Effusion-based lymphoma with morphological regression but with clonal genetic features after aspiration

Effusion-based lymphoma (EBL) is a rare but distinct entity of large B-cell lymphoma in effusion without association with human herpes virus-8 (HHV-8). Spontaneous regression after pleurocentesis has been observed; but to our knowledge, there are no reports on the morphological and molecular features of subsequent aspirations in regressing cases. Here, we report the case of a 92-year-old male with chronic obstructive pulmonary disease, who presented with right pleural effusion. He had no human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infection, and CT scans revealed no mass lesion. The first pleural effusion aspiration cytology revealed large lymphoma cells with vesicular nuclei, irregular nuclear contours, and prominent nucleoli, consistent with EBL. The second aspiration cytology showed a few slightly enlarged lymphocytes in a background of small lymphocytes. Immunohistochemical study on cell block of the second aspiration revealed equal amounts of CD3-positive and CD20-positive cells. All these cells on the section tested negative for HHV-8 through immunohistochemistry and Epstein-Barr virus by in situ hybridization. Our initial impression was EBL in regression. However, flow cytometric immunophenotyping showed monotypic light chain expression of the gated B-cells. B-cell receptor gene rearrangement study showed a clonal result. Furthermore, fluorescence in situ hybridization revealed rearrangement of IGH gene. The diagnosis of the second aspiration was EBL with morphological regression but retained clonal genetic features. The patient passed away one month after diagnosis without chemotherapy. This case illustrated the importance of ancillary studies in confirming the clonal nature of a morphologically regressing EBL.

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Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid-stimulating hormone receptor gene mutations

Background

Thyroid-stimulating hormone receptor (TSHR) gene mutations play a critical role in thyroid cell proliferation and function. They are found in 20%-82% of hyperfunctioning nodules, hyperfunctioning follicular thyroid cancers (FTC), and papillary thyroid cancers (PTC). The diagnostic importance of TSHR mutation testing in fine needle aspiration (FNA) specimens remains unstudied.

Methods

To examine the association of TSHR mutations with the functional status and surgical outcomes of thyroid nodules, we evaluated 703 consecutive thyroid FNA samples with indeterminate cytology for TSHR mutations using next-generation sequencing. Testing for EZH1 mutations was performed in selected cases. The molecular diagnostic testing was done as part of standard of care treatment, and did not require informed consent.

Results

TSHR mutations were detected in 31 (4.4%) nodules and were located in exons 281-640, with codon 486 being the most common. Allelic frequency ranged from 3% to 45%. Of 16 cases (12 benign, 3 FTC, 1 PTC) with surgical correlation, 15 had solitary TSHR mutations and 1 PTC had comutation with BRAF V600E. Hyperthyroidism was confirmed in all 3 FTC (2 overt, 1 subclinical). Of 5 nodules with solitary TSHR mutations detected at high allelic frequency, 3 (60%) were FTC. Those at low allelic frequency (3%-22%) were benign. EZH1 mutations were detected in 2 of 4 TSHR-mutant malignant nodules and neither of 2 benign nodules.

Conclusion

We report that TSHR mutations occur in ∼5% thyroid nodules in a large consecutive series with indeterminate cytology. TSHR mutations may be associated with an increased cancer risk when present at high allelic frequency, even when the nodule is hyperfunctioning. Benign nodules were however most strongly correlated with TSHR mutations at low allelic frequency.

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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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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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Visual-olfactory Interactions: Bimodal Facilitation and Impact on the Subjective Experience

Abstract

Odors are inherently ambiguous and therefore susceptible to redundant sensory as well as context information. The identification of an odor object relies largely on visual input. Thus far, it is unclear whether visual and olfactory stimuli are indeed integrated at an early perceptual stage and which role the congruence between the visual and olfactory inputs plays. Previous studies on visual-olfactory interaction used either congruent or incongruent information, leaving it open whether nuances of visual-olfactory congruence shape perception differently. We aimed to answer 1) whether visual-olfactory information is integrated at early stages of processing, 2) whether visual-olfactory congruence is a gradual or dichotomous phenomenon, and 3) whether visual information influences bimodal stimulus evaluation and odor identity. We found a bimodal RT speedup that is consistent with parallel processing according to race models. Subjectively, pleasantness of bimodal stimuli increased with increasing congruence, and orange images biased odor composition toward orange. Visual-olfactory congruence was perceived in gradual and distinct categories, consistent with the notion that congruence is a gradual phenomenon. Together, the data provide evidence for bimodal facilitation consistent with parallel processing of the visual and olfactory stimuli, and that visual-olfactory interactions influence various levels of the subjective experience.

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Acidic pH weakens the bonding effectiveness of silane contained in universal adhesives

Publication date: Available online 7 March 2018
Source:Dental Materials
Author(s): Chenmin Yao, Jian Yu, Yake Wang, Chuliang Tang, Cui Huang
ObjectivesSome silane-containing universal adhesives were introduced that a separate ceramic primer was unnecessary to glass-ceramic bonding because of incorporated silane. We aimed to investigate the effectiveness of silane in universal adhesives with acidic media.MethodsA functional γ-methacryloxypropyltrimethoxysilane (γ-MPTS) was used, and its pH value was adjusted to 2.7 by adding hydrochloric acid (HCl) or 10-methacryloxydecyl phosphate (MDP). The prepared acidic silane solutions after 2h or 10d storage were characterized by Fourier transform infrared spectroscopy (FTIR), ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy. Micro-shear bond strength (μSBS) was used to evaluate the bonding performance of glass ceramics. Two silane-containing and two silane-free universal adhesives were included. Field-emission scanning electron microscopy fractography analysis was also performed.ResultsFTIR, ¹H and ¹³C NMR revealed that the hydrolysis of γ-MPTS and the self-condensation reaction of silanol groups occurred over time under acidic conditions (HCl or MDP solution). This reaction formed the siloxane oligomers. For glass-ceramic bonding, the μSBS of acidic silane after 10 d storage was lower than that of silane stored for 2h storage (p<0.05), although the difference among the μSBS of the four universal adhesives were nonsignificant (p>0.05). Additionally, cohesive failure was the main fracture pattern of universal adhesive bonding.SignificanceThe effectiveness of silane contained in low pH universal adhesives can be weakened by dehydration self-condensation and consequently became unstable. For the enhancement of glass-ceramic bonding efficiency with universal adhesives, a separate ceramic primer was recommended.

Graphical abstract

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Freshly-mixed and setting calcium-silicate cements stimulate human dental pulp cells

Publication date: Available online 7 March 2018
Source:Dental Materials
Author(s): Mariano S. Pedano, Xin Li, Shuchen Li, Zeyi Sun, Stevan M. Cokic, Eveline Putzeys, Kumiko Yoshihara, Yashuhiro Yoshida, Zhi Chen, Kirsten Van Landuyt, Bart Van Meerbeek
ObjectivesTo evaluate the effect of the eluates from 3 freshly-mixed and setting hydraulic calcium-silicate cements (hCSCs) on human dental pulp cells (HDPCs) and to examine the effect of a newly developed hCSC containing phosphopullulan (PPL) on HDPCs.MethodsHuman dental pulp cells, previously characterized as mesenchymal stem cells, were used. To collect the eluates, disks occupying the whole surface of a 12-well plate were prepared using an experimental hCSC containing phosphopullulan (GC), Nex-Cem MTA (GC), Biodentine (Septodont) or a zinc-oxide (ZnO) eugenol cement (material-related negative control). Immediately after preparing the disks (non-set), 3ml of Dulbecco's Modified Eagle Medium (DMEM) with 10% fetal bovine serum (FBS) were added. The medium was left in contact with the disks for 24h before being collected. Four different dilutions were prepared (100%, 50%, 25% and 10%) and cell-cytotoxicity, cell-proliferation, cell-migration and odontogenic differentiation were tested. The cell-cytotoxicity and cell-proliferation assays were performed by XTT-colorimetric assay at different time points. The cell-migration ability was tested with the wound-healing assay and the odontogenic differentiation capacity of hCSCs on HDPCs was tested with RT-PCR.ResultsConsidering all experimental data together, the eluates from 3 freshly-mixed and setting hCSCs appeared not cytotoxic toward HDPCs. Moreover, all three cements stimulated proliferation, migration and odontogenic differentiation of HDPCs.SignificanceThe use of freshly-mixed and setting hCSCs is an appropriate approach to test the effect of the materials on human dental pulp cells. The experimental material containing PPL is non-cytotoxic and positively stimulates HDPCs.

Graphical abstract

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The effect of ultraviolet induced fluorescence on visually perceived tooth color under normal light conditions

Publication date: Available online 7 March 2018
Source:Dental Materials
Author(s): Sascha Hein, Jaap J. ten Bosch
ObjectiveRestorative and prosthetic materials should provide an appearance similar to natural teeth under all light conditions, including UV-rich environments and daylight. Various studies claim that UV-induced fluorescence makes teeth whiter and brighter in daylight. The aim of this paper is to determine experimentally the significance of tooth fluorescence in natural sunlight on perceived tooth color.MethodsA total of 35 extracted, hydrated teeth without restorations or endodontic treatments were evaluated in an experimental setup. A UV/VIS spectrometer using a reflectance/backscattering probe was used to collect the reflected spectrum. Unfiltered and filtered sunlight was used for irradiation of the samples so as to use the combined ultraviolet and visible spectrum (UV/VIS) and the visible spectrum (VIS) exclusively. Color coordinates for each group were measured using the CIE L*a*b* 1976 system, averaged, and compared.ResultsThe average color difference between both groups (UV/VIS and UV) was ΔE* 0.527. The average tooth color for the VIS group was L*VIS 72.21, a*VIS −2.42, and b*VIS 22.35, and for the UV/VIS group was L*UV/VIS 72.00, a*UV/VIS −2.47, and b*UV/VIS 22.44.SignificanceUV induced fluorescence from sunlight does not make teeth whiter and brighter.



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Virtual Surgical Planning: The Pearls and Pitfalls

A new study examines the benefits and drawbacks of virtual surgical planning in craniofacial surgery.
Plastic Reconstructive Surgery-Global Open (PRS Global Open)

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Obstructive Sleep Apnea: an Ill Eye in the Wind

Publication date: Available online 8 March 2018
Source:Journal of Oral and Maxillofacial Surgery
Author(s): Arthur H. Friedlander, JoAnn A. Giaconi, Urie K. Lee, Tina I. Chang, Michelle R. Zeidler




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Association of the preoperative body mass index with postoperative complications after treatment of oral squamous cell carcinoma

Publication date: Available online 8 March 2018
Source:Journal of Oral and Maxillofacial Surgery
Author(s): Susanne Wolfer, Annika Kunzler, Stefan Schultze-Mosgau
PurposeNutritional status is believed to influence surgical outcome. Because of a lack of actual reports in literature, the purpose of this study is to evaluate the surgical outcome of patients after treatment for oral squamous cell carcinoma (OSCC), with special focus on the preoperative body mass index (BMI).Patients and methodsThis retrospective cohort study investigates the association of the preoperative BMI with the surgical outcome for OSCC patients, focusing on local and medical complications. This research also analyzes common clinical and demographic parameters such as age, sex, TNM stage, tumor differentiation, risk behavior, Karnofsky Index, duration of operation, and length of hospital stay. Statistics were performed using the Chi-square test or Fisher's exact test for categorical analysis and with the t-test or ANOVA test and Pearson correlation test for continuous variables. Multivariate analysis was computed for BMI with a multivariate linear regression model and for local and medical complications with the multivariate Poisson regression.ResultsIn the sample of 419 OSCC patients, 8.6% were underweight, 54.7% were normal weight, and 36.8% were overweight patients with an overall mean BMI of 24.28 kg/m². BMI was significantly associated with age (p = 0.0017), consumption of nicotine (p = 0.0178) and alcohol (p = 0.0008), dental status (p = 0.0163), tumor differentiation (p = 0.0288), and T-status (p = 0.0005). Underweight patients in particular are negatively correlated with local postoperative complications (p = 0.0047). Local complications are associated with the need for operative revisions (p < 0.0001) and with an increase of the length of hospital stay (p < 0.0001) after multivariable analysis.ConclusionOur results indicate that evaluation of preoperative morbidity and nutritional status, especially in underweight patients, is worthwhile to improve the postoperative outcome after surgical therapy of OSCC patients for medical and economic aspects.



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Evaluating the Effect of Resveratrol on the Healing of Extraction Sockets in Cyclosporine A-treated rats

Publication date: Available online 8 March 2018
Source:Journal of Oral and Maxillofacial Surgery
Author(s): Ayse Ozcan Kucuk, Hilal Alan, Mehmet Gul, Umit Yolcu
PurposeThe objective of this study was to investigate the effects of resveratrol on alveolar socket healing after tooth extraction in normal and cyclosporin A (CsA)-treated rats.Materials and MethodsSeventy-two female Sprague Dawley rats were separated into four groups of 18. Group 1 was injected with a placebo solution intraperitoneally. Group 2 was injected with resveratrol (10 μmol/kg) intraperitoneally. Groups 3 and 4 were injected with CsA (10 mg/kg) subcutaneously for 8 days once daily before the tooth extraction. Next, the teeth were extracted and continued to CsA injection until the animals were sacrificed. Eight days after commencing the CsA injections, Group 4 was injected with resveratrol while continuing with CsA injections. Nine rats from each group were sacrificed on days 14 and 28, and sections were examined to assess the degree of inflammation, the formation of connective tissue, and new bone formation. Immunohistochemical analysis was employed to evaluate the alveolar socket healing process using osteocalcin and osteopontin markers; p<0.05 was considered significant.ResultsThere was more new bone formation in Group 2 than in the other three groups on day 14 after the tooth extraction (p<0.05), and there was more new bone formation in Group 2 than in Groups 3 and 4 on day 28 after the extraction (p<0.05). Based on the immunohistochemical assessment, the amount of osteocalcin and osteopontin labelling was higher in Group 2 compared to the other three groups on day 14 (p<0.05); however, on day 28 after the extraction it was higher in Group 4 compared to Group 3 (p<0.05).ConclusionsResveratrol improves alveolar socket healing in normal and CsA-treated rats. Resveratrol also increases the levels of osteocalcin and osteopontin in normal and CsA-treated rats. These results suggest that the use of this natural compound is useful for alveolar socket healing after tooth extraction.



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Comparative Evaluation Of Healing Pattern After Surgical Excision Of Oral Mucosal Lesions By Using Platelet Rich Fibrin (Prf) Membrane And Collagen Membrane As Grafting Materials- A Randomized Clinical Trial

Publication date: Available online 8 March 2018
Source:Journal of Oral and Maxillofacial Surgery
Author(s): Monica Mahajan, Mithilesh Kumar Gupta, Chandrashekhar Bande, Vikas Meshram
PurposeTo compare the healing potential of platelet rich fibrin membrane (PRF) and collagen membrane in oral mucosal healing.Patients and MethodsThirty patients having oral premalignant lesions were randomly included in the study and divided in two Groups A and B. After excising lesions under local anesthesia, Group A and B patients were grafted with PRF membrane and collagen membrane, respectively. Patients were evaluated at 7^th, 15^th, 30^th and 60^th days postoperatively for pain, healing and complications such as recurrence, fibrosis, scar hypertrophy and loss of vestibular depth.ResultsIn Group A, 66.66% of patients reported significantly less pain postoperatively at 15^th day follow-up than those treated in Group B. 30^th day follow-up showed 86.66% cases in Group A showing no pain as compared to 60% in Group B. Pain scores were similar at the 7^th and 60^th follow-up days. Healing was accelerated in Group A on 15^th and 30^th day follow-up, but it was the same on the 60^th day. Complications like fibrosis, loss of vestibular depth and scar hypertrophy was seen in Group B. Recurrence were seen in 1 patient from Group A at the 60^th day follow-up.ConclusionPRF proved to be a better alternative to collagen membrane for grafting of the oral mucosal surgical defects. However, further study with larger sample size is required to prove its efficacy.



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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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Trajectories in hypnotic use and approaching death: a register linked case–control study

Publication date: Available online 7 March 2018
Source:Sleep Medicine
Author(s): Erkki Kronholm, Pekka Jousilahti, Tiina Laatikainen, Tea Lallukka, Markku Peltonen, Johanna Seppänen, Lauri Virta
PurposeWhether the association between hypnotic and increased mortality risk is created by causation or confounding, has been long debated. We examined further the possibility of confounding by indication with a comprehensive approach.MethodsThe National FINRISK Study cohorts of 1997, 2002, and 2007 (25,436 participants aged 25–74) were followed up until July 2012. There were 1,822 deaths, and at least one gender, baseline age and cohort matched 'control' was found for 1,728 'cases' yielding a final analytical sample of 3,955 individuals. An index age, equivalent to the age at death of their respective cases' was set for each control. Hypnotic drug purchases were followed from the Finnish nationwide register during a 36-month run-up period before the date of death/index date. The prevalence and incidence of hypnotic purchases were compared between cases and matched controls. In addition, latent developmental trajectories of purchases were modelled and their relations with specific and all-cause death risks were analysed.ResultsAn increasing difference between cases and controls was observed as regards the use of hypnotic drugs. During the last 30 months before the date of death/index date, the rate ratio of incident purchases between cases and controls was 2.37 (95% CL, 1.79–3.12) among older and 3.61 (95% CL, 2.37–5.89) among younger individuals. The developmental trajectories of hypnotic drug purchases were differently and by interpretation plausibly associated with specific mortality risks.ConclusionsIn most cases the association between hypnotics and mortality risk is created by symptomatic treatment when death is approaching.



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Pain after root canal treatment with different instruments: A systematic review and meta-analysis

Abstract

Objectives

The aims of this systematic review were to compare the incidence and intensity of postoperative pain after single-visit root canal treatment using manual, rotary and reciprocating instruments.

Methods

An extensive literature search in PubMed, EMBASE, Cochrane Library, and Web of Science was performed to identify investigations that evaluated the effects of different instruments on post-endodontic pain. Meta-analyses and additional analyses, including subgroup and sensitivity analyses, were conducted.

Results

We included seventeen trials in this study. Pooled results showed that patients treated with rotary instruments experienced a significantly lower incidence of postoperative pain (RR, 0.32, P = 0.0005) and reduced pain intensity than did patients treated with manual instruments. In addition, patients treated with multiple rotary-file systems experienced a significantly lower incidence of postoperative pain than did those treated with reciprocating systems (RR, 0.73; P < 0.0001).

Conclusion

The use of rotary instruments contributed to a lower incidence and intensity of postoperative pain than did the use of hand files in patients who received single-visit root canal treatment. In addition, the use of multiple rotary-file systems contributed to a lower incidence of postoperative pain than did the use of reciprocating systems.

This article is protected by copyright. All rights reserved.

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Editorial Board/Reviewing Committee

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Systematic review of measurement property evidence for eight financial management instruments in populations with acquired cognitive impairment

Publication date: Available online 7 March 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Lisa Engel, Adora Chui, Dorcas E. Beaton, Robin E. Green, Deirdre R. Dawson
ObjectiveTo critically appraise the measurement property evidence (i.e., psychometric) for eight observation-based financial management assessment instruments.Data sourcesSeven databases were searched in May 2015.Study SelectionTwo reviewers used an independent decision-agreement process to select studies of measurement property evidence relevant to populations with adulthood acquired cognitive impairment, appraise the quality of the evidence, and extract data. Twenty-one articles were selected.Data extractionThis review used the COnsensus-based Standards for the selection of health Measurement Instruments review (COSMIN) guidelines and four-point tool to appraise evidence. After appraising the methodological quality, adequacy of results and volume of evidence per instrument were synthesized. Measurement property evidence with high risk of bias was excluded from the synthesis.Data synthesisVolume of measurement property evidence per instrument is low; most instruments had one to three included studies. Many included studies had poor methodological quality per measurement property evidence area examined. Six of the eight instruments reviewed had supporting construct validity/hypothesis-testing evidence of fair methodological quality. There is a dearth of acceptable quality content validity, reliability, and responsiveness evidence for all eight instruments.ConclusionsRehabilitation practitioners assess financial management functions in adults with acquired cognitive impairments. However, there is limited published evidence to support using any of the reviewed instruments. Practitioners should exercise caution when interpreting results of these instruments. This review highlights the importance of appraising the quality of measurement property evidence prior to examining the adequacy of the results and synthesizing the evidence.



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Functional Electrical Stimulation-A new therapeutic approach to enhance exercise intensity in Chronic Obstructive Pulmonary Disease patients : a randomised controlled cross-over trial.

Publication date: Available online 7 March 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Clément Medrinal, Guillaume Prieur, Yann Combret, Aurora Robledo Quesada, David Debeaumont, Tristan Bonnevie, Francis Edouard Gravier, Elise Dupuis Lozeron, Jean Quieffin, Olivier Contal, Bouchra Lamia
ObjectiveTo evaluate the effect of quadriceps Functional Electrical Stimulation (FES)-Cycling on exertional VO2 compared with Placebo FES-cycling in patients with COPD.DesignA randomised, single-blind, placebo-controlled, cross-over trialSettingPulmonary Rehabilitation DepartmentParticipants23 consecutive patients with COPD GOLD stage 2, 3 or 4 (mean FEV1 : 1.4±0.4 L (50.3% pred)) who had recently begun a respiratory rehabilitation program.InterventionTwo consecutive 30-minute sessions were carried out at a constant load with active and placebo FES-Cycling.Main outcome measuresThe primary outcome was mean VO2 during the 30-minute exercise session. The secondary outcomes were respiratory gas exchange and hemodynamic parameters averaged over the 30-minute endurance session. Lactate values, dyspnea and perceived muscle fatigue were evaluated at the end of the sessions.ResultsFES-Cycling increased the physiological response more than the placebo, with a greater VO2 achieved of 36.6 (95% CI 8.9-64.3) mL/min (p=0.01). There was also a greater increase in lactate after FES-Cycling (+1.5 (95% CI 0.05 to 2.9) mmol/L; p=0.01). FES-Cycling did not change dyspnoea or muscle fatigue compared with the placebo condition.ConclusionFES-Cycling effectively increased exercise intensity in patients with COPD. Further studies should evaluate longer-term FES-Cycling rehabilitation programs.



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Cannabis Use in Individuals with Spinal Cord Injury or Moderate to Severe Traumatic Brain Injury in Colorado

Publication date: Available online 7 March 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Lenore Hawley, Jessica M. Ketchum, Clare Morey, Kathleen Collins Pharm.D., Susan Charlifue
ObjectiveTo describe the prevalence of cannabis use in an adult sample with spinal cord injury (SCI) or traumatic brain injury (TBI) in Colorado, and to describe the self-reported reasons and side effects of cannabis use in this sample.DesignMixed methods observational study, using focus group data and telephone surveySettingCommunityParticipantsColorado adults who have sustained SCI or moderate to severe TBI and have received services through the rehabilitation hospital conducting the study.InterventionsNone; Measures: SurveyResultsFocus group participants identified issues that were then included in the survey development. Seventy percent of the 116 surveyed reported cannabis use pre-injury (67% SCI, 74% TBI) with 48% reporting use after injury (53% SCI, 45% TBI). Overall, the most common reason for use was recreational (67%), followed by reducing stress/anxiety (62.5%), and improving sleep (59%). Among the respondents with SCI, the most common reasons for use were to reduce spasticity (70%), recreation (63%), and to improve sleep (63%). Among those with TBI, reasons endorsed were recreational (72%), reducing stress/anxiety (62%), and improving sleep (55%). Smoking was the most common method of use.ConclusionsA majority of this sample report using cannabis prior to injury, and approximately half report using cannabis post-injury. Both groups report recreational use, while the group with SCI also highly endorses using cannabis to address chronic medical conditions. Clinicians should be aware of the high prevalence of cannabis use in these populations and the impact such use may have on the individual's medical management. Further research in this area is needed.



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Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches

Publication date: Available online 7 March 2018
Source:Acta Otorrinolaringológica Española
Author(s): José Ferreira Penêda, Nuno Barros Lima, Francisco Monteiro, Joana Vilela Silva, Rita Gama, Artur Condé
IntroductionImmune Mediated Inner Ear Disease (IMIED) is a rare form of sensorineural bilateral hearing loss, usually progressing in weeks to months and responsive to immunosuppressive treatment. Despite recent advances, there is no consensus on diagnosis and optimal treatment.MethodsA review of articles on IMIED from the last 10 years was conducted using PubMed^® database.ResultsIMIED is a rare disease, mostly affecting middle aged women. It may be a primary ear disease or secondary to autoimmune systemic disease. A dual immune response (both cellular and humoral) seems to be involved. Cochlin may be the inner ear protein targeted in this disease. Distinction from other (core common) forms of neurosensory hearing loss is a challenge. Physical examination is mandatory for exclusion of other causes of hearing loss; audiometry identifies characteristic hearing curves. Laboratory and imaging studies are controversial since no diagnostic marker is available.ConclusionDespite recent research, IMIED diagnosis remains exclusive. Steroids are the mainstay treatment; other therapies need further investigation. For refractory cases, cochlear implantation is an option and with good relative outcome.



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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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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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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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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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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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Monoclonal Antibodies for Emerging Infectious Diseases — Borrowing from History

Although antibodies play pivotal roles in the immune response to infection, they have seen limited use as therapeutic agents for infectious diseases. Yet there is a long history of plasma-derived treatments for several pathogens. Emil Adolf von Behring, for example, won the Nobel Prize in…

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Editorial Board w/barcode

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Table of Contents

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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.

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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.

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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].

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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.

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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].

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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.

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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.

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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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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].

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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.

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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].

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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.

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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].

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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).

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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].

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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.

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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.

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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.

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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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Vocal Acoustic and Auditory-Perceptual Characteristics During Fluctuations in Estradiol Levels During the Menstrual Cycle: A Longitudinal Study

Estradiol production varies cyclically, changes in levels are hypothesized to affect the voice. The main objective of this study was to investigate vocal acoustic and auditory-perceptual characteristics during fluctuations in the levels of the hormone estradiol during the menstrual cycle. A total of 44 volunteers aged between 18 and 45 were selected. Of these, 27 women with regular menstrual cycles comprised the test group (TG) and 17 combined oral contraceptive users comprised the control group (CG).

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