tbuckley/cabot-search huggingface dataset:
Re: Tom J.H. Arends, Ofer Nativ, Massimo Maffezzini, et al. Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guerin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non–Muscle-invasive Bladder Cancer. Eur Urol 2016;69:1046–52
Authors: Harshit Garg, Brusabhanu Nayak, Prabhjot Singh
Journal: European Urology (2018)
Identification of disease specific methylation markers and utilization in non-invasive colorectal cancer (CRC) diagnostics via deep cfDNA methylation sequencing.
Authors: Jinke Sui, Fuao Cao, Chenyang Wang, Wenjun Li, Wanglong Deng, Han Han-Zhang, Guanyu Yu, Zhihong Zhang, Wei Zhang
Journal: Journal of Clinical Oncology (2018)

e15610 Background: CRC is known to develop from the early precancerous lesion to full blown malignancy due to the accumulation of genetic and epigenetic aberrations. The role of aberrant DNA methylationin the process of CRC initiation both at individual genes and a genome-wide scale has been well elucidated, thus capable of serving as a diagnostic biomarker. Methods: We interrogated the methylation statuses of 7572 regions containing about 100,000 CpG sites from plasma samples of 56 Chinese CRC patients with various stage CRC and 23 with benign polyps using targeted bisulfite sequencing. A region-based methylation statistic was used in classify model. Results: We constructed a diagnostic classification model using elastic net and random forest based on 4,000 DMRs selected by logistic regression between benign and malignant lesions using fresh tissue samples. Within this cohort, 61 patients had malignant tumor (8 stage I, 29 stage II, 24stage III and above) and 25 patients had benign polyps. We performed 5-fold cross-validation with 20 time repeats to gain a robust estimation of model performance, achieving a sensitivity of 94.2%, specificity of 96% and AUC of 96.9%. We further refined the selected DMRs, we used plasma obtained from 68 healthy volunteer as a baseline, and subsequently constructed a weighting decision tree model for plasma samples of 56patients with malignant tumor (10 stage I, 25 stage II, 21 stage III and above) and 23 patients with benign polyps, achieving a sensitivity of 89.3%, specificity of 91.3% and AUC of 96% based on 336markers. Conclusions: Our study identified a CRC specific methylation signature for differentiating benign and malignant lesions using ultra-sensitive deep cfDNA methylation sequencing. We demonstrated the utility of assessing DNA methylation profile as an early diagnostic method. This method has potential to serve as a supplementary or alternative approach in CRC early detection. The general concept can be further extended to other types of cancer diagnostics.
Factors influencing KI67 count in neuroendocrine tumors.
Authors: Miluska Castillo Garcia, Carlos Castaneda Altamirano, Sandro Casavilca Zambrano, Juvenal Sanchez, Luis Cano, Carlos Gonzales, Carolina Belmar Lopez, Valeria Villegas, Claudio J Flores, Marco Galvez, Rosario Villa, Tatiana Vidaurre
Journal: Journal of Clinical Oncology (2016)

e23260 Background: Neuroendocrine tumors(NETs) and NET-like lesions are an infrequent and heterogenous group of neoplasms sharing uniform histologic features. The WHO2010 grading of Gastro Entero Pancreatic-NETs is based on Ki67 and NET-like lesions are usually similarly classified. Methods: We selected 70 NET and NET-like tumors who came to the Institute between 2007 and 2013. Most common primary was intestinal(18.5%), female genitale(15.7%), pancreas(14.3%), liver & gallbladder(12.9%), esophagus & stomach(11.4%) and thorax(8.6%). Results: One pathologist and a pathology assistant performed a manual count of Ki67 in more than 2000 cells by case, 3 pathologists performed an eyeball Ki67 evaluation and pathology assistant run immunoratio (IR) software. Manual count of Ki67 was accepted as the standard methodology and was inversely associated with outcome(p < 0.001). 58.6% cases had a Ki67 > 20% and 22.9% had 3- 20%. First Pathologist obtained 4(4.2%) cases of Ki67 upgradation and 5.7% of downgradation. Second obtained 32% cases of Ki67 upgradation. Third obtained 13.6% of Ki67 upgradation and 13.6% of downgradation. Ki67 by IR score resulted in 17.14% cases of upgradation and 8.57% cases of dowgradation. We evaluated factors related to these differences and we found better concordance between eyeball and manual count when Ki67 was < 3%(-0.88 ± 0.74, 0.66 ± 0.78 -1.88 ± 5.30), and worst concordance when the Ki67-labeling index was in the range of 3% to 20%(1.81 ± 5.27, -0.07 ± 4.57 and 6.06 ± 3.29) and > 20%(-6.13 ± 16.0, -3.13 ± 17.4 and 12.85 ± 15.0). Level of tumoral fibrosis, quality of ki67 staining, quality of sample, biopsy/ resection, cellularity, level of infiltrating lymphocytes and neutrophyles dont influence variation between eyeball and manual Ki67 count(p = 0.120- 0.862, p = 0.094- 0.873, p = 0.099- 0.731, p = 0.099- 0.731, p = 0.054- 0.882, p = 0.013- 0.803, p = 0.583- 0.841, p = 0.102- 0.842, respectivelly). Same factors dont influence variation between IR and manual Ki67(p = 0.586, p = 0.496, p = 0.071, p = 0.271, p = 0.071, p = 0.284, p = 0.574, p = 0.216, respectivelly). Conclusions: There is differences of Ki67 measurement among pathologist and even for immunoratio software. Better concordance is found among pathologists when Ki67 is lower than 4%.
Efficacy and safety of single agent pan-HER inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer (sSCC).
Authors: Paolo Bossi, Stefano Cavalieri, Federica Perrone, Rosalba Miceli, Paolo Antonio Ascierto, Laura D. Locati, Cristiana Bergamini, Roberta Granata, Salvatore Alfieri, Carlo Resteghini, Donata Galbiati, Adele Busico, Nicholas Paielli, Roberto Patuzzo, Andrea Maurichi, Gianfranco Gallino, Roberta Ruggeri, Luigi Mariani, Marco Palla, Lisa Licitra
Journal: Journal of Clinical Oncology (2017)

9543 Background: In recurrent/metastatic skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. We investigated the role of pan-HER inhibitor dacomitinib within a phase II trial in this setting. Methods: Patients (pts) with diagnosis of sSCC not amenable to curative approaches were included. Oral dacomitinib was started at a dose of 30 mg daily for 15 days, followed by 45 mg daily. Primary endpoint was response rate (RR). Tumor samples were analyzed through Next Generation Sequencing methods (pgm, Ion torrent) using a custom panel targeting 36 genes associated with sSCC. Results: Forty-two pts (33 M, 9 F; median age 77 years, range 45-92) were treated. ECOG PS was 0 in 58%, 1 in 40% and 2 in 2%. One fifth of the pts had distant metastasis. Most pts (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). Among evaluable pts, overall RR was 28% (complete response CR 2%, partial response PR 26%), disease control rate 86%. Median duration of response was 11 months (range 1-26+). Median treatment duration was 4 months (range 1-26+). Reason for discontinuation were disease progression in 69%, adverse events (AEs) in 19%, non drug-related death in 5%; 3 pts are still on treatment. Median PFS and OS were 6 and 12 months, respectively. Most pts (93%) had at least one AE, mainly consisting in diarrhea and skin rash (71% each), fatigue (36%) and stomatitis (31%). G3/G4 AEs occurred in 36% of pts (diarrhea and skin rash 17% each). Tumor material was available from 7 responding (R: 6 PR, 1 CR) and 15 non-responding (NR: 13SD, 2PD) pts. Frequent TP53 (60%), NOTCH1/2 (60%) and FAT1 (40%) mutations were observed. NR pts showed a higher occurrence of HRAS/BRAF/NRAS mutations (40%) than R ones (28%). Moreover, HER3 (27%) CASP8 (27%), KMT2C (33%) and DCLK1 (27%) mutations were restricted to NR pts. Conclusions: In sSCC dacomitinib showed activity, similar to what observed with anti-EGFR monoclonal antibody cetuximab and panitumumab (RR 28% and 31%); safety profile was comparable to previous experiences in other diseases. Molecular pt selection could improve therapeutic ratio. Clinical trial information: NCT02268747.
Characteristics of <i>K-ras</i> mutation lung cancer in an East Asian institute.
Authors: Passakorn Wanchaijiraboon, Virote Sriuranpong, Sutima Luangdilok, Poonchavist Chantranuwat
Journal: Journal of Clinical Oncology (2018)

e21206 Background: East Asian lung cancer is dominated by EGFR driven non-small cell lung cancer (NSCLC). Though less common, K-ras mutation lung cancer in East Asian population remain a major challenge in both diagnosis and treatment. Here we report the prevalence and characteristic of lung cancer with K-ras mutation in our institute. Methods: Among 95 lung cancer patients treated during 2014 and 2017 at the King Chulalongkorn Memorial Hospital, we screened for EGFR and ALK mutation in these patients. After excluding EGFR and ALK mutation, we identified these NSCLC patients for K-ras mutation with the FDA approved Cobas test. Together with matched NSCLC without K-ras mutation, we analyzed clinical and pathological characteristics including demographic data, smoking status, TNM staging by 8th edition AJCC, and cyclinD1 expression by immunohistochemistry (IHC). Results: Total 95 patients included in this study. There were 52 patients showed no EGFR and ALK mutation. Among these patients, 25 from 52 (48%) had K-ras mutation in their tumor tissue. Clinical characteristics of this K-ras mutation NSCLC included more male (p = 0.001), more smoker (p = 0.005). There was a trend of poorer overall survival in K-ras NSCLC than without K-ras mutation (p = 0.053). We found higher level expression of cyclinD1 measured by intensity of staining in K-ras mutant vs wild-type, 64.5% and 49.3%, respectively (P = 0.03). Conclusions: In Thailand where prevalence of K-ras mutation NSCLC is moderate, clinical characteristics of these patients are similar to Caucasian patients. Greater expression of cyclinD1 was detected and may serve as a useful biomarker for targeted therapy targeting cell cycle proteins.
Metronomic chemotherapy using oral etoposide in metastatic osteosarcoma.
Authors: Julien Domont, Sarah Dumont, Arslane Skander Rahal, Julien Adam, Philippe Terrier, Haroun Ali Khalfallah, Françoise Rimareix, Andrea Cavalcanti, Isabelle Sourrouille, Nicolas Leymarie, Gilles Missenard, Charles Court, Leila Haddag-Miliani, Charles Honoré, Axel Le Cesne, Olivier Mir
Journal: Journal of Clinical Oncology (2016)

e22504 Background: Therapeutic options in adult patients with advanced or metastatic osteosarcoma (OS) are limited, and effective systemic treatments are needed in this setting. Methods: Retrospective, electronic records review of adult patients (pts) with metastatic OS treated with metronomic etoposide (25 mg orally tid, 2 weeks/3) from January 1st, 2004 to December 31st, 2015. Results: With a median follow-up of 8.0 months, 20 pts were eligible for this analysis [median age 48 (range : 21-75), 10% with synchronous metastases, 75% with ≥ 2 metastatic sites, median PS 2 (range: 1-3)]. All pts had documented progressive disease according to RECIST v1.1 before treatment initiation. Median number of previous treatment lines in the metastatic setting was 2 (range: 1-5). Toxicity profile was acceptable, with grade ≥ 2 anaemia in 25% and thrombocytopenia in 10% of pts, and one febrile neutropenia (5%). Alopecia was seen in all pts. Dose reduction (25 mg bid) was needed in 11 patients, all having received ≥ 2 previous treatment lines. Best response (RECIST v1.1) was: 15% PR, 35% SD, for an overall disease control rate of 50%. Progression-free rate at 3 months was 45%. Median PFS was 3.7 months, and median OS was 7.4 months. No baseline parameter significantly influenced treatment efficacy. Conclusions: Oral, metronomic etoposide chemotherapy exerts effective palliation along with acceptable toxicity in adult pts with metastatic OS.
A risk-based approach to cancer surveillance after completion of primary therapy in rectal cancer.
Authors: Jonathan M. Loree, Gillian K. Gresham, Hagen F. Kennecke, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2016)

e23089 Background: For cancers with a high risk of recurrence, most guidelines recommend 5 years of surveillance after primary treatment in order to detect relapses that are still amenable to further curative therapy. We hypothesized that the duration of surveillance in rectal cancer (RC) can be individualized since cancer follow up mainly offers value if the risk of recurrence or death from cancer is higher than that of death from non-cancer causes. We used a cohort of early stage RC patients (pts) to test this hypothesis. Methods: We identified RC pts diagnosed from 1999 to 2009 and referred to any 1 of 5 cancer centers in British Columbia, Canada. Time-to-event data were analyzed using competing risks methods with Weibull distributions. The Weibull models were plotted to characterize the time point at which the hazard rate of non-RC death exceeded that of RC related recurrence or death in order to determine the optimal duration of surveillance. The analysis was stratified by age and stage. Results: We included 2995 pts: median age 66 (IQR 57-74) years and 63% men. There were 428 (14%) stage I, 865 (29%) stage II, and 1702 (57%) stage III cases. Median follow up was 7.4 (IQR 5.6-9.8) years during which 943 (32%) relapses occurred. We observed significant variations in the ideal duration of surveillance (see Table). In pts aged >80 with stage II disease, for example, the risk of non-RC death surpassed the risk of recurrence at only 1.5 years after curative treatment whereas this did not occur until >15 years in pts aged <60. While the time point at which non-RC death exceeded relapse was not modified by ECOG, it was affected by site of relapse whereby the ideal duration of surveillance for locoregional recurrences is shorter than that for distant recurrences. Conclusions: A risk-based approach that considers key baseline characteristics may customize the optimal duration of follow up for specific cancer pts. This strategy balances the benefits of surveillance with the increasing need for value-based healthcare resource allocation. Time point (years) when risk of non-RC death exceeds risk of relapse. Age Stage I Stage II Stage III <50 >15 >15 >15 50-59 >15 >15 >15 60-69 4.5 8.5 >15 70-79 2 3.5 7.5 80+ 1 1.5 3.5
Phase IIIb randomized study of lenalidomide plus rituximab (R<sup>2</sup>) followed by maintenance in relapsed/refractory NHL: Analysis of patients with double-refractory or early relapsed follicular lymphoma (FL).
Authors: David Jacob Andorsky, Abdulraheem Yacoub, Jason M. Melear, Morton Coleman, Kathryn S. Kolibaba, Heather Dawn Brooks, Jacob D. Bitran, Suzanne R. Fanning, Frederick Lansigan, Justin L. Ricker, Kenneth A. Foon, Dongfang Liu, Mary Llorente, Jiahui Li, Jeff Porter Sharman
Journal: Journal of Clinical Oncology (2017)

7502 Background: Chemoresistant patients with FL and those who progress within 2 y after initial diagnosis have poor outcomes (Casulo. JCO. 2015) and highlight an unmet need. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of relapsed/refractory (R/R) NHL patients, including grades 1-3b or transformed FL (tFL). Patients receive 12 cycles of lenalidomide plus rituximab (R 2 ); those with stable disease or better are randomized 1:1 to maintenance R 2 or rituximab alone. The primary endpoint is progression-free survival (PFS). This analysis focuses on FL: double-refractory (DR) patients are refractory to both rituximab (as monotherapy or combination) and an alkylating agent, and early relapse (ER) patients progressed or relapsed within 2 y of initial diagnosis. Results: As of July 19, 2016, the R/R FL population (N = 117) included 32 (27%) DR and 43 (37%) ER patients, median ages of 64 and 65 y, respectively, mostly grade 1-3a FL (94%; 91%) and 2 tFL (1 DR; 1 ER); 72% and 49% were stage IV at study entry. Patients had a median of 2 prior regimens (DR 3; ER 2). Of ER patients, 31 had first-line R-chemo vs 12 with R-mono/other. Response rates are in Table 1. Median time to response was 2.8 mo for DR and 2.7 mo for ER patients, with median duration not reached. 1-y PFS for FL patients was 66% (DR 66%; ER 45%); 1-y PFS for ER patients with first-line R-chemo was 50% vs 27% in others. Common grade ≥3 treatment-emergent AEs for DR and ER patients were neutropenia (53%; 33%), leukopenia (9%; 12%), and lymphopenia (9%; 5%). Conclusions: R 2 followed by maintenance showed favorable activity and tolerable safety profiles in FL patients who are double-refractory or had early relapse ( &lt; 2 years) after initial diagnosis. Enrollment in MAGNIFY is ongoing. Clinical trial information: NCT01996865. [Table: see text]
Concussion among military service academy members: identifying risk factors, recovery trajectories, and the role of mental health
Authors: Kathryn Lacey O’Connor
Journal: British Journal of Sports Medicine (2018)

From a sample of 10 604 cadets, I investigated 800 concussions at three US service academies to identify factors that increase concussion risk, prolong recovery, and the relationship between concussion and psychological symptoms. The primary aim was to use multivariate methods across all concussion settings (sport, military and free time related) to achieve a more comprehensive understanding of concussion burden and outcomes.

Concussion is a growing concern among athletes and military personnel. Concussion rates among athletes have increased over the last 20 years1 2 and has become the signature injury of recent military conflicts.3 However, the majority of concussions among service members occur within the continental USA,4 with a mechanism similar to civilian injuries. To better understand who is at risk for concussion, specific concussion settings, such as sport-related or military-related injury, have been evaluated, but this method limits our understanding of the true concussion burden and identifying concussion-related risk factors. Additionally, most concussion recovery studies have focused on male football athletes …
P04.48 Role of the expression of protein kinase D1 and its phosphorylated forms in glioma-derived cell line exposed to modified isothiourea derivative ZKK-3 combined with hyperbaric oxygen therapy
Authors: K Zembrzuska, R P Ostrowski, E B Pucko, E Grzywaczewska, E Matyja
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most malignant primary tumour of the central nervous system. Its standard treatment includes surgery, radiotherapy and chemotherapy using temozolomide. Despite this, therapies still seems to be insufficient and median survival of the patients with GBM is less than 16 months. One of the main factors involved in glioma progression is the high level of tumour hypoxia, which contributes also to its resistance to treatment. In our previous studies we demonstrated that combination of hyperbaric oxygenation with novel pentabromobenzylisothiourea ZKK-3 resulted in an improvement of GBM cells oxygenation status and the reduction of their proliferation and viability in vitro. There is a high structural similarity between isothioureas and known casein kinase 2 (CK2) inhibitors. Nevertheless, ZKK-3 does not suppress CK2 expression, while it inhibits other protein kinases, including protein kinase D1 (PKD1), which promotes tumour growth and mediates detoxification of mitochondrial reactive oxygen species. The aim of this study was to assess the changes of the expression of PKD1 and its phosphorylated forms - pPKD1 (Ser 916) and pPKD1 (Ser 744/748), in glioma-derived cells treated with ZKK-3 under various oxygen conditions in vitro. Studies were performed on human glioblastoma T98G cell line (ATCC). Cells were cultured in MEM medium supplemented with N,N’-dimethyl-S-(2,3,4,5,6-pentabromobenzyl)-isothiouronium bromide (ZKK-3) in concentrations of 10 μM, 25 μM and 50 μM. Cultures were sustained in various oxygen conditions: normoxia, hypoxia, HBO, double hypoxia, hypoxia/HBO for 24 hour and then lysed with RIPA Lysis Buffer System (Santa Cruz). Using Western Blot protocol and appropriate primary and secondary antibodies, levels of tested protein kinases were determined. As the loading control β-actin was used. Administration of ZKK-3 did not affect PKD1 expression in glioblastoma cell line. Nevertheless, treatment with 50 µM of selected agent resulted in significant changes in the level of phosphorylated form of tested protein: diminution of pPKD1 (Ser 916) level and elevation of pPKD1 (Ser 744/748) level. Exposition of T98G cells to various oxygen conditions only slightly altered the expression of PKD1 and its phosphorylated forms in comparison to standard conditions, in both control and ZKK-3-treated groups, but observed differences were generally statistically insignificant. Obtained results suggested that PKD1-inhibiting properties of ZKK-3 were related with blocking the phosphorylation of that kinase at Ser 916. Unchanged expression of PKD1 as well as its phosphorylated forms under the influence of different oxygen conditions allowed to exclude PKD1 as a key protein for antitumour properties of ZKK-3/HBO combination strategy. The research was supported by KNOW-MMRC project.
Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis
Authors: Hai-Yan Chen, Dan-Ting Shen, Dong-Ze Ji, Pei-Chun Han, Wei-Ming Zhang, Jian-Feng Ma, Wen-Sen Chen, Hemant Goyal, Shiyang Pan, Hua-Guo Xu
Journal: Gut (2018)

Hepatitis D virus (HDV) is a defective virus that completes its life cycle only with hepatitis B virus (HBV). The HBV with HDV super-infection has been considered as one of the most severe forms of the chronic viral hepatitis. However, there is a scarcity of data on the global burden of HDV infection.We searched PubMed, Embase, Cochrane Library and China Knowledge Resource Integrated databases from 1 January 1977 to 31 December 2016. We included studies with a minimum sample size of 50 patients. Our study analysed data from a total of 40 million individuals to estimate the prevalence of HDV by using Der-Simonian Laird random-effects model. The data were further categorised according to risk factors.From a total of 2717 initially identified studies, only 182 articles from 61 countries and regions met the final inclusion criteria. The overall prevalence of HDV was 0.98% (95% CI 0.61 to 1.42). In HBsAg-positive population, HDV pooled prevalence was 14.57% (95% CI 12.93 to 16.27): Seroprevalence was 10.58% (95% CI 9.14 to 12.11) in mixed population without risk factors of intravenous drug use (IVDU) and high-risk sexual behaviour (HRSB). It was 37.57% (95% CI 29.30 to 46.20) in the IVDU population and 17.01% (95% CI 10.69 to 24.34) in HRSB population.We found that approximately 10.58% HBsAg carriers (without IVDU and HRSB) were coinfected with HDV, which is twofold of what has been estimated before. We also noted a substantially higher HDV prevalence in the IVDU and HRSB population. Our study highlights the need for increased focus on the routine HDV screening and rigorous implementation of HBV vaccine programme.