tbuckley/cabot-search huggingface dataset:
Comparison of D2 and D2 plus radical surgery for advanced distal gastric cancer: A randomized controlled study.
Authors: Pengfei Yu, Yian Du, Zhiyuan Xu, Ling Huang, Xiangdong Cheng
Journal: Journal of Clinical Oncology (2019)

e15546 Background: The optimal extent of lymph node (LN) dissection for advanced distal gastric cancer remains controversial. The present study compared the safety and efficacy of extended LN dissection (D2 plus) with standard D2 radical surgery for advanced distal gastric cancer. Methods: Eligible patients were enrolled and randomly assigned into two groups: D2 group and D2 plus group. Patients in the D2 group received standard D2 LN dissection, while patients in the D2 plus group received an additional no. 8p, 12b, 13 and 14v LNs dissection. The clinicopathological and surgical data of these two groups was compared and the factors that may influence survival were analyzed. Results: 70 patients were enrolled, out of which 64 patients were analyzed. There were no significant differences in the operative time, blood loss and complications between the two groups. In the D2 plus group, the positive rate of the no. 12b, 13 and 14v LN was 3.1%, 9.4% and 12.5%, respectively. The positive rate of the no. 13 LN correlated with the duodenal involvement, while the positive rate of the no. 14v LN correlated with no. 6 LN metastasis. The survival analysis indicated that among patients with duodenum involvement, the 3-year disease free survival rate of the D2 plus group was significantly better than that of the D2 group. Conclusions: Duodenum involvement and positive no. 6 LN were high risk factors of advanced distal gastric cancer. D2 plus radical surgery turned out to be safe and feasible, and may improve the prognosis of these patients. However, further clinical trials are still warranted. Clinical trial information: #NCT01836991.
Comparison of the mutation profile between pancreatic head/neck and body/tail cancers.
Authors: Junliang Lu, Zhiyong Liang, Huanwen M. Wu, Junyi Pang, Xiaolong Liang, Junchao Guo, Yang Shao, Xiaohan Zuo
Journal: Journal of Clinical Oncology (2019)

e15752 Background: Carcinomas in the pancreatic head/neck and body/tail represent different clinicopathological characteristics, but little is known about the underlying genetic mechanisms. The present study aims to explore the differences in mutation profile between pancreatic head and body/tail cancers. Methods: Fifty-four patients were retrospectively enrolled in the present study. DNA was purified from qualified formalin-fixed, paraffin-embedded tissue blocks of the tumor and corresponding adjacent normal tissue and subjected to target-capture next generation sequencing (TGS). Somatic mutations were identified, which further underwent gene ontology (GO) and KEGG pathway analysis. Results: The most frequently mutated genes in carcinomas of the pancreatic head were KRAS (61.3%), TP53(38.7%), and CDKN2A (16.1%), while that of the pancreatic body/tail were KRAS (95.7%), TP53(87%), CDKN2A (26.1%), and ARID1A (26.1%). The prevalence of TP53 and KRAS mutations in pancreatic head and body/tail cancers were significantly different from each other (p = 0.0006 and p = 0.0037, respectively). Pancreatic head/neck cancers also preserved a broader KRAS mutation spectrum than their counterparts of the body/tail. Pathway analyses revealed that mutations in cancer of pancreatic head/neck were enriched for genes involved in the protein amino acid phosphorylation, regulation of cell proliferation, transmembrane receptor protein tyrosine kinase signaling pathway, and phosphorylation pathways, while cancers of the pancreatic body/tail were enriched for genes involved in colorectal cancers. Conclusions: Cancer of the pancreatic head/neck and body/tail have distinct mutation profiles.
Quantification of circulating free and circulating tumor DNA in pretreated EGFR mutant NSCLC to inform patient outcomes.
Authors: Alexandra Pender, Curtis Hughesman, Elaine Law, Amadea Kristanti, Kelly McNeil, Tracy Tucker, Ian Bosdet, Sean Young, Janessa J. Laskin, Aly Karsan, Stephen Yip, Cheryl Ho
Journal: Journal of Clinical Oncology (2019)

9080 Background: EGFR T790M testing is standard of care for EGFR mutant (EGFRm) NSCLC progressing on 1 st /2 nd generation TKIs to select patients for osimertinib. Circulating free DNA (cfDNA) levels are measured prior to circulating tumour DNA (ctDNA) testing using droplet digital PCR (ddPCR) to measure activating/resistant EGFR mutations. We reviewed cfDNA levels and ctDNA mutational status to determine the influence on patient outcome. Methods: Following extraction of cfDNA from plasma using the QIAamp Circulating Nucleic Acid Kit, cfDNA levels are measured with a Qubit 2.0 Fluorometer. Custom ddPCR assays were used to test for the appropriate EGFR activating mutation and the EGFR T790M resistance mutation using the Bio-Rad QX200 system. The custom designed ddPCR assays have a limit of detection of &lt; 0.1% variant allele fraction. All patients undergoing ctDNA testing from February-December 2018 were identified. Baseline characteristics and follow up data were collected retrospectively. OS was calculated from date of metastatic diagnosis to death/last follow-up. Results: 142 patients with EGFR mutant adenocarcinoma had EGFR ctDNA testing: results 52% indeterminant, 32% T790M, 16% activating EGFRm only. At the time of testing: median age 66, 64% female, 57% never smokers 53% Asian; systemic treatment (tx) 62% first line only, 25% two lines and 13% ≥ three lines. First TKI therapy: 32% afatanib, 66% gefitinib, 2% erlotinib. Median cfDNA concentration was 5.65 ng/ml (range 0.50-217.72). The 5 yr OS was 72% below cfDNA median and 25% above the median. Tx after ctDNA testing for below and above cfDNA median: 52 vs 33% original TKI, 34 vs 55% osimertinib, 14 vs 12% other systemic tx. Multivariate analysis shows that even accounting for age, sex and ctDNA mutation result, cfDNA concentration remains an independent predictor of outcome (HR 2.36, 95% CI 1.08-5.18, p = 0.032). Conclusions: cfDNA concentration can predict patient outcome in patients with EGFR mutant NSCLC progressing on TKI regardless of ctDNA testing results. Clinicians may consider switching to chemotherapy for patients with high cfDNA and without detectable EGFR T790M ctDNA to avoid missing the window for therapy instead of awaiting repeat EGFR T790M testing
Alteration in tumor immune microenvironment after chemo-radiotherapy for locally advanced non-small cell lung cancer.
Authors: Kazue Yoneda, Taiji Kuwata, Masataka Mori, Masatoshi Kanayama, Koji Kuroda, Yoshinobu Ichiki, Fumihiro Tanaka
Journal: Journal of Clinical Oncology (2019)

8530 Background: The consolidation treatment with durvalumab, an anti-PD-L1 antibody, after concurrent chemo-radiotherapy (CCRT) has become a new standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). The rationale of the addition of anti-PD-L1 antibody is based on preclinical evidence suggesting that chemotherapy and radiotherapy may up-regulate PD-L1 expression on tumor cells. However, there has been reported no clinical evidence showing up-regulation of PD-L1 expression after CCRT. Methods: LA-NSCLC patients with paired sufficient histologic specimens for immune-histochemical analysis of tumoral PD-L1 expression (tumor proportion score, TPS) and stromal CD8-positive tumor-infiltrating lymphocyte density (CD8+density) before and after pre-operative treatment were eligible in this study. Twenty-three patients who underwent CCRT were reviewed in comparison with 18 patients who underwent chemotherapy. Results: PD-L1 expression was significantly enhanced after CCRT (median TPS, 48 from 1; P&lt;0.01), but not after chemotherapy (median TPS, 7.5 from 1; P=0.62). No significant correlation between baseline TPS and TPS after CCRT (P=0.119). Stromal CD8+density was significantly increased after CCRT (median, 39 from 11; P&lt;0.01) and after chemotherapy (median, 23 from 12; P&lt;0.01). No significant correlation between baseline TPS and TPS after CCRT (P=0.378). Among CCRT cases, stromal CD8+density after treatment was significantly higher in cases with higher pathologic response to CCRT (median, 55 versus 27; P&lt;0.01), and higher stromal CD8+density was a significant factor to predict a favorable survival after surgery (P=0.03 for recurrence-free survival; P=0.02 for overall survival). Conclusions: PD-L1 expression was significantly upregulated after CCRT regardless of baseline PD-L1 status, which may provide a pathologic rationale for the use of anti-PD-L1 agent after CCRT to improve the prognosis. Stromal CD8+density also increased after CCRT, which was correlated with pathologic response to CCRT and provided a significant prognostic impact.
Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study
Authors: Douglas B. Johnson, Ali Manouchehri, Alexandra M. Haugh, Henry T. Quach, Justin M. Balko, Benedicte Lebrun-Vignes, Andrew Mammen, Javid J. Moslehi, Joe-Elie Salem
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized. <h3>Methods</h3> We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC<sub>025</sub> (lower end of the IC 95% credibility interval) &gt; 0 is considered statistically significant. <h3>Results</h3> Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5–18.9]; IC<sub>025</sub> 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2–11.8]; IC<sub>025</sub> 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC<sub>025</sub> 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5–3.9]; IC<sub>025</sub> 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6–12%), later onset (median 61–80 days), and were non-overlapping. <h3>Conclusions</h3> ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.
High-throughput screening (HTS) of natural products with triple-negative breast cancer (TNBC) organoids.
Authors: Zhijian Sun, Bailin Zhang
Journal: Journal of Clinical Oncology (2019)

e12558 Background: Breast cancer is one of the most malignant diseases threatening the health of our society. Triple negative breast cancer (TNBC) is an aggressive histological subtype representing 15–20% of all breast cancers. Comparing with other breast cancer subtypes, TNBC is characterized with limited treatment options and a worse clinical outcome. Resistance to chemotherapies is common for TNBC. Therefore, continuously developing new anti-cancer drugs is of great importance for TNBC. Nature products a source of medicinal leads, but lacking suitable pre-clinical models, which could faithfully reflect in vivo tumor property, prevents these compounds from further characterizing. Now cancer organoids, as a new in vitro 3-D culture technique, were demonstrated to largely retain the biological characteristics of tumors from patients, and potentially served as an ideal platform for drug sensitivity test. Methods: Here we set up system to efficiently establish breast cancer organoids from clinical patients and further test the sensitivity of these organoids to various nature products. Results: A total of 29 TNBC organoid models were established with fresh biopsy or surgery tumor tissues from TNBC patients. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in TNBC PDOs were evaluated with qPCR, western blot, Immunohistochemistry (IHC). A high-throughput cell viability assay was established for identifying lead compounds from a unique collection of 969 natural products. Primary hits were serial diluted and further evaluated for IC 50 and percentage of inhibition. Preliminary mechanism of action (MOA) studies was performed with gene reporter assays, western blot and qPCR. Interestingly, organoids derived from paclitaxel resistant TNBC patients also show less sensitivity to paclitaxel in vitro, which indicated a high clinical relevance. Conclusions: Triple negative breast cancer organoid, as a good pre-clinical model largely containing tumor in vivo property, provides an ideal platform for new drug discovery and inhibitor screening. Moreover, serving as in vitro replacements for breast cancer, organoid models make it possible to test drug sensitivity for individual patient to achieve precise and personalize medication.
Updated survival date of phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non-small cell lung cancer.
Authors: Atsushi Horiike, Yuko Kawano, Tomonari Sasaki, Hiroyuki Yamaguchi, Katsuya Hirano, Miyako Satouchi, Shinobu Hosokawa, Ryotaro Morinaga, Kazutoshi Komiya, Koji Inonue, Yuka Fujita, Ryo Toyozawa, Tomoki Kimura, Kosuke Takahashi, Kazuo Nishikawa, Junji Kishimoto, Yoichi Nakanishi, Isamu Okamoto
Journal: Journal of Clinical Oncology (2019)

8529 Background: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non–small cell lung cancer (NSCLC). Methods: Patients between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. In the phase II part of the study, patients received weekly nab-paclitaxel at 50 mg/m 2 together with weekly carboplatin at an area under the curve (AUC) of 2 mg mL –1 min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. The primary end point of the phase II part of the study was progression-free survival (PFS). Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0 to 49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1% to 76.8 %). The median PFS was 11.8 months (60% CI, 10.6 to 16.8 months; 95% CI, 8.2 to 21.0 months). The overall response rate was 76.8% (95% CI, 64.2% to 85.9%), and the disease control rate was 94.6% (95% CI, 85.4% to 98.2%). Subgroup analysis according to histology or age revealed no significant differences in median PFS or OS. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). Pneumonitis of grade 3 was observed in two patients during the study period. No treatment-related deaths occurred. Conclusions: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m 2 and carboplatin at an AUC of 2 mg mL –1 min in patients with locally advanced NSCLC. Clinical trial information: UMIN000012719.
A multicenter analysis of melanoma recurrence following adjuvant anti-PD1 therapy.
Authors: Carina N. Owen, James M.G. Larkin, Alexander Noor Shoushtari, Matteo S. Carlino, Christian U. Blank, Belinda Lee, Joanna Mangana, Victoria Atkinson, Michael Millward, Farzana Zaman, Arissa Young, Muhammad Adnan Khattak, Sapna Pradyuman Patel, Christoph Hoeller, Peter Hersey, Dharmisha Chauhan, David James Palmieri, Serigne Lo, Alexander M. Menzies, Georgina V. Long
Journal: Journal of Clinical Oncology (2019)

9502 Background: Adjuvant anti-PD1 monoclonal antibodies (mAbs) prolong recurrence-free survival in high-risk resected melanoma, however patients (pts) recur during or after therapy. The patterns of recurrence and optimal management are unclear. Methods: Pts from 15 melanoma centres who recurred having received adjuvant anti-PD1 mAbs (adj-PD1) for resected stage III/IV cutaneous melanoma were included. Disease characteristics, adjuvant treatment, recurrence characteristics, subsequent management and outcomes were examined. Results: 137 pts had melanoma recurrence; 97 (71%) during adj-PD1 and 40 (29%) following treatment cessation (25 had stopped early for toxicity after a median 3 months, 14 after completing 12 months, 1 who withdrew consent after 1 month). Median time to recurrence from start of anti-PD1 was 4.6 months (IQR 2.7-8.5), and median follow up from recurrence was 7.7 months (IQR 3.8-12.3). At 1st recurrence, 78 (57%) pts had distant disease (including 22 with both locoregional and distant), 59 (43%) had locoregional disease only. Of those who recurred locally, 22/59 (37%) later developed distant disease. 26 (19%) pts have died. 81 (59%) pts had systemic therapy for distant recurrence (either 1 st recurrence or subsequent). Of those who recurred during adj-PD1, no pts (0/20) subsequently responded to anti-PD1 alone (N = 8) or with any investigational agent (N = 12; anti-LAG3, IDOi, MEKi, TLR9 agonist); 9/27 evaluable pts (33%) responded to ipilimumab-based therapy (alone or in combination with anti-PD1), and 15/19 (79%) responded to BRAF/MEKi . Of those who recurred after ceasing adj-PD1, 2/5 (40%) responded to anti-PD1 monotherapy, 2/5 (40%) responded to ipilimumab-based therapy, 7/8 (88%) responded to BRAF/MEKi. Conclusions: These data suggest minimal activity of further anti-PD1 monotherapy in those who recur while on adj-PD1, but possible activity in those who recur off treatment. Anti-CTLA4 and BRAF/MEKi therapy appear active in those who recur on or following adj-PD1. Data on locoregional recurrence and its management will also be presented.
Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC): Cohort C of the phase 1b/2 KEYNOTE-365 study.
Authors: Peter C.C. Fong, Margitta Retz, Alexandra Drakaki, Christophe Massard, William R. Berry, Emanuela Romano, Johann S. De Bono, Susan Feyerabend, Leonard Joseph Appleman, Henry Jacob Conter, Srikala S. Sridhar, Neal D. Shore, Mark David Linch, Anthony M. Joshua, Howard Gurney, Helen Wu, Charles Schloss, Christian Heinrich Poehlein, Evan Y. Yu
Journal: Journal of Clinical Oncology (2019)

5010 Background: Pembro has activity as monotherapy in pts with pretreated advanced mCRPC. A phase 2 study suggested that pembro + enza after progression on enza may have clinical activity. Data from cohort C (pembro + enza) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC, are presented. Methods: Pts who were unsuccessful with or became intolerant to ≥4 weeks of abi in the prechemotherapy mCRPC state, with either PSA or radiologic progression within 6 mo before screening were included. Pts received pembro 200 mg IV Q3W with enza 160 mg/day orally. Primary end points were safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points were investigator-assessed ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 69 pts began treatment (median age, 69 y; visceral disease, 26%; measurable disease, 36%). Median (95% CI) follow-up was 9 (7-13) mo. Efficacy is outlined in the table. Treatment-related AEs occurred in 63 (91%) pts; most frequent (≥20%) were fatigue (30%), rash (23%), and nausea (22%). Grade 3/4 treatment-related AEs occurred in 28 (41%) pts; most common was rash (10%); no deaths were from treatment-related AEs. Conclusions: The pembro + enza combination showed sustained activity in abi-pretreated chemotherapy-naive mCRPC. AEs were considered tolerable for the treatment combination; incidence of rash resolved with standard-of-care treatment. Clinical trial information: NCT02861573. [Table: see text]
Non-clinical needs of cancer patients in Spain under different perspectives: A comparative study.
Authors: Juan J. Cruz-Hernández, Isabel Ruiz, Ana Fernandez-Marcos, Rosana Martin, Enrique Aranda, Alfredo Carrato, Eduardo Díaz-Rubio, Vicente Guillem, Rafael Lopez, Margarita Feyjoo, Ramon Ferrer, Nerea Gonzalez-Garcia, Ana Nieto-Librero, Alicia Gonzalo-Gomez, Carlos Camps
Journal: Journal of Clinical Oncology (2019)

e18266 Background: Patients with cancer and their caregivers express unmet needs beyond the clinical approach to cancer. The ECO Foundation (Quality and Excellence in Oncology) and the Spanish Association Against Cancer (AECC) have promoted a qualitative research study with the objective to compare the perceptions of newly diagnosed and 2-3 years after diagnosis cancer patients, caregivers, oncologists, nurses and social workers in relation to a set of non-clinical needs expressed by cancer patients and caregivers, and to obtain concrete and feasible proposals for improvement aimed at satisfying these needs. Methods: A multidisciplinary group of experts developed a questionnaire containing information processes for cancer patients and caregivers, shared decision-making, healthcare circuits, the architecture of consultations, psychological support, support of associations and hospital social workers. Fourteen Medical Oncology Services of Spanish hospitals have participated in this study collecting 310 forms. Data were statistically analyzed using Fisher's exact test. Results: Information processes. The opportunity to have a second opinion is positively valuated for 72.6% of patients and 70.2% of caregivers. However, although 62.5% of oncologists referred to offer this option to their patients, only 10.9% of patients reported having received it. Shared decision-making. For 58% of oncologists, patients are sufficiently trained to share decision-making, but only 24.6% of newly diagnosed patients consider being prepared. In addition, although 95.8% of oncologists report offering the participation of their patients in decision-making, only 45.8% of newly diagnosed patients and 64.4% of 2-3 years after diagnosis patients, consider having received this opportunity. Psychological support. Psychological assistance was considered positive for 94.2% of the patients, 97.4% of the caregivers, 85.4% of the oncologists and 97.1% of the nurses. However, only 21.3% of oncologists and 31.4% of nurses recognize offering such proffessional care given by psychologists to patients. Conclusions: Knowing the non-clinical needs, not only of patients and caregivers, but also from the health care professionals, is essential when designing health strategies that should align the perceptions of patients and health care professionals.