCGA cohort were included in the study. Immune cell infiltration was evaluated by immunohistochemical staining or CIBERSORT method. Five immune features were selected out of 22 immune features to construct immunotype based on LASSO Cox regression model. Result: Using the LASSO model, we classified MIBC patients into stromal immunotype A subgroup (CTL high NK high Treg low Macrophage low MC low) and stromal immunotype B subgroup (CTL low NK low Treg high Macrophage high MC high). Significant differences were found between immunotype A and immunotype B in the combined cohort with 5-year overall survival (76.0% vs. 44.0%; P<0.001) and 5-year disease-free survival (62.8% vs. 48.3%; P<0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately. Either overall survival or disease-free survival was not improved by adjuvant chemotherapy (ACT) in pT2 stage patients or pT3+pT4 patients. But further analysis revealed that overall survival and disease-free was significantly improved by ACT in pT3+pT4 patients. (P=0.016 and P=0.006, respectively). Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, CTLA-4) expression. Conclusion: The stromal immunotypes could predict survival and recurrence of MIBC effectively. Furthermore, the immunotypes might be a practical predictive tool to identify pT3+pT4 patients who would benefit from ACT.

http://ift.tt/2Fkpe9R

The Magnitude of Androgen Receptor Positivity in Breast Cancer is Critical for Reliable Prediction of Disease Outcome

Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically-validated primary breast cancer cohorts (training cohort n=219; validation cohort n=418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively). The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22/46 (48%) of previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1 nor 10% cut-points were robustly prognostic. ROC analysis revealed a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR 0.41, P=0.015) and validation (HR 0.50, P=0.014) cohorts. Ten-fold cross validation confirmed the robustness of this AR cut-point. Patients with ERα positive tumors and AR positivity >78% had the best survival in both cohorts (P<0.0001). Among the combined ERα positive cases, those with comparable or higher levels of AR (AR:ERα positivity ratio >0.87) had the best outcomes (P<0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.

http://ift.tt/2D8VSFE

Enhanced Intratumoral Delivery of SN38 as a Tocopherol Oxyacetate Prodrug Using Nanoparticles in a Neuroblastoma Xenograft Model

Purpose: Currently, <50% of high-risk pediatric solid tumors like neuroblastoma (NB), can be cured, and many survivors experience serious or life-threatening toxicities, so more effective, less toxic therapy is needed. One approach is to target drugs to tumors using nanoparticles, which take advantage of the enhanced permeability of tumor vasculature. Experimental Design: SN38, the active metabolite of irinotecan (CPT-11), is a potent therapeutic agent that is readily encapsulated in polymeric nanoparticles (NPs). Tocopherol oxyacetate (TOA) is a hydrophobic mitocan that was linked to SN38 to significantly increase hydrophobicity and enhance NP retention. We treated NBs with SN38-TOA NPs and compared the efficacy to the parent prodrug CPT-11 using a mouse xenograft model. Results. NP treatment induced prolonged event-free survival (EFS) in most mice, compared to CPT-11. This was shown for both SH-SY5Y and IMR-32 NB xenografts. Enhanced efficacy was likely due to increased and sustained drug levels of SN38 in the tumor compared to conventional CPT-11 delivery. Interestingly, when recurrent CPT-11-treated tumors were retreated with SN38-TOA NPs, the tumors transformed from undifferentiated NBs to maturing ganglioneuroblastomas. Furthermore, these tumors were infiltrated with Schwann cells of mouse origin, which may have contributed to the differentiated histology. Conclusion. NP delivery of SN38-TOA produced increased drug delivery and prolonged EFS compared to conventional delivery of CPT-11. Also, lower total dose and drug entrapment in NPs during circulation should decrease toxicity. We propose that NP-based delivery of a rationally designed prodrug is an attractive approach to enhance chemotherapeutic efficacy in pediatric and adult tumors.

http://ift.tt/2FiSLRa

COX-2/PGE2 Axis Regulates HIF-2{alpha} Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

Purpose: Hypoxia-inducible factor (HIF)-2α is regarded as a preferential target for individualized HCC treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF-2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF-2α activity and of sorafenib resistance in hypoxic HCC cells. Experimental Design: The cell viability, migration and invasion abilities were measured to analyze the effects of HIF-2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF-2α level and activity, which then reduce the sensitivity of sorafenib treatment in hypoxic HCC cells. Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF-2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF-2α activity by promoting HIF-2α nuclear translocation via MAPK pathway. The activation of HIF-2α then led to the enhanced activation of VEGF, cyclin D1, and TGF-α/EGFR pathway to mediate HCC progression and reduce the sensitivity of sorafenib. More importantly, COX-2 specific inhibitors synergistically enhanced the antitumour activity of sorafenib treatment. Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF-2α expression and activity to promote HCC progression and attenuate sorafenib sensitivity by constitutively activating the TGF-α/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment.

http://ift.tt/2FpSGai

Genome-wide discovery and identification of a novel miRNA signature for recurrence prediction in stage II and III colorectal cancer

Purpose The current TNM (Tumor Node Metastasis) staging system is inadequate at identifying high-risk colorectal cancer (CRC) patients. Using a systematic and comprehensive-biomarker discovery and validation approach, we aimed to identify a miRNA-recurrence classifier (MRC) that can improve upon the current TNM-staging as well as superior to currently offered molecular assays. Experimental Design Three independent genome-wide miRNA-expression profiling datasets were used for biomarker discovery (N=158) and in-silico validation (N=109 and N=40) to identify a miRNA signature for predicting tumor recurrence in CRC patients. Subsequently, this signature was analytically trained and validated in retrospectively collected independent patient cohorts of fresh frozen (N=127, cohort 1) and FFPE (N=165, cohort 2 and N=139, cohort 3) specimens. Results We identified an 8-miRNA signature that significantly predicted recurrence free interval (RFI) in the discovery (p=0.002) and two independent publicly available datasets (p=0.00006 and p=0.002). The RT-PCR based validation in independent clinical cohorts revealed that MRC-derived high-risk patients succumb to significantly poor RFI in stage II and III CRC patients [cohort 1: HR: 3.44 (1.56-7.45), P=0.001, cohort 2: HR: 6.15 (3.33-11.35), P=0.001 and cohort 3: HR: 4.23 (2.26-7.92), P=0.0003]. In multivariate analyses, MRC emerged as an independent predictor of tumor recurrence, and achieved superior predictive accuracy than the currently available molecular assays. Conclusions This novel miRNA-recurrence classifier works superior to currently used clinicopathological features, as well as NCCN criteria, and works independent of adjuvant chemotherapy status in identifying high-risk stage II and III CRC patients. This can be deployed in clinical practice with FFPE specimens.

http://ift.tt/2FjQVzE

The transcriptional co-activator TAZ is a potent mediator of alveolar rhabdomyosarcoma tumorigenesis

Purpose: Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature PAX3-FOXO1 (P3F) fusion gene. 5-year survival for aRMS is <50%, with no improvement in over four decades. Although the transcriptional co-activator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis. Experimental Design: After determining from public datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays. Using constitutive and inducible RNAi, we examined the impact of TAZ loss-of-function on aRMS oncogenic phenotypes in vitro and tumorigenesis in vivo. Last, we performed pharmacological studies in aRMS cell lines using porphyrin compounds, which interfere with TAZ-TEAD transcriptional activity. Results: TAZ is upregulated in our P3F-initiated aRMS model, and aRMS cells and tumors have high nuclear TAZ expression. In vitro, TAZ suppression inhibits aRMS cell proliferation, induces apoptosis, supports myogenic differentiation, and reduces aRMS cell stemness. TAZ-deficient aRMS cells are enriched in G2/M. In vivo, TAZ suppression attenuates aRMS xenograft tumor growth. Preclinical studies show decreased aRMS xenograft tumor growth with porphyrin compounds alone and in combination with vincristine. Conclusions: TAZ is oncogenic in aRMS sarcomagenesis. While P3F is currently not therapeutically tractable, targeting TAZ could be a promising novel approach in aRMS.

http://ift.tt/2FpSFTM

Osteoblast-secreted factors mediate dormancy of metastatic prostate cancer in the bone via activation of the TGF{beta}RIII-p38MAPK-pS249/T252RB pathway

Bone metastasis from prostate cancer (PCa) can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTC are initially induced into a dormant state in the bone remains to be elucidated. We show here that the bone microenvironment confers dormancy to C4-2B4 PCa cells, as they become dormant when injected into mouse femurs but not under the skin. Live-cell imaging of dormant cells at the single cell level revealed that conditioned medium from differentiated, but not undifferentiated osteoblasts induced C4-2B4 cellular quiescence, suggesting that differentiated osteoblasts present locally around the tumor cells in the bone conferred dormancy to PCa cells. Gene array analyses identified GDF10 and TGFβ2 among osteoblast-secreted proteins that induced quiescence of C4-2B4, C4-2b, and PC3-mm2, but not 22RV1 or BPH-1 cells, indicating PCa tumor cells differ in their dormancy response. TGFβ2 and GDF10 induced dormancy through TGFβRIII to activate phospho-p38MAPK, which phosphorylates RB at the novel N-terminal S249/T252 sites to block PCa cell proliferation. Consistently, expression of dominant-negative p38MAPK in C4-2b and C4-2B4 PCa cell lines abolished tumor cell dormancy both in vitro and in vivo. Lower TGFβRIII expression in PCa patients correlated with increased metastatic potential and decreased survival rates. Together, our results identify a dormancy mechanism by which DTC are induced into a dormant state through TGFβRIII-p38MAPK-pS249/pT252-RB signaling and offer a rationale for developing strategies to prevent PCa recurrence in the bone.

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The use of whole exome sequencing and murine patient derived xenografts as a method of chemosensitivity testing in sarcoma

Abstract

Background

Soft tissue and bone sarcoma represent a broad spectrum of different pathology and genetic variance. Current chemotherapy regimens are derived from randomised trials and represent empirical treatment. Chemosensitivity testing and whole exome sequencing (WES) may offer personalized chemotherapy treatment based on genetic mutations.

Methods

A pilot, prospective, non-randomised control experimental study was conducted. Twelve patients with metastatic bone or soft tissue sarcoma that had failed first line chemotherapy treatment were enrolled for this study. Human tissue taken at surgical biopsy under general anaesthetic was divided between two arms of the trial. Subsections of the tumour were used for WES and the remainder was implanted subcutaneously in immunodeficient mice (PDX). Results of WES were analysed using a bioinformatics pipeline to identify mutations conferring susceptibility to kinase inhibitors and common chemotherapeutic agents. PDX models exhibiting successful growth underwent WES of the tumour and subsequent chemosensitivity testing.

Results

WES was successful in all 12 patients, with successful establishment PDX tumours models in seven patients. WES identified potential actionable therapeutics in all patients. Significant variation in predicted therapeutics was demonstrated between three PDX samples and their matched tumour samples.

Conclusion

Analysis of WES of fresh tumour specimens via a bioinformatics pipeline may identify potential actionable chemotherapy agents. Further research into this field may lead to the development of personalized cancer therapy for sarcoma.

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Osteoblast-secreted factors mediate dormancy of metastatic prostate cancer in the bone via activation of the TGF{beta}RIII-p38MAPK-pS249/T252RB pathway

Bone metastasis from prostate cancer (PCa) can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTC are initially induced into a dormant state in the bone remains to be elucidated. We show here that the bone microenvironment confers dormancy to C4-2B4 PCa cells, as they become dormant when injected into mouse femurs but not under the skin. Live-cell imaging of dormant cells at the single cell level revealed that conditioned medium from differentiated, but not undifferentiated osteoblasts induced C4-2B4 cellular quiescence, suggesting that differentiated osteoblasts present locally around the tumor cells in the bone conferred dormancy to PCa cells. Gene array analyses identified GDF10 and TGFβ2 among osteoblast-secreted proteins that induced quiescence of C4-2B4, C4-2b, and PC3-mm2, but not 22RV1 or BPH-1 cells, indicating PCa tumor cells differ in their dormancy response. TGFβ2 and GDF10 induced dormancy through TGFβRIII to activate phospho-p38MAPK, which phosphorylates RB at the novel N-terminal S249/T252 sites to block PCa cell proliferation. Consistently, expression of dominant-negative p38MAPK in C4-2b and C4-2B4 PCa cell lines abolished tumor cell dormancy both in vitro and in vivo. Lower TGFβRIII expression in PCa patients correlated with increased metastatic potential and decreased survival rates. Together, our results identify a dormancy mechanism by which DTC are induced into a dormant state through TGFβRIII-p38MAPK-pS249/pT252-RB signaling and offer a rationale for developing strategies to prevent PCa recurrence in the bone.

http://ift.tt/2Fltwhk

The use of whole exome sequencing and murine patient derived xenografts as a method of chemosensitivity testing in sarcoma

Abstract

Background

Soft tissue and bone sarcoma represent a broad spectrum of different pathology and genetic variance. Current chemotherapy regimens are derived from randomised trials and represent empirical treatment. Chemosensitivity testing and whole exome sequencing (WES) may offer personalized chemotherapy treatment based on genetic mutations.

Methods

A pilot, prospective, non-randomised control experimental study was conducted. Twelve patients with metastatic bone or soft tissue sarcoma that had failed first line chemotherapy treatment were enrolled for this study. Human tissue taken at surgical biopsy under general anaesthetic was divided between two arms of the trial. Subsections of the tumour were used for WES and the remainder was implanted subcutaneously in immunodeficient mice (PDX). Results of WES were analysed using a bioinformatics pipeline to identify mutations conferring susceptibility to kinase inhibitors and common chemotherapeutic agents. PDX models exhibiting successful growth underwent WES of the tumour and subsequent chemosensitivity testing.

Results

WES was successful in all 12 patients, with successful establishment PDX tumours models in seven patients. WES identified potential actionable therapeutics in all patients. Significant variation in predicted therapeutics was demonstrated between three PDX samples and their matched tumour samples.

Conclusion

Analysis of WES of fresh tumour specimens via a bioinformatics pipeline may identify potential actionable chemotherapy agents. Further research into this field may lead to the development of personalized cancer therapy for sarcoma.

http://ift.tt/2FoIU8F

Can lateral decubitus cause uvular necrosis after general anesthesia?

Uvular necrosis or ulceration is a rare cause of post-operative sore throat after endotracheal intubation (40%) or Laryngeal Mask Airway (7–12%) insertion. Till date, only 17 cases of uvular necrosis have been reported. According to literature, overzealous suctioning, upper GI endoscopy, bronchoscopy via nasal approach, long-term intubation and trans-esophageal echocardiography can cause uvular necrosis (2, 3). Patients present with post-operative severe pain and swollen, elongated, erythematous uvula with odynophagia and dysphagia which require urgent attention and treatment.

http://ift.tt/2oTiNAx

Editorial Board w/barcode

http://ift.tt/2oRQFgV

Flexible gastroendoscope as a rescue device for an anaesthetist

Managing the airway of a patient with temporo-mandibular joint (TMJ) ankylosis is very challenging. Securing the airway by awake fiberoptic bronchoscopy is considered as a gold standard [1]. Easy and ubiquitous availability of the gastroendoscopes in the endoscopy room makes them a good alternative to fiberoptic bronchoscope. So we present a unique case of TMJ ankylosis posted for upper gastrointestinal endoscopy, wherein anaesthesia was given to the patient while the flexible gastroendoscope was also used as a rescue device for emergency airway management.

http://ift.tt/2tp8yIV

Epidural management for obstetric patient with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) undergoing emergent cesarean section

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare, autosomal dominant disorder that results from mutations of the NOTCH 3 gene on chromosome 19. The resultant dysfunctional NOTCH 3 protein leads to impaired cerebrovascular autoregulation. CADASIL is characterized by recurrent subcortical ischemic infarcts that can lead to migraine, with or without aura; cognitive problems; seizures; psychiatric symptoms; dementia; walking difficulties; and urinary incontinence [1].

http://ift.tt/2oRQzG5

Anesthesia management of a newborn with Pena-Shokeir Syndrome

Perinatal diagnosis of Pena-Shokeir Syndrome (PSS) characterized by multiple joint contractures, intrauterine growth retardation, craniofacial deformities, multiple ankyloses, camptodactilia, short umbilical cord, polyhydramnios, and pulmonary hypoplasia is possible up to 14th week of pregnancy with abnormal position of fetal organs, abnormal fetal movements or fetal akinesia and those anomalies which may lead to mortality are considered to provide reasonable criteria for decision of termination of pregnancy [1].

http://ift.tt/2oRfRV4

Efficacy of ultrasound imaging for differential diagnosis of cervical swelling after brachial plexus block for shoulder arthroscopy

Various complications associated with peripheral brachial plexus nerve block have been reported, such as pneumothorax, hemodynamic collapse, and hematoma leading to airway obstruction [1]. Here, we report the successful use of ultrasound imaging in the differential diagnosis of cervical swelling after brachial plexus block for shoulder arthroscopy.

http://ift.tt/2tqla2m

Ultrasound guided distal adductor canal block provides effective postoperative analgesia in lower leg surgery

In order to provide adequate postoperative analgesia in patients undergoing lower extremity surgeries, blockage of both lumbar and sacral plexus originating nerves are required as part of multimodal analgesia regimens. Block of the sciatic nerve from the popliteal region is a frequently used regional anesthesia/analgesia technique in lower leg surgery. Additionally, saphenous nerve block at the adductor canal level or femoral nerve block may also be included. Runge et al. reported that local anesthetic injected at the distal of the adductor canal around the femoral artery spread both proximally to the saphenous nerve and distally to the popliteal area, around the sciatic nerve in a cadaver model [1].

http://ift.tt/2oQW33M

Serratus plane block in thoracoscopic sympathectomy surgery

Video-assisted thoracic surgery (VATS), a minimally invasive procedure, has allowed less impairment of pulmonary function compared with thoracotomy. Besides that, there have been reports of significant acute and chronic pain following it [1].

http://ift.tt/2oV5107

Supraglottic airway for upper gastrointestinal endoscopy in children: A review of 10years' experience

Children undergoing diagnostic EGD require deep sedation or general anesthesia [1] [2]. The anesthesiologist may choose to protect the airway with an endotracheal tube, or use sedation using a variety or combinations of sedatives and analgesics, while relying on the patient's native airway, and without airway protection [2] [3]. There can, in these instances, however, be serious cardiorespiratory complications; specifically, apnea, hypoventilation and oxygen desaturation; and hypercarbia from periods of apnea during deep sedation go unmeasured.

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Table of Contents

http://ift.tt/2ttR4ei

Diagnostic accuracy of radiology (CT, X-ray, US) for predicting difficult intubation in adults: A meta-analysis

The aim of this study was to evaluate the overall accuracy of radiological measurements in prediction of difficult airway and compare the diagnostic value between the radiological measurements and the modified Mallampati score through a meta-analysis of published studies.

http://ift.tt/2tnh62K

Obstructive sleep apnea as a risk factor associated with difficult airway management - A narrative review

The association between obstructive sleep apnea (OSA) and difficult airway had been studied in various clinical trials but the relationship between the two conditions has not been clearly established. The objective of this narrative review is to determine if OSA is a risk factor associated with difficult airway.

http://ift.tt/2oS2wvo

Laparoscope surgical Instrument usage to manage an extremely difficult airway

Airway management is an integral part of anaesthesia practice. Technical difficulty to intubate the patient may pose some critical challenges. We encountered one such case, a smiling girl of 6years posted for 2nd stage palatal fistula repair. Her tongue was attached to the palate (Fig. 1) four weeks back. After explaining the procedure, informed consent and permission to publication was obtained from the parent (mother), patient was prepared for anaesthesia. Surgeon requested for nasal intubation in view of better exposure.

http://ift.tt/2ttR3ae

Is CPAP treatment not effective after supratentorial craniotomy? Author's reply

We thank the authors for their comments [1] on our study "Efficacy of continuous positive airway pressure and incentive spirometry on respiratory functions during the postoperative period following supratentorial craniotomy: A prospective randomized controlled study" [2], which was published in your journal.

http://ift.tt/2ttcCI5

Intraoperative clevidipine use to manage an acute hypertensive episode in a patient with a simultaneous kidney-pancreatic transplant

Arterial hypertension represents one of the most common diagnoses pathology in general population and usually is associated with a high appearance of complications and an increase in the mortality and morbidity during the perioperative period [1]. Refractory hypertension episodes following a simultaneous kidney-pancreatic transplant (SKPT) are not described by the current literature, and usually are associated with a multifactorial pathogenesis (immunosuppressive drugs use, chronic allograft dysfunction, genetic susceptibility or vascular complications) [2].

http://ift.tt/2oTiMwt

The correlation of the depth of anesthesia and postoperative cognitive impairment: A meta-analysis based on randomized controlled trials

To comprehensively evaluate the associations between the depth of anesthesia and postoperative delirium (POD) or postoperative cognitive dysfunction (POCD).

http://ift.tt/2ttcGrj

Ultrasound guided low thoracic erector spinae plane block for management of acute herpes zoster

Interfascial plane blocks have become very popular in recent years. A novel interfascial plane block, erector spinae plane (ESP) block can target the dorsal and ventral rami of the thoracic spinal nerves but its effect in neuropathic pain is unclear [1]. If acute pain management for herpes zoster is not done aggressively, it can turn into chronic pain. However; ESP block is first described as inject local anesthetics around the erector spinae muscle at the level of T5 spinous process for thoracic region, if the block is performed at lower levels it could be effective for abdominal and lumbar region [2].

http://ift.tt/2oSSr1h

Anesthetic and pharmacologic considerations in perioperative care of obese children

Anesthetic management of obese pediatric patients is challenging. With increasing prevalence of childhood obesity, more severely obese children with comorbidities present for surgery every day. The purpose of this review is to provide an up-to-date comprehensive narrative review on the impact of pathophysiological changes imposed by pediatric obesity on the perioperative management of obese children, especially drug dosing. This knowledge is necessary to provide safe delivery of anesthesia for severely obese children.

http://ift.tt/2tr9Q5R

Anesthetic management of an adult patient with Cor Triatriatum Sinistrum: Utility of transesophageal echocardiography

Cor Triatriatum Sinistrum (CTS) is an uncommon congenital cardiac defect, reported in 0.1% to 0.4% of patients with congenital heart disease, and which results from the division of the left atrium into two chambers by a perforated fibromuscular septum [1]. CTS is commonly diagnosed in childhood, though cases with incomplete or fenestrated membranes may remain asymptomatic throughout adulthood.

http://ift.tt/2oSRR3B

Ultrasound guided erector spinae block for postoperative analgesia in pediatric nephrectomy surgeries

Erector spinae block (ESB) is a newly identified regional anesthesia technique, which became popular between the clinicians for its ease and relatively safer administration [1]. There were quite many cases reporting its use for many different indications in adults. By far its use in pediatric cases was just defined for thoracic surgery [2,3]. We would like to share our experience about the use of ESB for postoperative analgesia in two pediatric cases undergoing nephrectomy for Wilms tumor. Written informed consent of all patients' parents was provided for using data of the children in this report.

http://ift.tt/2tnXvQ5

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy, Published online: 08 March 2018; doi:10.1038/s41416-018-0016-y

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

http://ift.tt/2HfBGo1

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

AKR1C enzymes sustain therapy resistance in paediatric T-ALL, Published online: 08 March 2018; doi:10.1038/s41416-018-0014-0

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

http://ift.tt/2FymDbx

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer, Published online: 08 March 2018; doi:10.1038/s41416-018-0004-2

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

http://ift.tt/2FAAgqT

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy, Published online: 08 March 2018; doi:10.1038/s41416-018-0016-y

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

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AKR1C enzymes sustain therapy resistance in paediatric T-ALL

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

AKR1C enzymes sustain therapy resistance in paediatric T-ALL, Published online: 08 March 2018; doi:10.1038/s41416-018-0014-0

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

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Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer, Published online: 08 March 2018; doi:10.1038/s41416-018-0004-2

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

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Carboplatin (every 21 days) and divided-dose paclitaxel (days 1, 11): rationale and tolerance in chemotherapy naïve women with high-grade epithelial cancers of Mullerian origin

Abstract

Purpose

We report here on the tolerance of a carboplatin–'divided dose' paclitaxel (given on days 1 and 11) regimen in chemotherapy-naïve patients with resected and staged endometrial epithelial neoplasms deemed at high-risk of recurrence or early stage epithelial high-grade serous tubo-ovarian adenocarcinomas after risk-reducing surgery. More recently, we applied this regimen as neoadjuvant chemotherapy for advanced ovarian cancer presentations.

Methods

A retrospective chart review of patients receiving this day 1, 11 paclitaxel regimens in combination with carboplatin at AUC 6 every 3 weeks since 2004 was carried out by the second author with subsequent updates by the first and third authors. Tolerance over the first three cycles was analyzed.

Results

A total of 27 women were treated with at least three cycles of this paclitaxel 'divided dose' schedule combined with carboplatin: 6 had endometrial adenocarcinoma, 9 had early stage ovarian cancer, and 12 received it as part of neoadjuvant therapy prior to undergoing cytoreductive surgery. Only 14 of 27 patients required dose reductions to complete the first three cycles of treatment.

Conclusions

A median of three cycles of divided dose paclitaxel (D1, D11) concurrent with carboplatin dosed every 3 weeks was found to be safe and feasible as adjuvant to surgery in early endometrial and ovarian cancers or as neoadjuvant treatment in chemotherapy-naive women with ovarian cancer.

http://ift.tt/2trDqrZ

Carboplatin (every 21 days) and divided-dose paclitaxel (days 1, 11): rationale and tolerance in chemotherapy naïve women with high-grade epithelial cancers of Mullerian origin

Abstract

Purpose

We report here on the tolerance of a carboplatin–'divided dose' paclitaxel (given on days 1 and 11) regimen in chemotherapy-naïve patients with resected and staged endometrial epithelial neoplasms deemed at high-risk of recurrence or early stage epithelial high-grade serous tubo-ovarian adenocarcinomas after risk-reducing surgery. More recently, we applied this regimen as neoadjuvant chemotherapy for advanced ovarian cancer presentations.

Methods

A retrospective chart review of patients receiving this day 1, 11 paclitaxel regimens in combination with carboplatin at AUC 6 every 3 weeks since 2004 was carried out by the second author with subsequent updates by the first and third authors. Tolerance over the first three cycles was analyzed.

Results

A total of 27 women were treated with at least three cycles of this paclitaxel 'divided dose' schedule combined with carboplatin: 6 had endometrial adenocarcinoma, 9 had early stage ovarian cancer, and 12 received it as part of neoadjuvant therapy prior to undergoing cytoreductive surgery. Only 14 of 27 patients required dose reductions to complete the first three cycles of treatment.

Conclusions

A median of three cycles of divided dose paclitaxel (D1, D11) concurrent with carboplatin dosed every 3 weeks was found to be safe and feasible as adjuvant to surgery in early endometrial and ovarian cancers or as neoadjuvant treatment in chemotherapy-naive women with ovarian cancer.

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Intensity modulated radiotherapy in locally advanced thyroid cancer: Outcomes of a sequential phase I dose-escalation study

To determine the safety and tolerability of dose-escalation using modestly accelerated IMRT in high-risk locally advanced thyroid cancer requiring post-operative radiotherapy, and to report preliminary data on efficacy.

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Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

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Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

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AKR1C enzymes sustain therapy resistance in paediatric T-ALL

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Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

http://ift.tt/2p0t1Oq

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

http://ift.tt/2I9hghy

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

http://ift.tt/2oXvJEF

Masthead/Sub page

Publication date: March–April 2018
Source:Practical Radiation Oncology, Volume 8, Issue 2





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Editorial Board

Publication date: March–April 2018
Source:Practical Radiation Oncology, Volume 8, Issue 2





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Table of Contents

Publication date: March–April 2018
Source:Practical Radiation Oncology, Volume 8, Issue 2





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Masthead/Sub page

Publication date: March–April 2018
Source:Practical Radiation Oncology, Volume 8, Issue 2





http://ift.tt/2FzbiId

Editorial Board

Publication date: March–April 2018
Source:Practical Radiation Oncology, Volume 8, Issue 2





http://ift.tt/2Hf7CbY

Table of Contents

Publication date: March–April 2018
Source:Practical Radiation Oncology, Volume 8, Issue 2





http://ift.tt/2FBBUsm