tbuckley/cabot-search huggingface dataset:
Clinical outcomes of first-line FOLFIRINOX versus gemcitabine plus nab-paclitaxel in metastatic pancreatic cancer at the Yale Smilow Healthcare System.
Authors: Timil Patel, Thejal Srikumar, Joseph Anthony Miccio, Jill Lacy, Stacey Stein, Jeremy S. Kortmansky, Carol Staugaard, Melissa Gambaccini, Alfredo Axtmayer, Michael Cecchini
Journal: Journal of Clinical Oncology (2020)

769 Background: FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GN) are established first line (1L) therapies for metastatic pancreatic cancer (MPC) but real-world data on their comparative effectiveness is limited. Methods: All cases of MPC treated with 1L FFX or GN at Yale Smilow Cancer Hospital and the affiliated community care centers (CCC) from January 2011 – April 2019 were reviewed. Patient (pt) demographics, prior therapy, initial and subsequent dose reductions (DR), time to treatment discontinuation (TTD), overall survival (OS), and second line (2L) treatment data were manually abstracted from the electronic medical record. Categorical and continuous variables were compared between 1L FFX and GN cohorts via the Chi-squared and Wilcoxon rank-sum tests. Median OS was calculated by the Kaplan-Meier method. Results: We identified 363 MPC pts treated with 1L FFX or GN; 269 (74%) pts were treated with FFX and 94 (26%) with GN as 1L therapy. 204 (56%) pts were treated at the main campus and 159 (44%) at a CCC. Demographics and baseline characteristics (FFX/GN) were as follows: gender (male) 55% / 41%; race (white) 82% / 77%; age &lt; 76 90% / 71% ( P &lt; 0.001). 332 (91%) of pts received no prior therapy; 21 (6%) had prior surgery plus adjuvant gemcitabine and 10 (3%) had surgery alone. 98% of FFX-treated pts were treated with upfront DR, compared to 78% of GN-treated pts ( P= 0.003). 78% and 53% of FFX-treated and GN-treated pts, respectively, had subsequent DR ( P&lt; 0.001). Median TTD was 4.8 months with FFX and 3.4 months with GN ( P= 0.0029) and the median OS was 11.3 months with FFX versus 7.2 months with GN ( P &lt; 0.0001). After 1L, 33% and 61% of FFX- and GN-treated pts, respectively, received no further chemotherapy ( P&lt; 0.001). Conclusions: In the largest manually abstracted retrospective analysis to date, MPC pts treated with 1L FFX were younger, more likely to receive 2L therapy, and had increased survival compared to pts treated with GN. The OS of pts treated with FFX was similar to the OS reported by Conroy et al despite upfront dose attenuations in 98% of pts. A randomized trial is needed to confirm optimal sequencing of chemotherapy in MPC.
Treatment modalities and oncological outcomes in Mexican patients with localized gastric cancer.
Authors: Haydee Cristina Verduzco-Aguirre, Mónica Isabel Meneses Medina, Ana Karen Valenzuela, Vanessa Rosas Camargo, Luis Guillermo Anaya Sánchez, Edwin Ulises Cortez Dominguez, Fidel David Huitzil-Melendez
Journal: Journal of Clinical Oncology (2020)

319 Background: gastric cancer is common in Mexico. Evaluation of treatment strategies is greatly important in early gastric cancer. National institutions rarely report their outcomes, limiting feedback and policy improvements. Methods: single-center retrospective review of patients with histologically confirmed localized gastric cancer diagnosed from Jan 2005 to Dec 2017. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan-Meier curves and compared with log-rank rest. A p value &lt; 0.05 was significant. Results: we included 78 cases, median age 63 years, 52.6% men. Surgery was the initial treatment in 46 patients (59%) and 87% achieved R0 resection. Adjuvant treatment was administered to 63% of patients. 29 patients (37.2%) started perioperative chemotherapy with 86.2% of them being resected, and 75.9% having R0 resection. 13 patients (44.8%) also received postoperative chemotherapy. Better performance status (p=0.036) and lower albumin levels (p=0.039) were found in patients with initial surgery vs those with perioperative chemotherapy. At the time of surgery, most patients had stage III disease in both groups but 5 patients had M1 disease despite negative initial laparoscopy in the chemotherapy group and 5 patients did not require aduvant tx given early stage in the surgery first group. Median OS and RFS are reported in table. Conclusions: Most patients in our center undergo initial surgery. We report a differential survival according to initial treatment. More advanced disease in chemotherapy first group may explain differences. Given non-random assignment, we could not show survival benefit of chemotherapy treated patients. [Table: see text]
Rabies virus glycoprotein-amplified hierarchical targeted hybrids capable of magneto-electric penetration delivery to orthotopic brain tumor
Authors: Yu-Lin Su, Li-Wen Kuo, Chia-Hsien Hsu, Chi-Shiun Chiang, Yu-Jen Lu, Shing-Jyh Chang, Shang-Hsiu Hu
Journal: Journal of Controlled Release (2020)
Multicenter phase I/II study of intravenous gemcitabine + nab-paclitaxel combined with intraperitoneal paclitaxel for pancreatic ductal adenocarcinoma patients with peritoneal metastasis.
Authors: Suguru Yamada, Tsutomu Fujii, Tomohisa Yamamoto, Hideki Takami, Isaku Yoshioka, So Yamaki, Fuminori Sonohara, Kazuto Shibuya, Fuyuhiko Motoi, Satoshi Hirano, Yoshiaki Murakami, Hitoshi Inoue, Masamichi Hayashi, Yasuhiro Kodera, Mitsugu Sekimoto, Sohei Satoi
Journal: Journal of Clinical Oncology (2020)

702 Background: Pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal metastasis (peritoneal deposits and/or positive peritoneal cytology) have an extremely poor prognosis, and an effective treatment strategy remains elusive. Methods: The aim of this study were to determine the recommended dose (RD) for a combination of intravenous (IV) gemcitabine, intravenous nab-paclitaxel, and intraperitoneal (IP) paclitaxel in chemotherapy-naive PDAC patients with peritoneal metastasis and to evaluate the clinical efficacy and safety. Gemcitabine and nab-paclitaxel was administered IV combined with paclitaxel IP on days 1, 8 and 15, followed by 1 week of rest. The frequency of dose-limiting toxicity was evaluated and the RD was determined. The primary endpoint of the phase II part was 1-year overall survival (OS) rate. The secondary endpoints were antitumor effect, symptom relief effect, safety and OS. Results: In the phase I part, RD for IV gemcitabine, IV nab-paclitaxel and IP paclitaxel were determined as 800 mg/m 2 , 75 mg/m 2 , and 20 mg/m 2 , respectively. A total of 46 patients were enrolled in the phase II part and drugs were delivered at the RD. All patients had positive intraperitoneal cytology and 29 patients (63.0%) had the peritoneal dissemination. The median treatment period was 6.0 (0-22.6) months. The response rate and disease control rate were 45.7% and 95.7%, respectively. Ascites disappeared in 40.0% and cytology turned negative in 67.4%. Median CA19-9 decrease ratio was 84.4 (16.9-99.1) %. The median survival time was 12.8 (3.1-32.7) months, and the 1-year survival rate was 52.2%. Finally, conversion surgery was performed in 8 (17.4%) patients and those who received conversion surgery survived significantly longer than those who did not (not reached vs. 11.7 months, P = 0.0070). Grade 3/4 hematologic toxicities occurred in 76.0% and nonhematologic adverse events in 15.0%, of which 6.5% were bowel obstructions. Conclusions: This regimen has shown promising clinical efficacy with acceptable tolerability in chemotherapy-naive PDAC patients with peritoneal metastasis. Clinical trial information: 000018878.
Phylogenetic investigation of HCV-4d epidemic in Paris MSM HIV population reveals a still active outbreak and a strong link to the Netherlands
Authors: B. Visseaux, S. Hué, Q. Le Hingrat, M. Salmona, S. Lebourgeois, C. Delaugerre, D. Descamps, M.-L. Chaix, J. Ghosn
Journal: Clinical Microbiology and Infection (2020)
Beta-catenin mutations in hepatocellular cancer, tumor cell metabolism, and the response of these tumors to mTOR inhibition.
Authors: Satdarshan Monga, Mitesh J. Borad, Junyan Tao
Journal: Journal of Clinical Oncology (2020)

583 Background: Hepatocellular cancer (HCC) continues to grow in incidence despite approval of many new therapies including immune checkpoint inhibitors (ICIs) and TKIs. Genomic landscape of HCC is becoming increasing apparent through WGS and WES. One major driver of HCC is the Wnt/b-catenin pathway. Mutations in CTNNB1, which encodes for b-catenin, are evident in 26-37% of all human HCCs. However, expression of mutant-b-catenin in liver in mice is insufficient for HCC development. Indeed, analysis of HCC cases has revealed CTNNB1 mutations to significantly co-exist with other aberrations including activation/overexpression of Met and Myc and mutations in TERT promoter or mutations in NFE2L2/KEAP1, APOB and ARID2. Methods: Using sleeping beauty transposon/transposase and hydrodynamic tail vein injection, we co-expressed mutant-CTNNB1 (S45Y, S33Y or T41A) and one other clinically relevant co-occurrence to study significance and biology of HCC. Any novel findings in the preclinical model were validated in HCC patient cohorts. Results: Co-expression of mutant-CTNNB1 and one relevant co-occurrence led to development of HCC in mice in 6-10 weeks. All HCC in these models showed a dramatic increase in glutamine synthetase (GS), encoded by Glul, a known target of the Wnt/b-catenin signaling pathway in the liver. This led to an increase in glutamine levels in the tumor-bearing livers. Increased glutamine in the tumors in turn led to increased levels of phospho-mTOR-S2448, a marker of mTORC1 activation. In fact, examination of ~400 patient HCCs showed a significant correlation between positive GS and p-mTOR-S2448 staining. Treatment of Met-b-catenin model with Rapamycin led to notable and significant decrease in HCC burden. Conclusions: Our studydemonstrates b-catenin-mutated HCC to be positive for both GS and in turn mTORC1 active. This provides a novel opportunity for personalized medicine in HCC and CTNNB1-mutated HCCs may be vulnerable to therapeutic targeting by mTOR and more specially, mTORC1 inhibitors.
Interventions for Couples
Authors: Thomas N. Bradbury, Guy Bodenmann
Journal: Annual Review of Clinical Psychology (2020)

Because relationship discord and dissolution are common and costly, interventions are needed to treat distressed couples and to prevent distress among vulnerable couples. We review meta-analytic evidence showing that 60–80% of distressed couples benefit from behavioral and emotion-focused approaches to couple therapy, but we also note that treatment effects are weaker in actual clinical practice than in controlled studies, dissipate following treatment for about half of all couples, and may be explained by factors that are common across models. Meta-analyses of prevention programs reveal reliable but smaller effects, reflecting a need to know more about whether and how communication mediates effects, about how risk and diversity moderate effects, and about how technology-enabled interventions can reduce attrition in vulnerable populations. Interventions for couples are improving and expanding, but critical questions remain about how and for whom they work.
Genomic associations in metastatic pancreatic cancer (mPC).
Authors: Anil Kumar Rengan, Efrat Dotan, Karthik Devarajan, Namrata Vijayvergia
Journal: Journal of Clinical Oncology (2020)

765 Background: mPC is an aggressive cancer, and molecular profiling provides further insight into pathogenesis and treatment. We sought to illustrate the molecular landscape of mPC in relation to post-metastatic survival and VTE incidence. Methods: With IRB approval, we retrospectively analyzed charts of mPC patients who underwent molecular profiling. Fisher’s exact test (categorical) and Mann-Whitney test (continuous) were used to compare groups. Log-rank test, Cox proportional hazards model and weighted Cox regression were used for survival analysis. Results: Between 2009 and 2018, 98 out of 502 mPC patients (19.5%) underwent molecular testing. Of these, 70% were tested after 2015. The most common mutations were in KRAS (79.2%), TP53 (59.0%), CDKN2A (35.9%), BRCA (16.4%), PIK3CA (9.4%) and SMAD4 (7.4%). Concurrent KRAS and TP53 mutations were found in 62.3% of patients. KRAS mutation was positively associated with Jewish ancestry (OR 2.3; p &lt; 0.05), and TP53 mutation was positively associated with younger age at diagnosis (63.5 vs. 67 years; p &lt; 0.05). KRAS and TP53 mutations were negatively associated with tobacco use (OR 0.43 and 0.3, respectively; p &lt; 0.05). There was no association between any mutation and metastatic site. Both KRAS and TP53 mutations were positively associated with VTE (OR 2.55 and 2.71, respectively; p &lt; 0.05). Interestingly, TP53 mutation portends worse survival (HR 3.85; p &lt; 0.05) whereas CDKN2A mutation confers improved survival (HR 0.55; p &lt; 0.05). No patient received targeted therapy for their specific mutations. Conclusions: Molecular testing is becoming more prevalent in the mPC treatment paradigm. Among our cohort, concurrent KRAS and TP53 mutations were frequently identified. Incidence rates of the most common mutations were similar to those observed in prior literature. KRAS and TP53 mutations were associated with higher incidence of VTE. TP53 mutation was associated with poorer prognosis.
A phase II study of FOLFOXIRI plus bevacizumab (Bmab) as initial chemotherapy for patients (pts) with untreated metastatic colorectal cancer (mCRC): TRICC1414 (Be TRI).
Authors: Takeshi Yamada, Tomohiro Nishina, Junichiro Nasu, Toshihiko Matsumoto, Yasuhiro Yuasa, Takeshi Shiraishi, Hiroaki Nagano, Ichiro Moriyama, Toshiyoshi Fujiwara, Masashi Miguchi, Ryosuke Yoshida, Kimiyasu Nosaka, Hiroaki Tanioka, Takeshi Nagasaka, Yasuro Kurisu, Michiya Kobayashi, Kenji Tsuchihashi, Michio Inukai, Takashi Kikuchi, Katsunori Shinozaki
Journal: Journal of Clinical Oncology (2020)

134 Background: FOLFOXIRI-Bmab has been recognized as one of the standard first-line treatments for mCRC. We conducted a single arm, multicenter, phase II study to assess the efficacy and safety of FOLFOXIRI-Bmab in pts with untreated mCRC harboring UGT1A1(*6 and *28) wild or single hetero genotype. Methods: Pts received FOLFOXIRI-Bmab (irinotecan 165 mg/m 2 , oxaliplatin 85 mg/m 2 , l-leucovorin 200mg/m 2 , fluorouracil 3200 mg/m 2 and Bmab 5mg/kg repeated biweekly) up to a maximum of 12 cycles, followed by the sequential therapy which consisted of the remaining drugs if any of the individual drugs were discontinued at the investigator’s discretion. Protocol therapy was continued until progressive disease, an unacceptable adverse event, tumor resection or consent withdrawal. The primary endpoint was ORR evaluated by central reviewers. Secondary endpoints include TTF, PFS, OS, R0 resection rate, relative dose intensity (RDI) and safety. The exploratory objectives were early tumor shrinkage (ETS), depth of response (DoR). Results: 47 pts were enrolled from 16 centers between April 2015 and May 2017, of whom 1 was excluded for not meeting the inclusion criteria. The full analysis set consisted of 44 pts because 2 had no target lesions that were considered measurable lesion by central reviewers. 46 pts had the following characteristics: median age 58 (29-68), 57% male, 76% PS0, 22% right-sided tumors and 52% UGT1A1 wild. RAS status was 37% wild, 52% mutant, 11% unknown. Primary endpoint was met. The ORR was 63.6% (95% CI, 47.8-77.6). ETS and DoR was 70.5%, 43.9%, respectively. R0 resection rate was 23%. Median PFS was 15.5mo (95% CI, 11.5-23.4). Median TTF was 8.1mo (95% CI, 5.3-10.1). Median OS was 34.4mo (95% CI, 26.4-not reached). The mean RDI of fluorouracil, irinotecan and oxaliplatin were 71%, 67%, and 64%, respectively. Grade 3 or higher adverse events (≥10%) were neutropenia (65.2%), febrile neutropenia (FN) (26.1%), anorexia (10.9%), nausea (10.9%), and diarrhea (10.9%). No treatment-related deaths were observed. Conclusions: Our results of FOLFOXIRI-Bmab in Japanese pts showed to be beneficial and manageable although caution to FN is required. Clinical trial information: NCT02497157.
Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A
Authors: Jennifer M. S. Sucre, Kasey C. Vickers, John T. Benjamin, Erin J. Plosa, Christopher S. Jetter, Alissa Cutrone, Meaghan Ransom, Zachary Anderson, Quanhu Sheng, Benjamin A. Fensterheim, Namasivayam Ambalavanan, Bryan Millis, Ethan Lee, Andries Zijlstra, Melanie Königshoff, Timothy S. Blackwell, Susan H. Guttentag
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth that affects infants born in the saccular stage of lung development at <32 weeks of gestation. Although the mechanisms driving BPD remain uncertain, exposure to hyperoxia is thought to contribute to disease pathogenesis.Objectives: To determine the effects of hyperoxia on epithelial-mesenchymal interactions and to define the mediators of activated Wnt/β-catenin signaling after hyperoxia injury.Methods: Three hyperoxia models were used: A three-dimensional organotypic coculture using primary human lung cells, precision-cut lung slices (PCLS), and a murine in vivo hyperoxia model. Comparisons of normoxia- and hyperoxia-exposed samples were made by real-time quantitative PCR, RNA in situ hybridization, quantitative confocal microscopy, and lung morphometry.Measurements and Main Results: Examination of an array of Wnt ligands in the three-dimensional organotypic coculture revealed increased mesenchymal expression of WNT5A. Inhibition of Wnt5A abrogated the BPD transcriptomic phenotype induced by hyperoxia. In the PCLS model, Wnt5A inhibition improved alveolarization following hyperoxia exposure, and treatment with recombinant Wnt5a reproduced features of the BPD phenotype in PCLS cultured in normoxic conditions. Chemical inhibition of NF-κB with BAY11-7082 reduced Wnt5a expression in the PCLS hyperoxia model and in vivo mouse hyperoxia model, with improved alveolarization in the PCLS model.Conclusions: Increased mesenchymal Wnt5A during saccular-stage hyperoxia injury contributes to the impaired alveolarization and septal thickening observed in BPD. Precise targeting of Wnt5A may represent a potential therapeutic strategy for the treatment of BPD.
HIV Infection Is Associated With Variability in Ventricular Repolarization
Authors: Amir S. Heravi, Lacey H. Etzkorn, Jacek K. Urbanek, Ciprian M. Crainiceanu, Naresh M. Punjabi, Hiroshi Ashikaga, Todd T. Brown, Matthew J. Budoff, Gypsyamber D’Souza, Jared W. Magnani, Frank J. Palella, Ronald D. Berger, Katherine C. Wu, Wendy S. Post
Journal: Circulation (2019)

People living with human immunodeficiency virus (HIV+) have greater risk for sudden arrhythmic death than HIV-uninfected (HIV-) individuals. HIV-associated abnormal cardiac repolarization may contribute to this risk. We investigated whether HIV serostatus is associated with ventricular repolarization lability by using the QT variability index (QTVI), defined as a log measure of QT-interval variance indexed to heart rate variance.We studied 1123 men (589 HIV+ and 534 HIV-) from MACS (Multicenter AIDS Cohort Study), using the ZioXT ambulatory electrocardiography patch. Beat-to-beat analysis of up to 4 full days of electrocardiographic data per participant was performed using an automated algorithm (median analyzed duration [quartile 1-quartile 3]: 78.3 [66.3-83.0] hours/person). QTVI was modeled using linear mixed-effects models adjusted for demographics, cardiac risk factors, and HIV-related and inflammatory biomarkers.Mean (SD) age was 60.1 (11.9) years among HIV- and 54.2 (11.2) years among HIV+ participants (P<0.001), 83% of whom had undetectable (<20 copies/mL) HIV-1 viral load (VL). In comparison with HIV- men, HIV+ men had higher QTVI (adjusted difference of +0.077 [95% CI, +0.032 to +0.123]). The magnitude of this association depended on the degree of viremia, such that in HIV+ men with undetectable VL, adjusted QTVI was +0.064 (95% CI, +0.017 to +0.111) higher than in HIV- men, whereas, in HIV+ men with detectable VL, adjusted QTVI was higher by +0.150 (95% CI, 0.072-0.228) than in HIV- referents. Analysis of QTVI subcomponents showed that HIV+ men had: (1) lower heart rate variability irrespective of VL status, and (2) higher QT variability if they had detectable, but not with undetectable, VL, in comparison with HIV- men. Higher levels of C-reactive protein, interleukin-6, intercellular adhesion molecule-1, soluble tumor necrosis factor receptor 2, and soluble cluster of differentiation-163 (borderline), were associated with higher QTVI and partially attenuated the association with HIV serostatus.HIV+ men have greater beat-to-beat variability in QT interval (QTVI) than HIV- men, especially in the setting of HIV viremia and heightened inflammation. Among HIV+ men, higher QTVI suggests ventricular repolarization lability, which can increase susceptibility to arrhythmias, whereas lower heart rate variability signals a component of autonomic dysfunction.
Health-related quality-of-life results from JCOG0912: A phase III noninferiority trial comparing open and laparoscopy-assisted distal gastrectomy for stage I gastric cancer.
Authors: Takaki Yoshikawa, Masahiko Ando, Junki Mizusawa, Hitoshi Katai, Takanobu Yamada, Seiji Ito, Takeo Fukagawa, Etsuro Bando, Kazunari Misawa, Hiroshi Katayama, Masanori Terashima, Mitsuru Sasako
Journal: Journal of Clinical Oncology (2020)

293 Background: Laparoscopy-assisted distal gastrectomy (LADG) was non-inferior to open (ODG) in patients with stage I gastric cancer in randomized phase 3 non-inferiority trial (JCOG0912). Here, we present the results of health-related quality of life (HRQoL) which was a secondary endpoint in JCOG0912. Methods: Among 33 institutions participated in JCOG0912, 4 major cancer centers were selected for HRQOL assessment. HRQoL was assessed using EORTC QLQ-C30 and the EORTC-STO22 before (baseline) and at 1, 3, 12, and 36 months after surgery. The primary HRQOL scale was QLQ-C30 global health status. We defined clinically meaningful decrease of HRQoL as decrease in 10 points or more from the baseline. Missing data were regarded as decrease. Assuming that expected %decrease of global health status at 3 months was 61% in ODG and 45% in LADG with 80% power and two-sided alpha of 0.05, sample size for HRQOL assessment was calculated to be 304. When this hypothesis at 3 months was confirmed, statistical comparison was tested in turn at 12 and 36 months. Results: Among 921 enrolled patients in JCOG0912 from Mar 2010 to Nov 2013, 592 were enrolled from the 4 centers in this HRQoL study. The %decrease of global health status at 3 months was different between ODG and LADG (37.2% (109/293) in ODG vs 29.2% (86/295) in LADG, odds ratio [OR] 0.65 (95% CI: 0.45-0.93, p = 0.020)), but was not different in 1 month (56.0% (164/293) vs 55.3% (163/295), OR 0.92 (0.61-1.32)), 12 months (26.3% (77/293) vs 27.8% (82/295) (OR 1.07 (0.73-1.56))and 36 months (31.4% (91/293)vs 30.8% (91/295) (odds ratio, 0.96 (0.67-1.37))). Among the other subscales, LADG had significantly better symptom scores for pain at 1 and 3 months, constipation at 3 and 12 months, and eating restrictions at 3 months. Conclusions: Decrease of HRQoL was less frequently observed in LADG than ODG especially in the early phase after surgery. Considering non-inferiority and better HRQoL of LADG, LADG is strongly recommended for stage I gastric cancer. However, we have to be careful to expand the indication of LADG for advanced gastric cancer until a solid evidence is obtained. Clinical trial information: UMIN000003319.