tbuckley/cabot-search huggingface dataset:
Phase II trial of carboplatin and pemetrexed plus bevacizumab with maintenance bevacizumab as first-line treatment for elderly patients with advanced non-squamous non-small cell lung cancer.
Authors: Hiroaki Takeoka, Kazuhiko Yamada, Hidenobu Ishii, Takaaki Tokito, Koichi Azuma, Yoshiko Naito, Norikazu Matsuo, Masao Ichiki, Tomoaki Hoshino
Journal: Journal of Clinical Oncology (2018)

e21180 Background: Platinum-doublet chemotherapy combined with bevacizumab has been established as first line treatment option in patients with non-squamous non-small cell lung cancer (non-sq NSCLC). However, the safety and efficacy analysis of platinum-doublet chemotherapy plus bevacizumab for elderly patients have not yet been fully evaluated. Methods: Chemo-naïve non-sq NSCLC patients more than 75 years old with good performance status (Eastern Cooperative Oncology Group performance status 0–1) and adequate organ function were eligible. Patients received carboplatin at area under the curve 5, pemetrexed 500mg/m2, and bevacizumab 15mg/kg every 3 weeks (up to 4 cycles) followed by maintenance bevacizumab. The primary endpoint was objective response rate (ORR), with target ORR of 50% and threshold of 30% (SWOG two-stage design), secondary endpoints were the safety, progression free survival (PFS), and overall survival (OS). Results: From June 2013 to July 2017, 12 patients were enrolled. The study was closed because only 12 patients were enrolled within 4 years. Median age was 80 years. Eleven patients (92%) completed 4 cycles of induction chemotherapy. Seven patients achieved partial response, and the ORR was 58%. Median PFS was 8.6 months (95% confidence interval [CI]: 4.4-10.5), and median OS was 33.9 months (95% CI, 16.2-43.3), respectively. Toxicities were generally mild and consistent with previous reports. One patient experienced grade 3 hemorrhagic event (diverticulitis). There was no treatment-related death. Conclusions: Carboplatin and pemetrexed plus bevacizumab followed by maintenance bevacizumab is feasible and might have promising efficacy for elderly patients with non-sq NSCLC. Further investigation of this regimen is warranted. Clinical trial information: UMIN000011095.
Refining actionable <i>HER2</i> alterations in lung cancers through next generation sequencing (NGS).
Authors: Chongrui Xu, Mackenzie Myers, Darren J. Buonocore, Pedram Razavi, Ronglai Shen, Wei-Chu Victoria Lai, Lillian Mary Smyth, Tao Zheng, Ai Ni, David B. Solit, Ahmet Zehir, Edyta B. Brzostowski, Matthew David Hellmann, Alexander E. Drilon, Charles M. Rudin, Michael F. Berger, Marc Ladanyi, Mark G. Kris, Bob T. Li, Maria E. Arcila
Journal: Journal of Clinical Oncology (2018)

e24181 Background: Targeting HER2 alterations including mutation, amplification and protein overexpression has been an active area of new drug development. However, the relationships between these HER2 alterations are not well understood and the optimal method for assessing HER2 status in lung cancers for targeted therapy remains undefined. Methods: From 2014 to 2017, 2200 lung cancer specimens underwent prospective NGS by MSK-IMPACT. Specimens found to have HER2 mutation or amplification by NGS were further assessed by fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC). HER2 IQFISH pharmDx Dako probe was used for FISH with HER2/CEP17 ratio ≥2.0 defined as positive. The 4B5 Ventana antibody was used for overexpression by IHC. Results: A total of 114 patients were identified with HER2 mutation or amplification by NGS, including 67 (3%) with mutation only, 36 (2%) with amplification only, and 11 with both mutation and amplification. Clinical and molecular characters are listed in Table 1. There was no correlation between HER2 mutation and IHC or FISH. HER2 amplification by NGS captured 19 of 20 IHC3+, as well as 32 of 38 FISH positive cases. Conclusions: IHC and FISH are suitable methods for identifying HER2 amplification but are not surrogates for assessing HER2 mutation. NGS identified both HER2 mutation and amplification or high level overexpression, and constitutes an ideal method of upfront screening for HER2 status in selecting patients for HER2 targeted therapy. Table 1: Clinical and Molecular Characteristics in Patients with Cancers Driven by HER2 NGS Result: Mutant Only n(%) Amplified Only n(%) Mutant+ Amplified n(%) Age at Diagnosis (years) ≤ 60 15 (22) 16 (44) 8 (73) ˃60 52 (78) 20 (56) 3 (27) Sex Female 45 (67) 19 (53) 4 (36) Male 22 (33) 17 (47) 7 (64) Histology Adenocarcinoma 61 (91) 31 (86) 11 (100) Squamous Cell Carcinoma 2 (3) 4 (11) 0 (0) Misc 4(5) 1(1) 0(0) Smoking History Smoker 39 (58) 26 (72) 5 (45) Non-Smoker 28 (42) 10 (28) 6 (55) IHC Analysis Performed 42 (63) 21 (58) 9 (82) 0 18 (43) 0 (0) 4 (44) 1+ 9 (21) 1 (5) 0 (0) 2+ 14 (33) 2 (10) 4 (44) 3+ 1 (2) 18 (86) 1 (11) FISH Analysis Performed 50 (75) 26 (72) 10 (91) Positive 6 (12) 23 (88) 9 (90) Negative 44 (88) 3 (12) 1 (10) Total of 114 Patients 67 (59) 36 (31) 11 (10)
Hemorrhagic and thrombotic events in oncology patients treated with antiangiogenic therapy: Impact of study design on the results assessed by meta-analysis.
Authors: Jane-Chloe Trone, Céline Chapelle, Edouard Ollier, Laurent Bertoletti, Michel Cucherat, Patrick Mismetti, Nicolas Magné, Silvy Laporte
Journal: Journal of Clinical Oncology (2017)

e14058 Background: Antiangiogenic (AA) therapies emerge as a new cornerstone for cancer treatment, but carry their own particular risk profile. Several previous meta-analyses have showed increasing risk of bleeding and paradoxically thrombosis in cancer patients receiving antiangiogenic. The aim of the meta-analysis is to investigate the impact of studies design (open or double blind (DB)), on the incidence and the occurrence of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated by AA therapies. Methods: We searched Medline, Cochrane, ClinicalTrial databases, meeting abstracts of the American Society of Clinical Oncology and the European Society of Medical Oncology for relevant clinical trials. We included prospective phase II and III clinical trials that randomly assigned patients with solid cancer to AA therapy or control. Statistical analyses were conducted to calculate the summary incidence, ORs, and 95% CIs, using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: A total of 166 trials (72,024 patients) were included. For bleeding events, comparison on AA treatment versus control yielded an OR of 2.41 (95% CI 2.07 to 2.71; p &lt; 0.001) with an exaggeration of treatment effects by 68% (95% CI, 33 to 113) in open-label studies compared with DB trials. Concerning VTE, an OR of 1.18 (95% CI 1.04 to 1.35; p = 0.0115) was noted, with a significant enhancement of 53% (95% CI, 19 to 96) of treatment side effects with open trials compared with DB trials. AA don’t increase significantly the frequency of VTE when considering only DB trials. For ATE, an OR of 1.59 (95% CI 1.30 to 1.94; p &lt; 0.001) was observed, associated with a significant exaggeration of 65% (95% CI, 13 to 143) with open trials compared with DB trials. Conclusions: The present meta-analysis showed a significant interaction of study design for the tolerance assessment in the AA therapies in cancers. The increasing risk of hemorrhagic events, VTE and ATE appear to have been overestimated in the previous meta-analyses. In the future, meta-analyses should be restricted to DB trials for analysis of toxicity profile.
OS2.1 Objective responses to chemotherapy in recurrent glioma do not predict better survival: A prospective analysis from the German Glioma Network
Authors: O Bähr, B Hentschel, E Hattingen, M Reusche, M Tatagiba, J Tonn, O Schnell, G Schackert, M Westphal, U Herrlinger, T Pietsch, G Reifenberger, M Weller, M Löffler, J P Steinbach
Journal: Neuro-Oncology (2018)

Outside of clinical trials, the occurrence of objective responses (OR) to chemotherapy in patients with recurrent gliomas is poorly characterized. Further, the predictive value of OR for progression-free survival (PFS) and overall survival (OS) in glioma patients is unclear. We screened the German Glioma Network Database for patients who had received any chemotherapy for recurrent glioma from 2004–2008. Patients with a prior gross total resection of the recurrent tumor, patients receiving additional radiotherapy for the recurrent tumor and patients with spinal gliomas were excluded. As PFS was not available for a large number of patients we used the composite endpoint time-to-treatment-failure (progressive disease, start of a new therapy or death). We included 485 patients who received 646 chemotherapy regimens for treatment of recurrent glioma. Of these, only 32 chemotherapies in 32 patients resulted in an objective response (30 PR, 2 CR) after central neuroradiological review according to RANO criteria. OR rates were 2.8%, 11.0% and 10.6% for glioblastoma, anaplastic glioma WHO grade III and diffuse glioma WHO grade II, respectively. Temozolomide (n=232) resulted in ORs in 7.8% of the patients, while nitrosourea (n=212) and imatinib (n=27) resulted in ORs in 6.1% and 3.7%, respectively. Overall, responders showed a significantly improved OS compared to non-responders (median OS 33.3 versus 15 months, p=0.054). Yet, a Cox regression analysis adjusted for diagnosis (including WHO grade) and age did not reveal a significant association of objective responses with overall survival (relative risk 0.8, p=0.391). In addition, we generated a 1:3 cohort (n=96) of non-responders matched for histology and WHO grade. There was no relevant difference in OS comparing responders to the matched cohort (median OS 33.3 versus 25.6 months, p=0.929). When comparing non-responders with longer time-to-treatment-failure (>14 weeks, assumed stable disease as best response) with responders (n=32) the difference in outcome was lost (median OS 24.3 versus 33.3 months, p=0.86). In contrast, non-responders with shorter time-to-treatment-failure (<14 weeks, assumed progressive disease as best response) had dramatically shorter survival (median OS 6.4 versus 33.3 months, p<0.05). In this large, prospective study objective responses to chemotherapy in the recurrent setting were rare in glioma patients. Notably, when comparing responders with a matched cohort or patients with assumed stable disease as best response, objective responses do not seem to be associated with improved survival.
Coexistence of rearranged during transfection (RET) variants and activating EGFR mutations with their molecular implications in lung adenocarcinomas.
Authors: Jeong-Oh Kim, Jung-Young Shin, Min Young Kim, Kyoung Hwa Son, Chan-Kwon Jung, Tae-Jung Kim, Su Young Kim, Sook-Whan Sung, Jae Kil Park, Sang Mi Ro, Sang-Ju Bae, Hyun-Jung Min, Jin Hyoung Kang
Journal: Journal of Clinical Oncology (2017)

e20610 Background: RET rearrangements have been identified in 1-2% of lung adenocarcinomas. The most common fusion is the KIF5B-RET, the function and roles of the RET fusion oncogene, and its downstream signaling molecules remain unclear. Methods: We constructed a tissue microarray (TMA) comprising 581 resected tumor tissues from lung adenocarcinoma patients and investigated them using FISH with RET break-apart and KIF5B-RET SY translocation probes. NanoString’s nCounter technology was used to assay RETtranscripts. We evaluated the protein expressions of RET and RET-related signaling molecules, including p-AKT and p-ERK, using TMA-based IHC staining. Results: Using FISH, we identified 51 cases (8.8%) of RET variants and 10 cases (1.7%) of KIF5B-RET fusion genes among the 581 cases. RET protein expression was lower in the group harboring KIF5B-RET fusion gene than that in the group harboring a wild type RET gene. We found the activating EGFR mutations in 11 (21.6%) cases of 51 RET variants. For the group with KIF5B-RET fusion gene, the expression of p-ERK was significantly lower in EGFR mutation subgroup with presence of RET protein compared to EGFR mutation subgroup with absence of RET protein. For the group with RET rearrangement, there were significant differences in the expression level of p-AKT (P = 0.028) and, p-ERK protein expression was remarkably increased, especially in cases with no RET protein expression. Conclusions: Taken together, the expression of p-ERK protein was meaningfully increased in the RET variants group regardless of RET protein expression. This result suggests that RET inhibitors combined with ERK inhibitors may be an effective treatment strategy for lung adenocarcinoma patients harboring the RET variants.
Monitoring advanced non-small cell lung cancer (NSCLC) through plasma genotyping during systemic treatment: KRAS-mutated (m) cohort results.
Authors: Laura Bonanno, Elisabetta Zulato, Giorgia Nardo, Paola Del Bianco, Ilaria Attili, Alberto Pavan, Martina Verza, Lorenza Pasqualini, Giulia Alberti, Giulia Pasello, Giulia Zago, Stefano Frega, Matteo Fassan, Massimo Rugge, Gian Luca De Salvo, Fiorella Calabrese, Pier Franco Conte, Stefano Indraccolo
Journal: Journal of Clinical Oncology (2018)

e24074 Background: Detecting genetic alterations in plasma has the potentiality to monitor biological effects of treatment without invasive procedures. The aim of the study is to validate the method in advanced EGFR-ALK-ROS1 wild-type NSCLC and explore the correlation of dynamic variation of tumor-specific mutations in plasma with outcome. Methods: Advanced NSCLCs undergoing anti-cancer systemic treatment are prospectively enrolled in the trial. Tissue genetic alterations are screened through Sequenom massarray system and Next-generation sequencing. Plasma samples are collected at baseline (T1), after the first cycle of treatment (T2), at the moment of first radiological restaging (T3) and radiological progression (T4). KRAS-m cohort is analyzed in plasma by using digital droplet PCR. Semiquantitative index of fractional abundancy of mutated allele is used. Results: Since January 2017 we have prospectively enrolled 165 patients (pts), 55 (33%) treated with immunotherapy (IT). KRAS mutation was detected in plasma at baseline in 17 out of 34 cases mutated in tissue (50%;95% CI 32.4-67.6). 60% pts positive at baseline had progressive disease (PD) as best radiological response (RR) versus 40% negative pts (p = 0.4661). Predictive value of KRAS mutation in plasma increased at subsequent evaluations with an AUC of 0.67 (95%CI: 0.48-0.83, p = 0.0779) at T2, and became statistically significant at T3 with an AUC 0.73 (95%CI: 0.51-0.95, p = 0.0389); sensitivity and specificity for non-PD at a cut-off value of 0 were 80% (95% CI 44.4-97.5) and 66.7% (95% CI 29.9-92.5), respectively. The reduction of fractional abundancy of KRAS-m allele (T1-T3) showed an overall ability to discriminate between groups (PD vs non-PD) of 84% (95% CI: 61-97, p-value < 0.0001) with a sensitivity for detection of non-PD of 90% (95% CI 55.5-99.7) and a specificity of 66.7% (95% CI 29.9-92.5). A trend for improved survival in pts with reduction of fractional abundancy was also seen. Conclusions: Dynamic variations of KRAS mutation in plasma show correlation with RR warranting further investigation. A prospective trial in pts treated with IT is ongoing.
Dissemination of information on neutropenic diet (ND) by top U.S. cancer centers: In line with evidence?
Authors: Dhruvika Mukhija, Naveen Premnath, Arjun Gupta, Anand Venkatraman, Sajan Jiv Singh Nagpal
Journal: Journal of Clinical Oncology (2018)

e18940 Background: Neutropenic Diet (ND) is commonly recommended and widely practiced for cancer patients with neutropenia with the goal of reducing infections. However, multiple randomized trials suggest that the overall risks of infection and mortality with ND are equivalent to less restricted diets. Moreover, ND affects the quality of life of patients significantly and contributes to malnutrition and reduced patient satisfaction. Therefore, we aimed to ascertain if top cancer centers recommended for or against the use of ND on their official websites, a common source of information for patients. We also evaluated if these recommendations are supported by literature. Methods: Websites of the top 20 hospitals in the 2017 US News Best Hospitals for Cancer © were reviewed independently by two authors (DM and NP) and recommendations on ND were ascertained (i.e. for, against, equivocal, or not addressed) based on provided information. Further, it was determined if the recommendation provided was backed by evidence. Inter-rater agreement was 90%. The discordance in two instances was due to mention of a ‘low microbial diet’ which was resolved by including it with ND. Non-parametric statistics were used. Results: 7 out of 20 websites (35%) made recommendations for ND, 4 (20%) against and 9 (45%) did not address ND at all. Only 5 out of 20 (25%) backed any of their recommendations with evidence (4 against, 1 for ND), including 2 (10%) links to abstracts (both against), whereas 7 mentioned the FDA safe food handling guidelines (non-exclusive). Type of recommendation made (for or against) did not depend on US news rank (top vs bottom 10; p = n.s.). 7 (35%) websites mentioned date of last content update and the median age of the posts was 1075.5 days (range 32-5886 days). Age of website content did not impact recommendation for or against ND. Conclusions: ND continues to be recommended or not addressed on the majority (80%) websites of top US cancer centers, despite strong evidence against its use. The website content of major US cancer centers pertaining to ND should be updated sooner to better guide patients.
SAKK 16/14: Anti-PD-L1 antibody durvalumab (MEDI4736) in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small cell lung cancer (NSCLC)—A multicenter single-arm phase II trial.
Authors: Sacha Rothschild, Alfred Zippelius, Spasenija Savic, Michel Gonzalez, Walter Weder, Alexandros Xyrafas, Corinne Rusterholz, Miklos Pless
Journal: Journal of Clinical Oncology (2018)

TPS8584 Background: Improving the outcome of locally advanced non-small cell lung cancer (NSCLC) is one of the major challenges in thoracic oncology. Based on previous trials from the Swiss Group for Clinical Cancer Research (SAKK) neoadjuvant chemotherapy with 3 cycles of cisplatin/docetaxel is an accepted standard of care. Recently, the PACIFIC trial showed significantly improved progression-free survival (PFS) for durvalumab as consolidation therapy after definitive chemoradiotherapy in unresectable stage III NSCLC. Here, we give an update on the ongoing trial and present results from a predefined safety evaluation focusing on 30-day post-operative mortality rate. Methods: This is a single-arm phase II clinical trial evaluating the addition of perioperative immunotherapy with durvalumab to the previously established standard of care for stage IIIA(N2) patients. Eligible patients must have pathologically proven NSCLC stage IIIA(N2) (T1-3 N2 M0) according to the 7th edition of the TNM classification, irrespective of histological subtype, genomic aberrations or PD-L1 expression status. Tumor tissue has to be available for the mandatory translational research. Patients whose tumor is deemed resectable at diagnosis receive 3 cycles of chemotherapy with cisplatin 100 mg/m2 and docetaxel 85 mg/m2 every three weeks followed by two cycles of durvalumab 750 mg every two weeks. Following surgery, patients will be treated with durvalumab 750 mg every two weeks for 12 months. The primary endpoint of the trial is event-free survival at 12 months. Secondary endpoints include OS, objective response, nodal down-staging, complete resection, pattern of recurrence and toxicity. Additionally, a large translation research program accompanies the trial investigating potential predictive biomarkers of anti-PD-L1 therapy. Based on the protocol, a first safety evaluation has been done after the first 25 operated patients. This analysis demonstrated a 30-day post-operative mortality of less than 10%. According to the decision rule described in the protocol the trial thus shall continue as per protocol. Clinical trial information: NCT02572843.
The sarculator stratified prognosis of patients with high-risk soft tissue sarcomas (STS) of extremities and trunk wall treated with perioperative chemotherapy in a randomised controlled trial (RCT).
Authors: Sandro Pasquali, Chiara Colombo, Stefano Bottelli, Paolo Verderio, Javier Martin Broto, Antonio Lopez-Pousa, Stefano Ferrari, Andres Poveda, Antonino De Paoli, Vittorio Quagliuolo, Josefina Cruz, Alessandro Comandone, Giovanni Grignani, Rita De Sanctis, Elena Palassini, Antonio Llombart-Bosch, Angelo Paolo Dei Tos, Paolo Giovanni Casali, Piero Picci, Alessandro Gronchi
Journal: Journal of Clinical Oncology (2017)

11016 Background: Patients with extremity and trunk wall STS with high malignancy grade and size larger than 5cm are considered at high risk of death, but in fact this risk varies broadly depending on histologic subtype and size. The Sarculator, a nomogram for STS, can improve prognostic assessment of these patients. This tool was evaluated for stratifying risk of distant metastasis (DM) and overall survival (OS) in a RCT investigating perioperative chemotherapy. Methods: High-risk STS patients were randomly assigned to receive either three cycles of preoperative chemotherapy with epirubicin (120 mg/m2) and ifosfamide (9 g/m2) or the same three preoperative cycles followed by two further postoperative cycles. The Sarculator was used to stratify patient risk according to predicted 10-year cumulative incidence of DM and OS rates. Results: The Sarculator identified three different prognostic groups of patients at low (N = 101), intermediate (N = 102), and high (N = 107) risk. Cumulative incidence of DM was 0.26 (SE: 0.04), 0.31 (SE: 0.05), and 0.48 (SE: 0.05) for low, intermediate, and high risk patients, respectively. Similarly, OS rates were 0.78 (95%CI 0.68-0.85), 0.63 (95%CI 0.53-0.72), and 0.42 (95%CI 0.32-0.52), respectively. Patients in the low risk group were at significantly lower risk of death compared to those in the intermediate (HR 0.51, 95%CI 0.34-0.78, P = 0.002) and high (HR 0.28, 95%CI 0.17-0.46, P &lt; 0.001) risk groups. Subgroup analysis performed by jointly considering these three groups and the two study arms did not identify statistically significant survival differences between the treatment arms within each risk category. Conclusions: Patients with high-risk STS included in this RCT were not a homogeneous population. The Sarculator identified different risk groups for DM and OS even in patients included in a RCT investigating perioperative treatments. This tool should be considered for redefining high-risk STS and stratifying patient risk in future RCT investigating perioperative chemotherapy. Clinical trial information: 2004-003979-36.
Education from other sports medicine journals #11
Authors: Ronan Kearney, Christina, Y Le, Josh Heerey, Aoife O’Callaghan
Journal: British Journal of Sports Medicine (2018)

### J Sci Med Sport . 2018; 21:708–713

Have you ever considered that sitting is doing you harm? Prolonged inactivity has been linked with many diseases including cardiovascular disease and type 2 diabetes. Sitting less and exercising more is easier said than done. Increasing the amount of exercise one does can be challenging for a number of reasons. So, do other strategies exist for reducing sedentary behaviour and are they effective?

This randomised controlled trial compared an intervention aiming to increase moderate to vigorous intensity exercise (ExMore—increase moderate to vigorous activity to at least 30 min per day) against decreasing sedentary time (SitLess—reduce sitting time) in inactive obese people. The results revealed improvements in activity time and reduced sedentary time in the ExMore and SitLess groups as expected. Interestingly both groups had significant increases in maximal oxygen consumption. However, no changes were noted in body mass index, waist circumference or blood pressure. Dropouts amounted to 31% of the ExMore group and 23% of the SitLess group.

It appears that with simple approaches we can improve exercise frequency and reduce sitting time in sedentary people. Despite no obvious change in common body measurements, we know for …