tbuckley/cabot-search huggingface dataset:
Comprehensive circulating tumor DNA profiling of driver genes in Chinese NSCLC patients.
Authors: Jianji Guo, Yongyong Wang, Lei Dai, Xinyu Chen, Li Zhuang, Zhen Yue, Weiwei Shi, Ming Yao
Journal: Journal of Clinical Oncology (2018)

e21144 Background: Noninvasive methods, such as circulating tumor DNA (ctDNA) profiling, are required for real-time molecular monitoring of treatment, detection of recurrence, and tracking resistance. Identification of all classes of genomic alterations in actionable genes in NSCLC such as EGFR, ALK, ROS1 has led to first-line treatment decisions. Methods: Blood-derived ctDNA samples of 200 Chinese NSCLC patients including 104 males (52%) and 96 females (48%) with a median age of 61 were collected for NGS-based multi-genes panel assay. Genomic alterations including substitutions, short and long insertions/deletions (Indels), copy number variations, and gene rearrangement and fusions were assessed. Results: Different histological subtypes of adenocarcinoma (179/200, 89.5%), squamous carcinoma (14/200, 7%), and others (7/200, 3.5%) were included in our lung cancer cohort. The top ranked genomic alterations in driver genes were TP53 (65.7% of patients), EGFR (54.5%), PIK3CA (10.6%), KRAS (7.6%), PTEN (6.1%), HER2 amplifications (4.5 %), HER2 mutations (3.0%), RB1 (4.0%), ALK fusions (3.5%), BRAF (3.5%), MET amplifications (1.5%) and RET fusions (1.0%). About 65% of the patients harbored at least one actionable mutation in the genes recommended by the NCCN guideline. The most frequent alterations of EGFR were L858R (27.7%), exon19 deletions (29.0%), and T790M (23.9%). Comparing to the 3.8% mutation frequency of EGFR T790M in our 1,200 Chinese NSCLC cohort with tumor tissues tested, we identified obviously higher mutation frequency of T790M in ctDNA (23.9%). Not only substitutions or Indels, but HER2 and MET amplifications, ROS and ALK fusions detected from ctDNA also offers the potential to personalized treatment options as real-time marker from blood. Conclusions: Our findings demonstrated that NGS-based ctDNA detecting displays similar genomic profiling of driver genes in Chinese NSCLC cohort compared to tissue profiling. Meanwhile ctDNA has its potential advantages in monitoring of genomic alterations in advanced NSCLC patients and providing potential treatment options, including gene copy number alterations and fusions.
A single-arm confirmatory study of definitive chemoradiotherapy (dCRT) including salvage treatment in patients (pts) with clinical (c) stage II/III esophageal carcinoma (EC) (JCOG0909).
Authors: Yoshinori Ito, HIROYA TAKEUCHI, Gakuto Ogawa, Ken Kato, Masakatsu Onozawa, Keiko Minashi, Tomonori Yano, Kenichi Nakamura, Takahiro Tsushima, Hiroki Hara, Tatsuya Okuno, Shuichi Hironaka, Isao Nozaki, Takashi Ura, Keisho Chin, Takashi Kojima, Shiko Seki, Katsuyuki Sakanaka, Haruhiko Fukuda, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2018)

4051 Background: dCRT consisting of 5-fluorouracil (5-FU) and cisplatin (CDDP) with 60 Gy radiotherapy (RT) for cStage II/III EC is a standard treatment for pts refusing surgery (S) in Japan based on the previous trial (JCOG9906). However, poor survival, high incidence of late toxicities, and severe complications of salvage S are problems. We conducted this trial of CRT modifications including salvage treatment to reduce CRT toxicities and facilitate salvage treatment to improve survival. Methods: EC pts hoping esophagus preservation as initial treatment, with cStage II/III (UICC 6th, non-T4), PS 0-1, and age 20-75 years were eligible. Chemotherapy (CT) was CDDP (75 mg/m2 on days 1, 29) and 5-FU (1000 mg/m2/d on days 1-4, 29-32). RT was administered to a total dose of 50.4 Gy with elective nodal irradiation of 41.4 Gy. Good responders after dCRT received additional 1-2 cycles of CT. For residual or recurrent disease, salvage endoscopic resection (ER) or S was performed based on the prespecified criteria. The primary endpoint was 3-year OS. Key secondary endpoint was salvage treatment related toxicity. The sample size was 95, with one-sided alpha of 5% and power of 80%, expected and threshold 3-year OS as 55% and 42%. Results: From 4/2010 to 8/2014, 96 pts were enrolled, two were ineligible and 94 were included in efficacy analysis [M/F, 84/10; Age, median 63 (range 48-75); cStage IIA/IIB/III, 22/38/34]. Two cycles of CT and RT were completed in 93 pts (99%). Complete response was achieved in 55 pts (59%). Salvage ER and S were performed in 5 (5%) and 25 pts (27%). R0 resection of salvage S was achieved in 19 (76%). 3-year OS was 74.2% (90% CI 65.9-80.8%). 3-year progression-free survival and esophagectomy-free survival were 57.0% (95% CI 46.3-66.3%) and 63.6% (95% CI 52.9-72.4%). No complications occurred after salvage ER. Five pts (20%) showed ≥ grade 3 operative morbidities and 1 treatment related death due to bronchus-pulmonary artery fistula occurred after salvage S. Only 9 pts (9.6%) showed grade 3 late toxicities. Conclusions: This combined modality treatment of dCRT with salvage treatment could be a new standard treatment for cStage II/III EC. Clinical trial information: UMIN000003534.
Prevalent aberrations of CDK4 pathway in acral melanoma and implications for targeted therapy.
Authors: Yan Kong, Xinan Sheng, Xiaowen Wu, Lu Si, Meng Ma, Jiayi Yu, Zhihong Chi, Chuanliang Cui, Jie Dai, Yiqian Li, Junya Yan, Huan Yu, Tianxiao Xu, Huan Tang, Jun Guo
Journal: Journal of Clinical Oncology (2016)

9512 Background: Therapeutics for metastatic acral melanoma have not been successfully established. This study aims to investigate gene aberrations of CDK4 pathway in acral melanoma and evaluate the potential application of CDK4 inhibitors in targeted therapy of acral melanoma. Methods: A total of 428 cases of primary acral melanoma samples were included. The copy number variations of CDK4 pathway-related genes, including CDK4, CCND1 and p16INK4a, were examined by QuantiGenePlex DNA Assay. The aberrations of these genes were further correlated with the clinicopathological features of patients. And the sensitivity of established cell lines and patient-derived xenograft (PDX) models containing typical CDK4 aberrations to CDK4 inhibitors was also analyzed. Results: Among the 428 samples, 173 cases (62.0%), 117 cases (27.3%) and 265 cases (62.0%) showed CDK4 amplification,CCND1 amplification and p16INK4a loss respectively. Moreover, 36.4% of acral melanomas contained more than two simultaneous aberrations of these three genes, and 9.1% of the samples contained three aberrations. The frequency of acral melanomas that contain at least one aberrations in CDK4, CCND1 and p16INK4a was about 84.1%. The median survival time for acral melanoma patients with simultaneous CDK4 amplification and p16INK4a losswas significantly shorter than that for patients without CDK4 amplification and p16INK4a loss(P = 0.003). In acral cells with concurrent CDK4 amplification and p16INK4a loss, concurrent CCND1 amplification and p16INK4a loss, AT7519 and PD033299l dramatically inhibited the cell proliferation. AT7519 and PD033299l also abrogated tumor growth in a PDX model with concurrent CDK4 amplification and p16INK4a loss. Conclusions: It is the first study indicates that CDK4 pathway aberration is predominant in acral melanoma (more than 80%). The acral melanoma cells and PDX model containing CDK4 pathway aberration are sensitive to CDK4 inhibitors, thus providing key evidence for the significance of CDK4 inhibitors for acral melanoma and facilitating the establishment of strategy for targeted therapy to acral melanoma.
TCT-498 Tissue Protrusion After Coronary Stenting Is Associated with Poor Clinical Outcomes In Patients With ST-Segment Elevation Myocardial Infarction
Authors: Yoshiyuki Okuya, Yuichi Saito, Yoshiaki Sakai, Iwao Ishibashi, Yoshio Kobayashi, Takefumi Takahashi, Koichi Kishi, Yoshikazu Hiasa
Journal: Journal of the American College of Cardiology (2018)
Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine +/- oxaliplatin in locally advanced rectal cancer: Final results of PETACC-6.
Authors: Hans-Joachim Schmoll, Karin Haustermans, Timothy Jay Price, Bernard Nordlinger, Ralf Hofheinz, Jean-Francois Daisne, Jaak Janssens, Baruch Brenner, Peter Schmidt, Hans Reinel, Stephan Hollerbach, Karel Caca, Florian W.B. Fauth, Carla Hannig, John Raymond Zalcberg, Niall C. Tebbutt, Murielle E. Mauer, Sandrine Marreaud, Manfred P. Lutz, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2018)

3500 Background: The PETACC-6 trial investigated the role of oxaliplatin in combination with preoperative capecitabine-based chemoradiation (CRT) and postoperative capecitabine (CT) to improve disease-free survival (DFS) in locally advanced rectal cancer. Methods: Between 11/2008 and 09/2011, 1090 patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node-positive, with no evidence of metastatic disease and considered either resectable at the time of entry or expected to become resectable, to 5 weeks preoperative CRT with capecitabine, followed by 6 cycles of adjuvant capecitabine without (arm 1) or with oxaliplatin (arm 2) (before and after surgery). The primary analysis was intent-to-treat and adjusted for stratification factors (clinical T category, nodal status, distance from the tumor to the anal verge and method of locoregional staging) except the center. Results: An early release of DFS after a medium follow-up of 31 months per recommendation of the IDMC, did not show any difference between arms (adjusted HR = 1.04, 95% CI: 0.81 -1.33, P = 0.781) (Schmoll H et al, Proc ASCO 2014). We now report on the long-term results for DFS and OS. At median follow-up of 68 months, respectively 157 vs.156 DFS events and 97 vs. 109 deaths were observed in arm 1 and 2. In each arm, 58 patients died due to progressive disease. There is no difference in DFS between arms (adjusted HR = 1.02, 95% CI: 0.82-1.28, P = 0.835) nor in OS (adjusted HR = 1.17, 95% CI: 0.89 – 1.54, P = 0.252). 5-year DFS was 71.3% (95% CI: 67.1% - 75.0%) in arm 1, vs. 70.5% (95% CI: 66.3% - 74.3%) in arm 2. 5-year OS was 83.1 (95% CI: 79.5% - 86.1%) in arm 1, vs. 80.1% (95% CI: 76.2% - 83.4%) in arm 2. No major heterogeneity of the results for DFS according to baseline factors was identified except for the subgroup of non-german patients (N = 357) vs. german patients (N = 737) (p = 0.02 for Cochran's Q test). Adjusted HR was 1.27 (95% CI: 0.96-1.68, p = 0.091) in disfavor of oxaliplatin in german patients while adjusted HR was 0.65 (95% CI: 0.44 – 0.97, p = 0.033) in favor of oxaliplatin in non-german patients. Conclusions: Long-term results confirm that the addition of oxaliplatin to capecitabine plus radiotherapy does not improve DFS nor OS in the ITT population. Further prognostic and predictive factors will be defined by a multivariate analysis and be presented at the meeting, in particular the discrepancy of the german and non-german patients will be clarified as well. Clinical trial information: NCT00766155.
Patients making potentially life threatening delays in reporting neutropenic sepsis: Grounded theory study.
Authors: Catherine Mary Oakley, Cath Taylor, Emma Ream, Alison Metcalfe
Journal: Journal of Clinical Oncology (2017)

e21560 Background:Internationally the mortality rate for neutropenic sepsis (NS) is 2-21% (in patients who develop it). Within the United Kingdom NS causes around 700 deaths annually. Clinicians are concerned about patient delayed reporting of NS which may increase healthcare costs, mortality and chemotherapy delays, which can affect prognosis. Methods: Constructivist grounded theory was used to gain insight into the reasons for patient delays. Observations (n = 13 hours) of women with breast cancer being provided with information about NS by oncology doctors and nurses and 31 in-depth interviews. Analysis (and development of categories and supporting properties) commenced with the earliest data gathered and a rich theoretical picture was built through comparing perspectives, pursuing areas of inquiry and recruiting participants who became of interest. Data were collected until saturation. A coding framework was applied to examine and explain connections between categories. Results: 35 participants. 13 women with breast cancer (median age, 56 years, 8 Caucasian, 9 adjuvant, 4 metastatic), 9 carers (partners, family or friends, 50% lived with patients) and 13 clinicians (4 oncologists, 7 chemotherapy nurses, 2 emergency department clinicians, most doctors were male, most nurses were female). The majority of patients and carers were highly educated ( &gt; degree level). All patients except 1, delayed reporting NS symptoms (2.5 hours - 8 days), sometimes repeatedly. The final grounded theory suggests patient delays are due to an interplay of behaviours between clinicians, patients and carers where they subconsciously collude to underplay the seriousness and possibility of NS occurring.Moderators of delay included metastatic disease, bereavement, fatalism, religious beliefs and quality of relationships with clinicians. Conclusions: Relationships with clinicians directly impacted on delayed patient reporting of NS.Findings have implications for health risk communication, development of holistic service models and the design of future research to develop interventions, to promote earlier recognition and treatment for this important chemotherapy complication.
What should doctors say to men asking for a PSA test?
Authors: Martin Roland, David Neal, Richard Buckley
Journal: BMJ (2018)

Schwannomas are benign tumours arising from Schwann cells in the peripheral nerve. The schwannoma of the accessory nerve is a very rare entity. We report a case of Schwannoma of the extracranial accessory nerve. A 22-year-old man presented with a slow-growing mass, located on the right upper neck. The patient did not have any neurological deficit. CT scan showed a hypodense mass behind sternocleidomastoid muscle. The suspected diagnosis was an adenopathy of the accessory spinal chain. Surgery was done via transcervical approach. The histopathological analysis concluded with a diagnosis of schwannoma. No recurrence was noted at the follow-up examination 29 months after surgery.
Exosomal microRNAs as putative predictive biomarkers for targeted therapy in stage IV cutaneous malignant melanoma (CMM).
Authors: Hanna Eriksson, Warangkana Lohcharoenkal, Fernanda Costa-Svedman, Eniko Sonkoly, Suzanne Egyhazi Brage, Johan Hansson, Andor Pivarcsi
Journal: Journal of Clinical Oncology (2016)

9579 Background: MicroRNAs (miRs) are short, non-coding RNAs that regulate gene expression at the post-transcriptional level. Exosomes are nanometer sized extracellular vesicles secreted by all types of cells and found in body fluids. MiRs are carried within exosomes as intercellular communication vesicles. MAP-kinase inhibitors (MAPKi) are widely used to treat patients with incurable CMMs harboring BRAFV600 mutations, inducing rapid tumor responses but limited durable benefit due to the emergence of resistance. Our aim was to identify possible predictive biomarkers of treatment response to MAPKi in stage IV CMM. Methods: Plasma samples were obtained before and during therapy with MAPKi. Clinical data for each patient was collected. Exosomes were isolated from plasma, RNA was extracted and used for miRNA expression profiling using Exiqon PCR Array. Differential expression of the identified miRNAs in repeated sampling was correlated with therapy response and PFS. Results: After data filtering and normalization, an average of 135 miRs were detectable in the circulation from 14 CMM patients treated with MAPKi. Through pair-wise comparison 14 miRs were identified to be differentially expressed between the pre-therapy (PT) and during therapy (DT) samples (p < 0.05). The extent of changes in miR-191-5p levels correlated with PFS and could have predictive value (Cox regression model). Patients with low expression of miR-191-5 PT had longer PFS (HR = 0.21; 95% CI = 0.046 - 0.95; p = 0.042) compared to patients with high expression PT. The median survival was 205.0 vs. 98.0 days in the low vs. high miR-191-5 PT patient groups, respectively. A low miR-191-5 DT/PT ratio was associated with longer PFS (HR = 0.23; 95% CI = 0.060 - 0.89; p = 0.0332). The median survival was 234.5 vs. 121 days in the low vs. high miR-191-5 DT/PT ratio patient groups, respectively. Conclusions: MiR-191-5p may be a possible candidate as predictive biomarker for treatment outcome in stage IV CMM patients receiving MAPKi therapy.
Neoadjuvant chemoradiotherapy to convert borderline-resectable, locally-advanced esophageal carcinoma to resectable disease.
Authors: Zachary D. Horne, Weijing Sun, Michael K. Gibson, Arjun Pennathur, James D. Luketich, Joel S. Greenberger
Journal: Journal of Clinical Oncology (2016)

e15500 Background: The treatment of T3-4/N+ esophageal cancer is challenging, outcomes are suboptimal and a conclusive management pattern is not well defined for borderline-resectable esophageal cancer (BREC). We present our retrospective institutional experience using preoperative chemoradiotherapy (CRT) to enable resection of BREC. Methods: We identified 67 patients with T3-4/N+ BREC who were treated with concurrent CRT between 2009 and 2014. Survival statistics were calculated with Kaplan-Meier curves and cohort comparisons were made with log-rank test and Cox regression. Results: We treated 67 patients (81% males, median age 61 years, and KPS of 80), primarily with T3N2 disease at high risk of R1 resection. Median follow up was 11 months. The most common CRT regimen was 58.8Gy in 28 fractions with carboplatin and paclitaxel. Median survival was 16.3 months. Factors predictive of overall survival (OS) on univariate analysis included age, KPS, tumor length, and surgical resection (all p < .01). Only KPS and surgery remained significant on multivariate analysis (both p < .05). Forty four (65.7%) patients without progressive disease underwent minimally invasive Ivor-Lewis esophagectomy within 100 days of CRT. Patients undergoing surgery had a median survival was 30.6 vs. 6.4 months without surgery (p < .01). Pathologic complete response rate was 27.3% and pN0 was 59.1%. The number of lymph nodes positive at surgery predicted for OS and progression-free survival (PFS) (p < .01) and was the only predictor of survival on multivariate analysis (HR 1.123 [95%CI 1.034-1.219] p = .006). Median survival for pN0 was 58.8 vs. 11.2 months for pN+ (p < .001) Acute grade 3+ toxicity was seen in 31.3% and late grade 3+ toxicity, in 43.3%. Three patients (4.5%) died during CRT or before surgery and one (2.3%) within 30 days of resection. Conclusions: Preoperative CRT enabled a significant proportion of patients with borderline-resectable disease to proceed with a potentially curative resection. Further investigation with careful patient selection is warranted in incorporating a trimodality strategy to optimize outcomes and better define a treatment algorithm for this complex cohort of patients.
Clinicopathological features of program death ligand-1 (PD-L1) expression with tumor-infiltrating lymphocytes (TILs), mismatch repair (MMR) and Epstein-Barr virus (EBV) status in a large cohort of gastric cancer.
Authors: Akihito Kawazoe, Takeshi Kuwata, Yasutoshi Kuboki, Kohei Shitara, Akiko Nagatsuma, Takayuki Yoshino, Toshihiko Doi, Atsushi Ohtsu, Atsushi Ochiai
Journal: Journal of Clinical Oncology (2016)

4053 Background: Antibody-based therapies for targeting programmed death 1 (PD-1) or its ligand PD-L1 (anti-PD1/PD-L1 therapies) have shown promising results in gastric cancer (GC). PD-L1 expression on tumor cell membrane and tumor-infiltrating lymphocytes (TILs) has been proposed as predictive biomarkers for anti-PD-1/PD-L1 therapies in several types of malignancies. TCGA has recently reported that PD-L1 gene was frequently amplified in Epstein-Barr virus (EBV)-positive GC. In addition, mismatch-repair deficiency (D-MMR) was associated with better clinical outcomes after anti-PD-1/PD-L1 therapies in solid tumors. However, little is known about clinicopathological features of PD-L1 expression with TILs, MMR and EBV status in a large cohort of GC cases. Methods: We performed a tissue microarray analysis in 487 advanced GC patients who underwent a gastrectomy without preoperative chemotherapy. PD-L1 expression on tumor cell membrane, densities as well as expressions of lymphocyte-associated markers (CD3, CD4, CD8, and FOXP3) of TILs and MMR status were evaluated by immunohistochemistry. EBV status was evaluated by in situ hybridization. Results: PD-L1 expression, D-MMR, and EBV were identified in 22.8, 5.1, and 5.1% of cases, respectively. PD-L1 expression was more frequently observed in elderly (P = 0.002), male (P = 0.029), poorly differentiated adenocarcinoma with solid-type histology (P < 0.001), D-MMR (P < 0.001), and EBV-positive status (P = 0.001). Regarding PD-L1 expression and TILs status, a strong association was observed between PD-L1 expression and high densities of either CD3 (+), CD8 (+), or FOXP3 (+) TILs (P < 0.001). In multivariate analysis, high density of CD8 (+) TILs was significantly associated with better survival (hazard ratio, 0.62; 95% CI, 0.39 to 0.99; P = 0.047), while PD-L1 expression and densities of other subtypes of TILs were not independent prognostic factors. Conclusions: In GC, PD-L1 expression was associated with distinct clinicopathological features including high density of TILs, D-MMR and EBV-positive status, but not a prognostic factor.
Blood-based multiplex kinase activity profiling as a predictive marker for clinical response to checkpoint blockade in advanced melanoma.
Authors: Daan Hurkmans, Els M.E. Verdegaal, Sabrina A. Schindler, Edwin A. Basak, Dianne M.A. van den Heuvel, Rik de Wijn, Rob Ruijtenbeek, John P. Groten, Reinhard Dummer, Stijn L.W. Koolen, Marij J.P. Welters, Ron H.J. Mathijssen, Ellen Kapiteijn, Joachim G.J.V. Aerts, Mitchell P. Levesque, Sjoerd H. van der Burg
Journal: Journal of Clinical Oncology (2018)

9579 Background: Prediction of clinical responses to checkpoint inhibitor therapies is urgently needed. Notably, a significant proportion of patients does not benefit from the treatment, agents are costly and may cause serious toxicity. The kinase activity of peripheral blood cells (PBMCs) may reflect biological mechanisms underlying response to immunotherapy. We hypothesized that kinase activity profiles from PBMCs may constitute a predictive marker for clinical response to CTLA4 and/or PD1 blockade immunotherapy in patients with advanced melanoma. Methods: In a multi-center effort, data were prospectively collected from 6 cohorts of anti-CTLA4- or anti-PD1-treated advanced melanoma patients (n = 138). Kinase activity profiles were generated by analyzing phosphorylation signatures of PBMC lysates on a peptide micro-array. The PamChip (PamGene, Netherlands) microarray comprises 144 different peptides derived from protein phosphorylation sites that are substrates for protein tyrosine kinases. Performance of the predictive model (PLS-DA) was estimated using cross-validation and described by correct classification rate (CCR). Analyses were based on binary grouping of best overall response (RECIST v1.1; CR/PR/SD vs PD) and early/late progression using PFS data (cut-off 140 days). Results: Predictive signatures were discovered for anti-CTLA4 in cohort 1 (anti-CTLA4; n = 10; CCR = 100%; 95%CI 69-100%) and confirmed in cohort 2 (anti-CTLA4; n = 28; CCR = 82%; 95%CI 63-94%), as well as for anti-PD1 in cohort 3 (anti-PD1; n = 17; CCR = 76%; 95%CI 50-93%), which was confirmed in cohort 4 (anti-PD1; n = 29; CCR = 72%; 95%CI 53-87%), cohort 5 (anti-PD1; n = 38; CCR = 75%; 95%CI 57-87%), and cohort 6 (anti-PD1; n = 16; non-evaluable due to the low number of responders). Conclusions: In advanced melanoma patients, kinase activity profiles of baseline PBMCs samples can predict the likelihood of response to anti-PD1 or anti-CTLA4 therapy. This assay may serve as a rapid and fast predictive liquid biomarker to stratify patients prior to treatment. Involvement of receptor tyrosine kinases underlying the mechanism are being further elucidated and a larger validation study is underway.