tbuckley/cabot-search huggingface dataset:
Open versus laparoscopic surgery for low rectal cancer: a large multicenter cohort study in Japan.
Authors: Koya Hida, Ryosuke Okamura, Yoshiharu Sakai, Tsuyoshi Konishi, Tomonori Akagi, Tomohiro Yamaguchi, Takashi Akiyoshi, Meiki Fukuda, Seiichiro Yamamoto, Michio Yamamoto, Tatsuto Nishigori, Kenji Kawada, Suguru Hasegawa, Satoshi Morita, Masahiko Watanabe
Journal: Journal of Clinical Oncology (2016)

3612 Background: Laparoscopic surgery for rectal cancer is widely performed all over the world and several randomized controlled trials have been reported. However, the usefulness of laparoscopic surgery compared with open surgery has not been demonstrated sufficiently, especially for the low rectal area. Therefore, a large multicenter cohort study with more than 1000 cases of low rectal cancer was planned to settle this issue. Methods: The data of patients with clinical stage II–III low rectal cancer below the peritoneal reflection were collected and analyzed retrospectively. The operations were performed from 2010 to 2011 and the cases were followed up until 2015. Short-term outcomes and long-term prognosis were analyzed. Results: A total of 1608 cases were collected from 69 institutes, and 1500 cases were eligible for analysis. The cases were matched using propensity scores (482 open cases and 482 laparoscopic cases). The median follow-up periods of each group were 3.6 years and 3.4 years, respectively. The median age was 64 years and the proportion of men was 69%. The mean height of the tumor from the anal verge was 4.6 cm. Preoperative treatment was performed in 35% of the patients. The conversion rate from laparoscopic to open surgery was 5.2%. Estimated blood loss during laparoscopic surgery was significantly less than that during open surgery (90 ml vs 625 ml, p < 0.001). Overall, the occurrence of complications after laparoscopic surgeries was less than that after open surgeries (30.3% vs 39.2%, p = 0.005), and the proportion of anal preservation was higher in the laparoscopic group than in the open group (60.0% vs 53.3%, p = 0.037). Three-year overall survival rates of R0 resection cases were 91.7% (95% CI 88.6—94.0) and 92.0% (89.0—94.2) in the laparoscopic and open groups, respectively, and no significant difference was shown between the two groups. No significant difference was observed in relapse-free survival between the two groups (72.1%, 67.6—76.1 vs 75.1%, 70.8—79.0). Conclusions: Even for advanced, very low rectal cancer below the peritoneal reflection, laparoscopic surgery could be considered a useful option based on the short- and long-term results of our large cohort study.
OS2.3 Updated results of REGOMA: A randomized, multicenter, controlled open-label phase II clinical trial evaluating regorafenib in relapsed glioblastoma &lt;GBM&gt; patients &lt;PTS&gt;
Authors: G Lombardi, G de Salvo, R Rudà, E Franceschi, M Eoli, M Faedi, A Pace, I Lolli, S Rizzato, D Germano, F Pasqualetti, M Farina, G Magni, L Bellu, M Caccese, A Pambuku, E Bergo, S Indraccolo, M Gardiman, R Soffietti, V Zagonel
Journal: Neuro-Oncology (2018)

There is no established treatment regimen for recurrent GBM. GBMs have activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR, and PDGFR. Regorafenib (REG), an oral multikinase inhibitor, inhibits these angiogenic kinases and the mutant oncogenic kinases KIT, RET, and B‐RAF. We present, after the first analysis, the updated results of REGOMA trial. The primary aim of this trial was to assess REG activity in prolonging overall survival (OS) in PTS with relapsed GBM after surgery and Stupp regimen (α = 0.2, 1-sided; β = 0.2). Secondary objectives were PFS, disease control rate (DCR), safety, quality of life (QoL); exploratory objectives included analysis of metabolic tissue biomarkers as possible predictors of response. PTS with histologically confirmed GBM, ECOG PS 0‐1, documented disease progression were randomized 1:1 to receive REG 160 mg/day (3 weeks on, 1 week off) or lomustine (LOM) 110 mg/m2 (every 6 weeks) until disease progression or unacceptable toxicity. Tumor response was evaluated by brain MRI every 8 weeks according to the RANO criteria. 119 PTS were randomized (n = 59 REG; n = 60 LOM) and stratified for surgery at recurrence; baseline characteristics, including MGMT methylation status, were balanced. Median age was 57.3 yrs; 27 PTS (22.7%) had surgery at recurrence, 22% and 23.3% in REG and LOM arm. At the time of analysis (cut-off date: Dec 31, 2017), median follow up was 15.4 months(m), 99 PTS had died. Median OS was 7.4m (95% CI 5.8–12.0) for REG and 5.6m (95% CI 4.7–7.3) for LOM (HR = 0.50, 80%CI 0.38–0.65; p = 0.0007; 1-sided Log-rank test); 12m-OS rates were 38.9% and 15.0% for REG and LOM. 6m-PFS rates were 16.9% and 8.3% (HR = 0.65; 95% CI 0.45‐0.95; p = 0.0223) for REG and LOM, DCR was 44.8% and 21.1% (p = 0.009) for REG and LOM. Grade ≥3 adverse events were reported in 56% and 40% for REG andLOM, no treatment-related deaths were reported. In this multicenter, randomized study, REG significantly improved OS, PFS and DCR in recurrent GBM PTS. REG treatment was feasible and well tolerated. QoL and biomarker analyses are ongoing. A phase 3 study will be planned
Ex vivo co-culture models for immunotherapy with patient-derived tumor infiltrating lymphocytes, peripheral blood mononuclear cells and autologous patient colorectal cancer (CRC) cell lines.
Authors: Si Qi Tan, Yunqin Lee, Fiona Yi Xin Lee, Who-Whong Wang, Ke Xin Bok, Lindsay Kua, Wan Jun Lim, Hui Min (Vivian) Teo, Shumei Chia, Jia Min Loo, Eugene Shen Ann Yeo, Wah Siew Tan, Ee-Lin Toh, Clarinda Chua, Si-Lin Koo, Yi-Chin Toh, Subhra Kumar Biswas, Han Chong Toh, Ramanuj Dasgupta, Iain Beehuat Tan
Journal: Journal of Clinical Oncology (2018)

e15531 Background: Response to immune checkpoint inhibition is dismal in colorectal cancer (CRC). There are limited experimental models to evaluate immunotherapy in human CRC. We developed an ex vivo co-culture system to interrogate pharmacologic or genetic perturbations that modulate anti-cancer immunotoxicity in CRC. Methods: Our system uses expanded CD8+ TILs & peripheral blood mononuclear cells (PBMC), cultured up to 6 weeks with engineered auxotrophic K562 aPCs, as effector cells. For target cells, we use both an engineered Hela-CD3+ GranzymeB FRET reporter system to identify immunogenic kill and expanded autologous tumor lines for patient specificity. We imaged Hela cytotoxicity by CD3-specific FRET-based fluorescence and autologous tumor cytotoxicity by Caspase-3/7 apoptosis. Results were validated by IFN-y ELISA and flow cytometry PMA/ionomycin stimulation. With a high content screen, we evaluated immunologic (E.g. IL-2, IL-15, IL-21), hypoxia, pharmacologic (anti-PD1 & other checkpoints) & genetic pertubations affecting effector cytotoxicity or target susceptibility. Results: We successfully expanded & characterized PBMC/TILs from 16 patients, achieving up to 65000 and 120000 cumulative fold expansion respectively, comparable to Rapid Expansion Protocol in metastatic melanoma. Expanded T cells were predominantly CD3+ (median 95%, range 20-99%, n = 16) with median 10% CD8+ T cells (range 0.27-47.4%) up to 42 days. TILs expressed higher PD-1 and more activated phenotype versus PBMC and normal tissue. When co-cultured with Hela-CD3+, 8 of 9 patient T cells demonstrated significant dose and time-dependent cytotoxicity. Pharmacologic perturbations and PD-1+CD8+% altered responses. There was autologous tumor specificity. A high-throughput screen identified mediators of target cell susceptibility and effector cell function. Conclusions: We have developed an ex vivo co-culture system to evaluate immunologic, pharmacologic or genetic modulation on immune and target cells for optimization of adoptive T cell therapy, facilitating discovery/testing of novel treatment strategies/targets in CRC.
ARID1A alterations in gynecological cancers as a therapeutic opportunity.
Authors: Laura Gonzalez-Malerva, Gargi D. Basu, Michael Syring, Subha Krishnan, Tracey White, Janine R LoBello, Kevin R Lau, Thomas Royce, Ahmet Kurdoglu, Michael J Demeure
Journal: Journal of Clinical Oncology (2016)

e17044 Background: Gynecologic cancers (GC) affect women's reproductive organs and are associated with the highest mortality rates due to late stage detection and lack of effective treatments. The tumor suppressor ARID1A regulates gene expression, maintains genomic integrity by interacting with ATR and is frequently inactivated in GC. We evaluated ARID1A alterations in gynecological cancers to identify new therapeutic options. Methods: Comprehensive genomic profiling was performed in 72 GC (10 primary, 60 metastatic, 2 unknown). Targeted sequencing was performed using a 562 cancer-associated gene panel on paired FFPE tumor and blood DNA samples. Results: ARID1A alterations were noted in 21% (15/72) of GC cancers, including 6/38 ovarian (2 each clear cell and ovarian serous tumor and 1 endometrioid), 5/14 endometrial, 2/7 cervical and 2/4 carcinosarcomas/MMMT. Alterations included frameshifts, nonsense mutations and INDELs, which are predicted to cause loss of ARID1A function. Interestingly, we found that 73% (11/15) of the tumors with ARID1A alterations frequently harbored alterations that lead to activation of the PI3K/AKT signaling pathway, which may increase sensitivity to PI3K/AKT pathway inhibitors, compared to only 32% (18/57) in tumors without ARID1A alterations. Mutations in the C-terminus of ARID1A, the region that interacts with ATR, mediating its recruitment to double stranded breakpoints, was observed in 40% (6/11) of tumors. Further, deleterious events in the DNA repair pathway were found in 33% (5/15) of ARID1A mutated samples, suggesting a role for PARP inhibitor therapy. Of 41 (57%) patients with TP53 mutations, only 7% were found to have concurrent ARID1A alteration. No pathogenic changes were present in the MMR genes of ARID1A altered samples. Conclusions: Targeted sequencing demonstrated that ARID1A alterations are a frequent event in GC, particularly in endometrial cancer. These alterations lead to an activation of the PI3K/AKT pathway, which indicate therapeutic opportunities with inhibitors of the PI3K/AKT pathway. The presence of pathogenic changes in the DNA repair pathway may predict clinical utility of PARP inhibitors in gynecologic cancers.
A lung cancer-derived CRAF mutation to activate ERK pathway and to predict sensitivity to LY3009120 and trametinib.
Authors: Amir Noeparast, Jacques De Greve, Sylvia De Brakeleer, Rajendra Bahadur Shahi, Erik Teugels
Journal: Journal of Clinical Oncology (2017)

e23197 Background: During the Belgian FIELT II clinical study, two non-small cell lung cancers among 41 were found to harbor a CRAF mutation. One of these mutations (P207S) was previously found in fibrosarcoma and characterized as not activating the ERK pathway at higher levels compared to the wild-type CRAF. The other mutation (P261A) has never been reported in cancer but found in Noonan syndrome. CRAF mutations can be oncogenic thereby activation of the ERK pathway. Serine 259 is a negative regulatory site and its phosphorylation is essential for keeping the CRAF auto-inhibited. P261A CRAF prevents phosphorylation of S259 but its role in cancer and its possible response to small molecule inhibitors has yet to be uncovered. Methods: We generated recombinant CRAF expression vectors by site-directed mutagenesis and investigated the ERK pathway activation status induced by CRAF mutants, in HEK293T cells and BEAS-2B (lung epithelial) cells. We tested the effect of candidate inhibitors at a clinically relevant dose on ERK pathway activity in BEAS-2B cells expressing CRAF mutants. Results: Expression of P261A CRAF in both HEK293T and BEAS-2B cells leads to increased ERK pathway activation compared to wtCRAF, accompanied by decreased phosphorylation of S259. P207S CRAF induces ERK pathway activity at levels comparable to wtCRAF and we observed that co-expression of BRAF with P207S CRAF does not lead to increased ERK activity compared to wtCRAF/BRAF. RAF-inhibitors LY3009120 and AZD-628 suppress ERK pathway activity induced by P261A CRAF in BEAS-2B cells. LY3009120 showed stronger ERK-inhibitory effect compared to AZD-628. In contrast, Dabrafenib (RAF-inhibitor) treatment of mutant or wtCRAF expressing cells leads to paradoxical ERK activation. Combinatorial treatment of LY3009120 with Trametinib (MEK-inhibitor) leads to stronger ERK-inhibitory effects compared to either single agent treatment in cells expressing mutant CRAF. Conclusions: The P261A CRAF mutation is ERK pathway activating and predicts sensitivity to LY3009120 and Trametinib. CRAF inhibition should be clinically explored in lung cancers and perhaps other cancers with sensitizing CRAF mutations.
Researcher cautions against initiatives to reduce student suicide that lack evidence
Authors: Laura Nunez-Mulder
Journal: BMJ (2018)

Universities are implementing policies to reduce suicide among students and improve mental health with little evidence that they will make any difference, a researcher has warned.

A total of 5821 suicides were reported in the UK in 2017, 10.1 deaths per 100 000 population, a proportion among the lowest since records began in 1981.1 About one in 60 deaths by suicide in 2017 (95) were carried out by a student in higher education.12

Data also show that the proportion of university students declaring a mental health condition has more than tripled in recent years, from 0.8% in 2010-11 to 2.5% …
Phase II study of nivolumab in Japanese patients with relapsed or refractory Hodgkin lymphoma previously treated with brentuximab vedotin (ONO-4538-15): An interim analysis.
Authors: Kiyohiko Hatake, Tomohiro Kinoshita, Noriko Fukuhara, Ilseung Choi, Masafumi Taniwaki, Kiyoshi Ando, Dai Maruyama, Yasuhito Terui, Yusuke Higuchi, Yasushi Onishi, Yasunobu Abe, Tsutomu Kobayashi, Yukari Shirasugi, Kensei Tobinai
Journal: Journal of Clinical Oncology (2016)

e19018 Background: The programmed death-1 (PD-1) immune checkpoint pathway regulates T-cell-mediated antitumor immune responses in various tumors. Nivolumab (Nivo) (Ono Pharmaceutical, Bristol-Myers Squibb), a human anti-human PD-1 monoclonal antibody, has shown its efficacy in various cancers. A phase I study of Nivo in patients (pts) with relapsed or refractory (R/R) hematologic malignancy (CA209039) revealed the tolerability and efficacy of Nivo monotherapy in R/R classical Hodgkin lymphoma (R/R cHL) pts. ONO-4538-15 is the first Japanese study on Nivo in R/R cHL pts given prior brentuximab vedotin (BV). Here we present the results of an interim analysis. Patients andMethods: BV is currently used for the treatment of R/R CD30-positive cHL based on its known efficacy. Nivo (3 mg/kg) was administered on Day 1 of a 14-day cycle to R/R cHL pts given prior BV. The primary endpoint, IRC-assessed overall response rate (ORR), was evaluated using the IWG criteria (Cheson, 2007). Adverse events (AEs) were assessed using NCI-CTCAE ver. 4.0. Results: A total of 17 R/R cHL pts were enrolled at 13 sites from Apr to Sep 2015 (men: 13, women: 4; median age: 63 years; PS 0: 8 1: 9; stage II: 4, III: 5, IV: 8) with a median follow-up period of 5.1 months. All pts had previously received BV. ORR was 75% in 16 efficacy-evaluable pts (12/16; 95% CI: 47.6–92.7), including CR in 4 pts and PR in 8 pts. In 8 BV-resistant pts, where PD or SD was assessed as best overall response (BOR) with BV, the BOR with Nivo included CR in 3 pts, PR in 4 pts, and NE in 1 pt. AEs were observed in all 17 pts. Two pts presented grade 3 or 4 AEs; lymphopenia in 1 pt, anemia, hyponatremia, and interstitialpneumonia in 1 pt. After data cut-off, 2 pts experienced serious AEs (fulminant type 1 diabetes mellitus in 1 pt; rash, hepatic function disorder, and pyrexia in 1 pt). All AEs were clinically manageable. Conclusions: The interim analysis of Japanese phase II study of Nivo suggested its high efficacy with acceptable safety profiles even in pts with BV-resistant R/R cHL. Clinical trial information: JapicCTI-142755 Clinical trial information: JapicCTI-142755.
Prevalence of quality of life(QoL) outcomes and association with survival in cancer clinical trials.
Authors: Bishal Gyawali, Thomas Hwang
Journal: Journal of Clinical Oncology (2018)

6573 Background: QoL outcomes provide essential information for patients and physicians in oncology care, but these data are not always reported in pivotal trials of new therapies. We investigated the prevalence of quality of life outcomes in modern cancer drug trials and the relation, if any, between quality of life and surrogate endpoints. Methods: Retrospective cohort study of all phase III clinical trials of drugs for advanced or metastatic solid tumors published between 2010 and 2015. We investigated the inclusion and reporting of QoL endpoints in clinical trials of cancer drugs and the association between positive progression-free survival (PFS) and QoL outcomes. Results: Of the 352 Phase 3 trials included, 147 (42%) reported QoL outcomes. There were 162 (46%) that did not include a QoL endpoint and 43 (12%) that did not report pre-specified QoL endpoints, cumulatively enrolling a total of 125 962 patients. Factors significantly associated with lower rates of inclusion of QoL endpoints were cancer type (head and neck and other solid malignancies), primary endpoints of response rates or non-PFS surrogate endpoints, and smaller studies. Among the 147 trials that reported QoL outcomes, 99 (67%) reported no effect, 38 (26%) reported a positive effect, and 10 (7%) reported a negative effect of treatment on patients' global QoL. The correlation between PFS and positive QoL was low (r = 0.34; area under the curve [AUC]: 0.72). Conclusions: Despite the palliative intent of treatments in the advanced/metastatic setting, the availability of QoL data remains poor, primarily due to non-inclusion of QoL endpoints in large cancer clinical trials. Greater inclusion of pre-specified QoL measures and improved reporting of QoL outcomes are needed.
Detection of early recurrence in HCC patients after TACE treatment with plasma cfDNA.
Authors: Xiao Du, Zhen Li, Henghui Zhang
Journal: Journal of Clinical Oncology (2018)

e16146 Background: Hepatocellular carcinoma (HCC) is the one of the most common prevalent fatal cancers worldwide with poor prognosis due to high incidence of recurrence. For patients with advanced HCC, transcatheter arterial chemoembolization (TACE), a minimal invasive clinical nonsurgical treatment is the standard first-line option. However, current surveillance approaches based on serological examination (including AFP) and imaging (ultrasound, CT, MRI, etc.) are limited in early detection of residual cancer and relapse that result in the bottleneck of long-term effects after TACE therapy. Methods: This study consists of two parts. In the first part, forty-one patients with HCC were included. According to number of tumor lesions, patients were classified into two groups: single lesion group (S) and multiple lesions group (M). In the second part, three patients with advanced HCC treated with TACE were included. Periodic evaluation of plasma cfDNA together with radiologic examination, laboratory testing (including AFP) were performed simultaneously to trace the dynamic response of HCC patients after TACE treatment. Tumor tissue DNA and matching cell-free DNA are subjected to enrichment for a 1.15M size panel covering exon regions of 1,086 genes. With next generation sequencing on an Illumina X10 platform, the captured sequencing data was further processed using bioinformatics analysis to identify variations. Results: We showed that the mutational profiles of plasma cfDNA is in consistency with that of tumor tissue DNA. Using the mutation burden of 7 genes (CTNNB1, PIK3CA, MET, EGFR, FBXMW7, TP53, and ERBB2.), the M group can be distinguished from S group. In addition, plasma cfDNA mutation burden of 10 genes (NRAS, BRAF, PIK3CA, KRAS, ARID1A, AXIN1, ARID2, TERT, TP53, CTNNB1) indicates relapse weeks prior to conventional computed tomography (CT) imaging and Alpha-Fetoprotein (AFP) changes. Conclusions: Our results suggest that plasma cfDNA serves as a promising surveillance tool of HCC patients treated with TACE. The high mutation burden status of 10 genes (NRAS, BRAF, PIK3CA, KRAS, ARID1A, AXIN1, ARID2, TERT, TP53, CTNNB1) might correlate with recurrence in HCC patients.
Utility or futility of preoperative thyroglobulin in patients undergoing thyroidectomy for differentiated thyroid cancer.
Authors: Rushad Patell, Gauri Bhuchar, Michael Tabet, James Bena, Shannon Morrison, Eren Berber, Ahmet Bahadir Ergin, Tobenna Igweonu Nwizu, Christian Nasr
Journal: Journal of Clinical Oncology (2016)

6098 Background: Thyroglobulin (TG) has an established role to detect recurrence of differentiated thyroid cancer (DTC). The role of preoperative TG measurement is more ambiguous, yet commonly performed in practice. This study aimed to determine if preoperative TG correlates with stage or metastatic burden. Methods: A retrospective review of consecutive patients undergoing thyroidectomy with preoperative TG, at Cleveland Clinic was conducted. Data collected included demographics, preoperative TG levels, pathology of resected specimen, stage of cancer and presence of metastasis. Associations between presurgical TG levels with size of largest malignant nodule, total thyroid size, stage of cancer and metastasis using Wilcoxon rank sum tests and Spearman correlations were made. Receiver Operator Curve (ROC) was generated to assess utility of presurgical TG to detect metastasis. Results: Study population consisted of 598; patients with positive TG antibodies were excluded (n = 176). 422 patients were included in the final analysis. Median age was 55 years and 76 % were female. 78% patients had malignancy on pathology of which papillary thyroid cancer was most frequent (92%). 18% had TG levels > 500 ng/mL and 29% < 35 ng/mL. 4% had distant metastasis and 18 % lymph node metastasis. Median length of follow up was 52 months. Preoperative TG led to additional imaging in 4%. A significant positive correlation between presurgical TG and thyroid size (rho, 0.49, p < 0.001) and size of malignant nodule (rho 0.27, p < 0.001) was observed. Using a cut-off of 500 for presurgical TG to detect metastasis sensitivity was 10.3% (95% CI 2.5-18.2), specificity 90.0% (95% CI 86.0-93.9), positive predictive value 21.4%, (95% CI 6.2-36.6) and negative predictive value 79.1% (95% CI 74.1-84.2). Area under curve for ROC generated was not significant (0.46 95% CI 0.38-0.54), indicating poor diagnostic ability of TG to predict metastasis. Conclusions: Although preoperative TG correlated significantly with the size of gland and T stage there was no correlation with metastasis. Presurgical TG is of limited utility in today’s value based healthcare environment.