tbuckley/cabot-search huggingface dataset:
The real-world practiсe of surgery in patients with metastatic gastric cancer (mGC).
Authors: Ekaterina Obarevich, Natalia Besova, Tatiana Titova, Elena Trusilova, Mikhail Davydov, Sergey Nered, Ivan Stilidi, Elena Artamonova
Journal: Journal of Clinical Oncology (2020)

363 Background: According to recent studies the results of treatment patients with initially mGC are still not sufficient: median overall survival varies between 6.1 and 12.4 months. The triplet-chemotherapy regimens demonstrate high efficacy and allow to downstage the disease and perform surgical treatment. Conversion treatment in stage IV GC is a modern trend and still an area of ongoing research. Methods: We analyzed the efficacy of first line chemotherapy (6-9 courses) for patients with mGC (n = 55) including the following regimens: 1) mFOLFIRINOX; 2) douplet: oxaliplatin/irinotecan + fluoropyrimidine; 3) triplet variations: docetaxel, platinum and fluoropyrimidine. 27/55 patients had &gt; 2 metastatic sites, 2/55 patient - 5 metastatic sites. The most common localizations of metastases were peritoneum (n = 34) and retroperitoneal lymph nodes (n = 11). Unlike in REGATTA trial all patients underwent surgical treatment with curative intent followed by complete response of distant metastases after chemotherapy. For patients with ovarian metastases ovariectomy was also perfomed. Results: Median progression-free survival and median overall survival were 18.5 and 33.27 months, respectively and the 3-year survival rate was 43.5%. Multivariate analysis showed that clinically determined ascites (p = 0.023), linitis plastica (p = 0.022), tumor grade 3 (p = 0.014), present of lymphovascular invasion (p = 0.037), absence of grade III-IV pathomorphosis (p = 0.037) and treatment free interval before surgery &lt; 3.4 month (p = 0.046) were poor independent prognostic factors. Conclusions: Surgery after effective combination chemotherapy may have significant clinical efficacy for selected patients with initially unresectable gastric cancer. According to our data the optimal time for surgery is a 3.4 and more months treatment-free interval in the absence of disease progression.
Optimizing FOLFIRINOX tolerability in patients with colorectal cancer through dosing irinotecan in the morning for men and in the afternoon for women.
Authors: Francis Levi, Annabelle Ballesta, Abdoulaye Karaboué, Qi Huang, C. N. J. Focan, Philippe Chollet, Mohamed Bouchahda, Rene Adam, Carlo Garufi, Pasquale Innominato
Journal: Journal of Clinical Oncology (2020)

120 Background: Irinotecan (IRI) toxicity was worse in female (F) than in male (M) patients (pts) on FOLFIRI for metastatic colorectal cancer (MCC). This finding could reflect different optimal administration timing of IRI in M and F pts along the 24 hours. IRI pharmacology is regulated by the circadian clock, and its least toxic daily time (LTT) occurred ~6 hours later in F as compared to M mice. The relevance of sex for the LTT of IRI is addressed here using data from an international randomized trial, whose primary endpoint was not met for all the 193 pts with MCC (EORTC 05011). Methods: 130 M and 63 F were randomized to receive chronomodulated IRI (180 mg/m2 over 6-h, with peak delivery in the morning (at 5:00 or 9:00), in the afternoon (at 13:00 or 17:00) or at night (at 21:00 or 01:00) on day (d) 1, followed by fixed-time chronomodulated oxaliplatin-5-fluorouracil-leucovorin for 4 d. Triplet combination was given q3 weeks as 1st or 2nd line, without prophylactic G-CSF. The relevance of IRI timing for main toxicities was determined separately in M and F, using Cosinor and Fisher Exact tests. Results: Baseline characteristics of M or F pts did not differ significantly according to IRI timing group. Main worse grade 3-4 toxicities per pt after 6 courses were diarrhea (M, 40.2%; F, 51.9%) neutropenia (M, 12.6%; F, 18.4%), fatigue (M, 13.4%; F, 17.3%) and anorexia (M, 8.2%; F, 9.6%). These toxicities were reduced following IRI delivery in the morning for M, but in the afternoon for F, with statistically significant rhythms (p &lt; 0.05 from cosinor) and sex*timing interactions (Fischer Exact, diarrhea, p = 0.023; neutropenia, p = 0.015; fatigue, p = 0.062; anorexia, p = 0.032). IRI timing was most critical for F, with Grade 3-4 toxicities ranging from 55.2% of the pts (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. IRI timing did not significantly influence efficacy. Conclusions: The present study results supports the administration of irinotecan in the morning for M and in the afternoon for F in order to minimize adverse events of triplet chemotherapy without impairing efficacy. Prospective trials testing sex specific timing issues are warranted. Clinical trial information: 05011.
A phase Ib study of near infrared photoimmunotherapy (NIR-PIT) using ASP-1929 in combination with nivolumab and for patients with advanced gastric or esophageal cancer (GE-PIT study, EPOC1901).
Authors: Tomohiro Kadota, Daisuke Kotani, Yusuke Yoda, Miki Fukutani, Masashi Wakabayashi, Shogo Nomura, Nozomu Fuse, Akihiro Sato, Tomonori Yano, Kohei Shitara
Journal: Journal of Clinical Oncology (2020)

TPS457 Background: Near Infrared Photoimmunotherapy (NIR-PIT) is a newly developed, molecular targeted cancer therapy based on conjugating a near infrared silica-phthalocyanine dye to a monoclonal antibody, which result in necrotic cell death of targeted cancer cell immediately after exposure to near infrared light. Phase IIa trial of NIR-PIT with RM-1929 (anti-EGFR antibody cetuximab conjugated to IRDye 700DX) showed a 43% objective response rate (ORR) for recurrent head and neck squamous cell carcinoma (Cognetti DM, et al.ASCO 2019 abstr 6014). Meanwhile, PD-1 blockade reverses adaptive immune resistance, resulting in activation of tumor infiltrating lymphocyte after NIR-PIT in syngeneic mouse models (Nagaya T, et al. Cancer immunology research. 2019). The objective of this study is to investigate the safety and efficacy of the NIR-PIT using ASP-1929 (analogous to RM-1929) in combination with nivolumab for advanced gastric or esophageal cancer. Methods: The study is an open-label, single-arm, single-center, Phase Ib clinical trial. Eligible patients are with unresectable esophagogastric squamous cell carcinoma or EGFR positive adenocarcinoma after standard chemotherapy. Dose escalation cohort is designed to determine the recommended dose of laser irradiation energy density in a “3+3” design (50, 75, and 100 J/cm 2 ). Nivolumab of 240 mg on Day 1 and ASP-1929 of 640 mg/m 2 on Day 8 is administered, and laser irradiation is performed under endoscopy using the laser PIT unit on Day 9. In expansion cohort, approximately 20 patients will be enrolled. The primary endpoint is proportion of incidence of dose-limiting toxicity, and the secondary endpoints are proportion of incidence of adverse events, ORR, local complete response rate, progression-free survival (PFS), local PFS, overall survival, and proportion of incidence of device malfunction. We also investigate several biomarkers using pre- and post-treatment biopsied samples. First patient will be enrolled in December 2019. Clinical trial information: JapicCTI-194969.
HEV superinfection accelerates disease progression in patients with chronic HBV infection and increases mortality in those with cirrhosis
Authors: Tai-Chung Tseng, Chun-Jen Liu, Crystal T. Chang, Tung-Hung Su, Wan-Ting Yang, Cheng-Hsueh Tsai, Chi-Ling Chen, Hung-Chih Yang, Chen-Hua Liu, Pei-Jer Chen, Ding-Shinn Chen, Jia-Horng Kao
Journal: Journal of Hepatology (2020)
Prognostic factor of nivolumab for advanced gastric cancer patients with poor performance status patients.
Authors: Toshihiko Matsumoto, Ukyo Okazaki, Yusuke Kurioka, Shogo Kimura, Takao Tsuzuki, Shinjiro Takagi, Masahiro Takatani, Hirofumi Morishita
Journal: Journal of Clinical Oncology (2020)

391 Background: Nivolumab has changed the treatment of advanced gastric cancer (AGC). Nivolumab shows better outcome compared to best supportive care in AGC patients who received at least two prior regimen. Although there is not reliable date of poor performance status(PS) AGC patients who received nivolumab. We investigated efficacy and safety of nivolumab for AGC patients with poor PS. Methods: We retrospectively collected clinicopathologic data from patients with AGC who received nivolumab monotherapy in Himeji Red Cross Hospital from October 2017 to June 2019. Results: 49 AGC patients who received nivolumab were analyzed. 27 patients were PS 0 or 1(Good Group), and 22 patients were PS 2 or 3(Poor Group). Median progression free survival and overall survival was 61 days and 180 days in Good Group and 36 days and 85 days in Poor Group. Overall survival (OS) was significantly shorter in Poor group(180 days vs 85 days, p = 0.0255). Disease control rate was 23% in Good group and 9% in Poor group. 33% patients were experienced immune related adverse event (iRAE) in Good Group, and 18% in Poor Group. We investigated prognostic factor of OS in Poor Group such as Royal Marsden Hospital Score(RMH score), modified Glasgow prognostic score(mGPS), and Japan Clinical Oncology Group (JCOG) prognostic index. RMH score and JCOG prognostic index good or moderate group was significantly longer overall survival than poor group (93 days vs 35 days (p = 0.0214)). JCOG prognostic index was most correlated with OS among these tools. Conclusions: This study suggested that nivolumab has a modest effect and is feasible as third line or later line for AGC patients. JCOG prognostic index was suggested to be effective in predicting prognosis in AGC patients who received nivolumab.
A Mutation in γ-Adducin Impairs Autoregulation of Renal Blood Flow and Promotes the Development of Kidney Disease
Authors: Fan Fan, Aron M. Geurts, Mallikarjuna R. Pabbidi, Ying Ge, Chao Zhang, Shaoxun Wang, Yedan Liu, Wenjun Gao, Ya Guo, Longyang Li, Xiaochen He, Wenshan Lv, Yoshikazu Muroya, Takashi Hirata, Jeremy Prokop, George W. Booz, Howard J. Jacob, Richard J. Roman
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement The genes and mechanisms underlying the association between diabetes or hypertension and CKD risk are unclear. The authors identified a recessive K572Q mutation in γ -adducin ( Add3 ), which encodes a cytoskeletal protein (ADD3), in fawn-hooded hypertensive (FHH) rats—a mutation also reported in Milan normotensive (MNS) rats that develop renal disease. They demonstrated that FHH and Add3 knockout rats had impairments in the myogenic response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. They confirmed the K572Q mutation’s role in altering the myogenic response in a genetic complementation study that involved crossing FHH and MNS rats. The work is the first to demonstrate that a mutation in ADD3 that causes renal vascular dysfunction also promotes susceptibility to kidney disease. Background The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for γ -adducin (ADD3), a cytoskeletal protein encoded by Add3 . Methods We investigated renal vascular function in vitro and in vivo and the susceptibility to CKD in rats with wild-type or mutated Add3 and in genetically modified rats with overexpression or knockout of ADD3. We also studied glomeruli and primary renal vascular smooth muscle cells isolated from these rats. Results This study identified a K572Q mutation in ADD3 in fawn-hooded hypertensive (FHH) rats—a mutation previously reported in Milan normotensive (MNS) rats that also develop kidney disease. Using molecular dynamic simulations, we found that this mutation destabilizes a critical ADD3-ACTIN binding site. A reduction of ADD3 expression in membrane fractions prepared from the kidney and renal vascular smooth muscle cells of FHH rats was associated with the disruption of the F-actin cytoskeleton. Compared with renal vascular smooth muscle cells from Add3 transgenic rats, those from FHH rats had elevated membrane expression of BK α and BK channel current. FHH and Add3 knockout rats exhibited impairments in the myogenic response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. We confirmed these findings in a genetic complementation study that involved crossing FHH and MNS rats that share the ADD3 mutation. Add3 transgenic rats showed attenuation of proteinuria, glomerular injury, and kidney fibrosis with aging and mineralocorticoid-induced hypertension. Conclusions This is the first report that a mutation in ADD3 that alters ACTIN binding causes renal vascular dysfunction and promotes the susceptibility to kidney disease.
Racial variation in molecular profile of advanced gastrointestinal cancers.
Authors: Shravanti Macherla, Sujitha Nandimandalam, Sriraksha Jayananda, Ebenezer Ofori Appah, Anushi Bulumulle, Sameer Baig, Anokhi Patel, Shanker Polsani, Mahvish Muzaffar
Journal: Journal of Clinical Oncology (2020)

236 Background: Heterogeneity in the tumor molecular profile based on race is poorly understood. We sought to review the utilization of next generation sequencing (NGS) in patients with advanced gastrointestinal (GI) malignancies treated at a rural academic center and analyze inter racial variations in the molecular tumor profile. Methods: We conducted a retrospective review of patients with advanced GI malignancies that underwent NGS between 2015 to 2018 at East Carolina University.104 patients met eligibility criteria but 8 patients were excluded due to insufficient tissue sampling. Patients with colorectal, gastric, pancreatic, biliary, small intestinal and esophageal cancers were included. Targeted NGS using Caris Life Sciences¨ platform was performed to obtain molecular analysis. We conducted descriptive univariate analysis, cox regression and Kaplan-Meier survival curve analysis. Results: Median age at diagnosis was 64yrs and 64% of patients were black. The study cohort had 41% (n=39) with colon cancer, 18%(17) gastric cancer, 30% (29) pancreatic cancer, 6%(6) biliary cancer, 4%(4) small intestinal cancer and 1%(1) esophageal cancer. 60% (55) had de novo Stage IV disease. Median overall survival (OS) was 25 months (mo), 30 mo in blacks and 32 mo in whites (p value =0.46). Microsatellite stability was seen in 94% (87) and instability in 3% (3). Overall cohort had mutations (mut) in KRAS (50%), TP53 (64%), BRAF (4%), and ERBB amplification (3%). On the cox regression model APC mutation was associated with worse outcome. Black patients had more alterations in KRAS, TP53 (both not significant), and APC (p=0.02). Conclusions: In our analysis we observed inter racial variations in molecular profile of advanced GI malignancies. Black patients had increased rates of APC, KRAS and TP 53 mut. Further studies are required to analyze the impact of these molecular variations on outcomes. Results. [Table: see text]
In vitro-generated alloantigen-specific Th9 cells mediate antileukemia cytotoxicity in the absence of graft-versus-host disease
Authors: Tanja Reisser, Daniel Halbgebauer, Jasmin Scheurer, Linda Wolf, Frank Leithäuser, Niklas Beyersdorf, Pamela Fischer-Posovszky, Klaus-Michael Debatin, Gudrun Strauss
Journal: Leukemia (2020)
CXCR1/2 blockade to enhance response to immune checkpoint inhibition in an aggressive orthotopic pancreatic adenocarcinoma model.
Authors: Nicholas A. Ullman, Luis I. Ruffolo, Katherine M. Jackson, Alexander Chacon, Mary Georger, Rachel Jewell, Brian A. Belt, Dean Maeda, John Zebala, David Linehan
Journal: Journal of Clinical Oncology (2020)

19 Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths, with the incidence expected to rise in the coming years. Despite conventional chemotherapy and advances in immune checkpoint blockade, 5 year survival remains a dismal 8%. Intratumoral accumulation of granulocytic myeloid derived suppressor cells (G-MDSC) pose a significant barrier to treatment as they contribute to immune evasion by PDAC and correlate with poor prognosis. The ELR + CXC chemokine receptors CXCR1 and CXCR2 (CXCR1/2) contribute to peripheral neutrophil migration into tissues and have been implicated in tumor mediated G-MDSC recruitment to the tumor microenvironment. Here we present our findings using an orally dosed CXCR1/2 inhibitor, SX-682, in an orthotopic PDAC model. Methods: C57BL/6 mice underwent orthotopic injections with KP2 cells. Mice were randomized into five groups (Table) receiving three weeks of FOLFIRINOX with combinations of SX-682 and/or checkpoint inhibition (anti-PD1/anti-CTLA4). FOLFIRINOX was dosed weekly for three weeks. Checkpoint inhibition was administered twice weekly. Chow weights were monitored for consumption of SX-682. Results: The simultaneous administration of FOLFIRINOX with SX-682 combined with checkpoint inhibition (triple therapy) resulted in a significant increase in survival compared to other groups (p = 0.0001). Notably, there was a significant increase in survival with triple therapy versus FOLFIRINOX plus checkpoint alone (p = 0.0259). Median survival of the triple therapy group was 42.5 days, compared to 37 days with checkpoint inhibition (p = &lt;0.05). There were no differences in chow consumption between the control and medicated chow groups. Conclusions: CXCR1/2 blockade combined with immune checkpoint inhibition and first line chemotherapy significantly enhanced survival in our PDAC mouse model. Thus, CXCR1/2 inhibition with SX-682 represents a promising target for clinical intervention in PDAC. [Table: see text]
Should adenosquamous esophageal carcinoma be treated like adenocarcinoma or squamous cell carcinoma?
Authors: Adriana C. Gamboa, Benjamin I Meyer, Jeffrey M. Switchenko, Manali Rupji, Rachel M. Lee, Michael K. Turgeon, Maria C. Russell, Kenneth Cardona, David A. Kooby, Shishir K. Maithel, Mihir M. Shah
Journal: Journal of Clinical Oncology (2020)

323 Background: Adenocarcinoma and squamous cell carcinoma of the esophagus have distinct outcomes, treatment strategies, and response profiles to therapy. Adenosquamous carcinoma (ASC) is thought to behave more aggressively than each of its counterparts. Our aim was to determine if ASC is best managed as adenocarcinoma or squamous cell carcinoma. Methods: The National Cancer Database (2004-15) was queried for patients with non-metastatic, esophageal ASC. Analysis was stratified by clinical node negative (cN0) or node positive (cN1-3) according to AJCC 8 th edition. Treatment types were categorized into chemoradiation alone, surgery alone, or preoperative chemoradiation followed by surgery. Primary outcome was overall survival (OS). Results: Among 352 pts, median age was 67 yrs, 80% were male (n = 281). Median f/u was 46 mos. 43% were cN0 (n = 151), 57% were cN1-3 (n = 201). 55% had chemoradiation alone (n = 194), 15% had surgery alone (n = 53) and 30% had preoperative chemoradiation (n = 105). Of pts who had preoperative chemoradiation, 20% had pathologic complete response (n = 17). For either cN0 or cN1-3, Charlson-Deyo Comorbidity Index did not differ among the treatment groups (all p &gt; 0.05). On KM analysis for cN0 disease, treatment with surgery alone had a comparable 5-yr OS to preoperative chemoradiation (47 vs 34% p = 0.5) and each had improved 5-yr OS compared to chemoradiation alone (30%; p = 0.02; p = 0.06). On UV analysis for patients with cN0 disease, clinical T-stage was not associated with 5-yr OS. For patients with cN1-3 disease, however, preoperative chemoradiation was associated with improved 5-yr OS when compared to chemoradiation alone or surgery alone (27 vs 19 vs 0% p &lt; 0.001). This persisted even when accounting for age and clinical T-stage (HR 0.45 p &lt; 0.001). Conclusions: Esophageal adenosquamous carcinoma behaves more like adenocarcinoma both in response to chemoradiation and survival outcomes based on the treatment modality. The complete response rate to chemoradiation is only 20% unlike what has been shown for squamous cell carcinoma, where chemoradiation is an acceptable definitive therapy. Esophageal adenosquamous carcinoma should be managed like adenocarcinoma and not squamous cell carcinoma.
Results of a phase Ib trial of encapsulated rapamycin in prostate cancer patients under active surveillance to prevent progression.
Authors: Phillip M. Kemp Bohan, Jessica L. Cindass, Robert Connor Chick, Timothy J. Vreeland, Diane F. Hale, Annelies Hickerson, Guy Travis Clifton, George Earl Peoples, Michael Liss
Journal: Journal of Clinical Oncology (2020)

34 Background: At low doses, rapamycin inhibits cell proliferation and angiogenesis while augmenting CD8 T-cell responses, cumulatively producing an antitumor effect. Oral rapamycin is limited by variable bioavailability. Encapsulated rapamycin (eRapa) incorporates submicron rapamycin particles into a pH-sensitive polymer, improving bioavailability and allowing for consistent and lower dosing. Here, we present results of a phase Ib trial evaluating safety and treatment effects of eRapa in patients with low-grade prostate cancer (PCa). Methods: PCa patients with Gleason ≤7 (3+4) under active surveillance were enrolled in a 3+3 study with 3 dosing cohorts (0.5mg weekly, 1mg weekly, and 0.5mg daily) to determine the optimal dosing. Patients were treated for 3 months (m) and followed for 6m. Safety, labs (including PSA), pharmacokinetics, immune response, and quality of life (QOL) were assessed for each cohort. Results: 14 patients were enrolled; 3 in cohort 1, 3 in cohort 2, and 8 in cohort 3. 2 patients withdrew for non-dose limiting toxicity (DLT) (grade 1-2) adverse events (AEs) in cohort 3, leaving 6 evaluable. A single grade 3 DLT (neutropenia) occurred in cohort 3. No AEs &gt; Grade 1 occurred in cohorts 1/2. Peak serum rapamycin concentration ([Rapa]) was 7 ng/mL after a 1 mg dose (2h after administration). Stable trough levels (2 ng/mL) were established after 48 hrs and persisted to 13wks. Central memory CD8 T cells and CD3+/CD56+ NK cells were more prevalent in cohort 3 than other cohorts at 1m (p = 0.027 and p = 0.041) and 3m (p = 0.023 and p = 0.049). There was no significant change in PSA level; no patients clinically progressed on therapy. In cohort 3, there were no differences between baseline and 3m QOL assessments but there was a suggestion of withdrawal effects at 6m. Conclusions: Treatment with low dose eRapa is safe and well-tolerated. The dose of 0.5mg daily produced stable serum [Rapa] through the duration of treatment and resulted in a positive immune impact. Further investigation with low dose and/or intermittent dosing of eRapa as a preventive agent in PCa and other indications will be required to establish clinical benefit. Clinical trial information: NCT03618355.