tbuckley/cabot-search huggingface dataset:
MONARCC: A randomized phase II study of panitumumab monotherapy and panitumumab (pan) plus 5 Fluorouracil (FU) as first-line therapy for RAS and BRAF wild type metastatic colorectal cancer (mCRC): An AGITG clinical trial.
Authors: Niall C. Tebbutt, Christopher B. Steer, Katrin Marie Sjoquist, Lorraine A. Chantrill, Christos Stelios Karapetis, Louise M. Nott, David Espinoza, Martinus Oostendorp, Sonia Yip, Jeff Cuff, Matthew E. Burge
Journal: Journal of Clinical Oncology (2020)

TPS271 Background: Pan added to combination chemotherapy is established first-line therapy for RAS and BRAF wild type mCRC. Elderly patients are not well represented in clinical trials and may be more suited to treatment protocols with lower toxicity risks; FU plus bevacizumab (bev) is commonly used. Treatment related efficacy, toxicity, impact on quality of life and other outcomes of pan based regimens in an elderly population have not been well studied. Methods: A prospective non-comparative randomized phase 2 study. Australian Clinical Trials Registry Number: ACTRN 12618000233224. Main inclusion criteria include: Untreated patients aged 70 years or older; RAS and BRAF wild type; ECOG performance 0-2. Randomisation 1:1, stratified by primary tumour side, performance status, number of metastatic sites; to pan 6mg/kg 2 weekly or panitumumab plus FU 400 mg/m² bolus; leucovorin 200mg/m²; FU 2400mg/m² 48 hour infusion 2 weekly. Primary endpoint is 6-month progression-free survival (PFS). Sample size is 80 patients based on expected 6-month PFS rate of 73% with FU and bev. Using the method of Metha-Cain, if 24 or more patients are progression free at 6 months, the one sided 95% confidence interval includes 73% and we declare similar activity. Secondary endpoints include overall survival; toxicity and overall treatment utility, a composite measure of treatment benefit based on radiology, clinical progress, toxicity and patient reflection of the impact of treatment on their daily lives. Patients undergo a comprehensive health assessment at baseline and limited health assessment at 4 months. Physical activity trackers are worn for 2 weeks at treatment commencement and again at week 16. Tumour tissue and blood samples (at baseline, cycle 3 day 1 and at 24 weeks) will be collected for translational research. First site opened in June 2018. Twelve patients have been recruited to date from 9 sites in Australasia. Eighteen sites were open as at September 2019. Clinical trial information: 12618000233224.
FKBP5 Genetic Variation and Expression Among Depressed Individuals with Chronic Hepatitis C
Authors: Duy Pham Anh, Sern Wei Yeoh, Diana Lewis, Darren Wong, Gursharan Chana, Chad Bousman, Ting Ting Lee, Shaki Mostaid, Alex Holmes, Michael Saling, Ian Everall, Amanda Nicoll
Journal: Hepatology (2018)
Early implementation of a postoperative nutrition support pathway for patients undergoing esophagectomy.
Authors: Rebecca Carr, Christina Stella, Diana Glauner, Erin Kenny, Lianne Russo, Meghan Garrity, Matthew Bott, James M. Isbell, Bernard Park, Smita Sihag, David Randolph Jones, Daniela Molena
Journal: Journal of Clinical Oncology (2020)

344 Background: A significant risk of malnutrition burdens patients with esophageal cancer undergoing esophagectomy as tumor-related dysphagia and side effects of chemoradiation impair the patients’ ability to maintain adequate nutrition. Moreover, patients lose 10% or more of their preoperative body weight in the first year following surgery. Implementation of nutrition protocols may reduce postoperative weight loss and enhance recovery in these patients. Methods: This is a retrospective study examining a postoperative nutrition protocol initiated in August of 2017. Patients with esophagogastric cancer who underwent Ivor Lewis esophagectomy from July 2016 to July 2019 were identified from a prospectively collected database. Patients that underwent surgery after implementation of this protocol were compared to those operated prior to it. Results: Patients’ and tumor characteristics were similar between the two groups. The protocol included preoperative evaluation by a dietician, postoperative feeding pathway, and regular post-discharge follow up by phone with a dietician. In the post protocol group, we observed a reduction in time to initiation of diet and decreased weight loss at patient follow up (Table). There was no difference in incidence of postoperative complication, length of stay, 30-day readmission, or in hospital mortality. Conclusions: In conclusion, postoperative nutrition support programs may help reduce postoperative weight loss and may have a role in the prevention of malnutrition in these patients. Initial results suggest that more aggressive nutritional supplement program is feasible and may lead to improved postoperative outcomes in patients undergoing esophagectomy. [Table: see text]
Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases
Authors: Lingxin Zhu, Yi Tang, Xiao-Yan Li, Evan T. Keller, Jingwen Yang, Jung-Sun Cho, Tamar Y. Feinberg, Stephen J. Weiss
Journal: Science Translational Medicine (2020)

Independent of cathepsin K, the osteoclast-derived matrix metalloproteinases MMP9 and MMP14 codependently drive bone resorption.
CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma
Authors: Xiao-Lu Ma, Bo Hu, Wei-Guo Tang, Su-Hong Xie, Ning Ren, Lin Guo, Ren-Quan Lu
Journal: Journal of Hematology & Oncology (2020)

Abstract Background Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. Methods CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. Results We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73– counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. Conclusions Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.
HGCSG 1301: A multicenter, double-blind, randomized controlled phase II trial comparing Hange-shashin-to versus placebo to prevent diarrhea in patients with metastatic colorectal cancer treated with IRIS/Bev as second-line therapy—Updated analysis of antitumor efficacy.
Authors: Atsushi Ishiguro, Hiroshi Nakatsumi, Tetsuhito Muranaka, Yasuyuki Kawamoto, Satoshi Yuki, Miki Tateyama, Atsushi Sato, Takuto Miyagishima, Michio Nakamura, Masayoshi Dazai, Hiroyuki Okuda, Yasuo Takahashi, Tomoe Kobayashi, Takashi Kato, Kazuteru Hatanaka, Toraji Amano, Yuh Sakata, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2020)

108 Background: IRIS (irinotecan plus S-1) plus bevacizumab (IRIS/Bev) is one of the standard chemotherapies in Japan for metastatic colorectal cancer (mCRC) as the first-line or second-line therapy. The most frequent non-hematological adverse event of IRIS was diarrhea. Hange-shashin-to (HST) is a Kampo medicine which is used in Japan for the treatment of gastritis, stomatitis, and diarrhea. We conducted this study to evaluate the usefulness of HST to prevent diarrhea in patients with mCRC receiving IRIS/Bev as the second-line therapy. Methods: This trial was designed as a multicenter, randomized, double-blind, placebo-controlled study. We administrated HST 2.5g or placebo PO t.i.d. x 3 months from the first treatment course of IRIS/Bev. The primary endpoint is proportion of ≥grade 3 diarrhea assessed by CTCAE v4.0. This study is registered with UMIN-CTR, number UMIN000012276. Results: Between Jan 1, 2014 and Mar 31, 2017, 59 patients from 11 institutes in Japan were randomly assigned to receive HST (n = 28, Group H) or placebo (n = 29, Group P). The proportions of ≥grade 3 diarrhea was 10.7% in Group H and 13.8% in Group P (p = 1.00). The other major adverse events of ≥grade 3 in Group H vs Group P were fatigue (3.6% vs 10.3%), anorexia (14.3% vs 10.3%), and nausea (0.0% vs 3.4%). The overall response rate was 13.6% in Group H vs 7.7% in Group P (p = 0.65). There were not statistically significant differences in median progression-free survival (mPFS), median time to treatment failure (mTTF), and median overall survival (mOS) between Group H and Group P ( mPFS 7.9 vs 5.9 months; p = 0.35; mTTF 3.8 vs 5.6; p = 0.466; mOS 17.0 vs 15.3 months; p = 0.750). Conclusions: Prophylactic HST could not reduce the severity of diarrhea during IRIS/Bev. The update analysis of anti-tumor efficacy showed that IRIS/Bev had promising survival benefit but there is not statistically significant difference between HST and placebo. Clinical trial information: UMIN000012276.
A novel preoperative risk score to optimize patient selection for performing concomitant liver resection with cytoreductive surgery/HIPEC.
Authors: Rachel M. Lee, Adriana C. Gamboa, Michael K. Turgeon, Travis Edward Grotz, Keith F. Fournier, Sean Patrick Dineen, Jula Veerapong, Callisia Clarke, Sameer H. Patel, Ryan James Henrix, Laura A. Lambert, Daniel Erik Abbott, Mustafa Raoof, Fabian McCartney Johnston, Charles A. Staley, Jordan Cloyd, Shishir K. Maithel, Maria C. Russell
Journal: Journal of Clinical Oncology (2020)

37 Background: While parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery(CRS) and heated intraperitoneal chemotherapy(HIPEC), liver resection(LR) is increasingly performed concomitantly with CRS/HIPEC. As this practice continues to expand, identification of preoperative factors associated with poor outcomes is paramount. Methods: Patients from the US HIPEC Collaborative(2000-2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0-1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival(OS). Results: 658 patients were included. Average age was 54 years and 45% were male; 83 (15%) underwent liver resection of colorectal (58%) or invasive appendiceal (42%) metastases. Liver resection patients had more complications (81 vs 60%; p = 0.001), greater number of complications (2.3 vs 1.5; p &lt; 0.001), and required more reoperations (22 vs 11%; p = 0.007) and readmissions (39 vs 25%; p = 0.014) than non-liver resection patients. Liver resection patients had decreased OS (2-year OS 62% vs 79%, p &lt; 0.001), which persisted on multivariable Cox regression when accounting for PCI and histology type. Preoperative factors associated with decreased OS on multivariable analysis in patients undergoing liver resection included age &lt; 60 years (HR:3.61), colorectal histology (HR:3.84), and multiple liver tumors (HR:3.45) (all p &lt; 0.05). When assigning one point for each factor, there was an incremental decrease in 2-yr survival as the risk score increased from 0 to 3 (0: 100%; 1: 91%; 2: 58%; 3: 0%; p &lt; 0.001). Conclusions: As concurrent liver resection with CRS/HIPEC has become more common, we created a simple risk score to stratify patients considered for CRS/HIPEC with liver resection. These data aid in striking the balance between an increased perioperative complication profile with the potential for improvement in overall survival.
Review of neurological side effects associated with checkpoint inhibitor therapy in cancer patients.
Authors: Lakshmi Manogna Chintalacheruvu, Kushal Naha, Vamsi Krishna Chilluru, Donald C. Doll
Journal: Journal of Clinical Oncology (2020)

72 Background: Checkpoint inhibitors have demonstrated efficacy in many cancer types. Neurological side effects are not well studied with check point inhibitors therapy. We conducted systematic review and meta analysis to evaluate the incidence of neurological side effects among various check point inhibitors. Methods: Eligible studies were searched for in PubMed and Google scholar. We searched for randomized controlled trials with cancer patients treated with check point inhibitors with neurological adverse effects. A total of 26 randomized controlled trials involving 6110 patients met eligibility criteria for the study. Results: Incidence rate of all grade neurological side effects include 5.6%(95% confidence interval [CI], 5.4-6.7%). Most common side effects include Headache (4.6%) (95% confidence interval [CI] 3.7-4.7%) followed by peripheral neuropathy (0.3%) (95% confidence interval [CI] 0.1-0.5%). Ipilimumab plus Nivolumab is associated with higher risk of headache and serious neurological side effects including myasthenia gravis, encephalitis, toxic encephalopathy and seizures. Conclusions: The incidence of neurological side effects associated with immune checkpoint inhibitors is low but not negligable. Patients on combination immunotherapy need more close monitoring for serious neurological side effects.
A comparison study of the intratumoral microbiome in younger verses older-onset colorectal cancer (COSMO CRC).
Authors: Benjamin Adam Weinberg, Hongkun Wang, Xue Geng, Shadi Shokralla, Emily Bakhshi, Krysta Chaldekas, Brent T. Harris, Dionyssia Clagett, John Marshall
Journal: Journal of Clinical Oncology (2020)

241 Background: Although colorectal cancer (CRC) incidence has declined overall, CRC in individuals under age 45 has risen dramatically, particularly in the distal colon and rectum (left-sided CRC). The intratumoral microbiome (MB) of young individuals may be responsible. Certain bacteria disrupt colonic luminal integrity and promote inflammation, leading to oncogenic mutations in colonic epithelial cells. Fusobacterium nucleatum ( F. nuc) promotes CRC by suppressing immune response within the tumor microenvironment, activating the β-catenin pathway, and causing chemoresistance due to autophagy. Methods: We compared the intratumoral MB in CRC patients (pts) diagnosed before age 45 and after age 65. Primary and metastatic tumors were included. DNA was extracted from tumors and analyzed using 16S ribosomal gene sequencing. We compared the frequency of F. nuc and other bacterial and fungal DNA in tumors from younger- vs. older-onset CRC pts. Results: Tumors from 18 younger pts (median age 39.2 years) and 13 older pts (median age 72.8 years) underwent analysis. In total, 478 unique bacterial and fungal species were detected. F. nuc was found in tumors of 5 younger pts (28%, 4 left-sided and 1 right-sided primary) and 3 older pts (23%, 1 left-sided and 2 right-sided; P = NS, Fisher’s Exact test). A significant difference was seen in the rate of Moraxella osloensis (11% vs. 46%, P = 0.043, Fisher’s Exact test) in younger vs. older pts. There was no significant difference in MB diversity in younger vs. older pts. Conclusions: F. nuc is present in a greater number of tumors in pts with CRC diagnosed before age 45 than previously thought. Intratumoral bacterial profiling may discover patterns that explain the rising incidence of CRC in younger individuals and might eventually inform the development of novel therapeutics and adaptive cancer screening methods.
Immune system development varies according to age, location, and anemia in African children
Authors: Danika L. Hill, Edward J. Carr, Tobias Rutishauser, Gemma Moncunill, Joseph J. Campo, Silvia Innocentin, Maxmillian Mpina, Augusto Nhabomba, Anneth Tumbo, Chenjerai Jairoce, Henriëtte A. Moll, Menno C. van Zelm, Carlota Dobaño, Claudia Daubenberger, Michelle A. Linterman
Journal: Science Translational Medicine (2020)

The composition and function of the immune system in African children is linked to age, location, and anemia.
Association of real-world agreement between HER2 expression and ERBB2 amplification with trastuzumab therapy benefit in advanced gastric/esophageal (adv GE) cancer patients (pts).
Authors: Stacey Stein, Jeremy Snider, Margaret Elizabeth McCusker, Rebecca A. Miksad, Brian Michael Alexander, Emily Castellanos, Daniel Backenroth, Alexa Betzig Schrock, Russell Madison, Kenneth Robert Carson, Siraj Mahamed Ali
Journal: Journal of Clinical Oncology (2020)

310 Background: Trastuzumab (T) plus chemotherapy is standard of care for pts with HER2+ adv GE cancer. Selection for T relies on HER2+ result by immunohistochemistry (IHC) +/- in-situ hybridization (ISH); ERBB2 amplification by comprehensive genomic profiling (CGP) also predicts benefit. As CGP use increases, it is important to explore associations of IHC/ISH and CGP result agreement with clinical outcomes in pts with adv GE cancer. Methods: Pts with adv GE cancer were selected from the Flatiron Health-Foundation Medicine (FMI) clinico-genomic database (CGDB), a nationwide de-identified EHR-derived clinical database linked to FMI genomic data. Pts treated from 01/2011-12/2018 with CGP data for tissue specimens collected before 1L were included. Agreement between HER2 status by IHC +/- ISH v ERBB2 amplification by CGP was assessed. For 1L containing T, time to tx discontinuation (TTD) and overall survival (OS) from 1L start stratified by HER2:ERBB2 agreement and ERBB2 copy number (CN) [ERBB2+ = CN &gt;4] were estimated with unadjusted Kaplan-Meier analysis and adjusted (practice type, sex, age at adv dx) hazard ratios (aHR) from Cox proportional hazards models. Results: Of 596 HER2-tested pts with adv GE cancer in CGDB, 174 (29%) were HER2+ by IHC/ISH. Median age at adv dx was 63 y; 76.5% were male and 97% had adenocarcinoma. Overall HER2:ERBB2 agreement was 91%. Of 123 HER2+ 1L T-treated pts, median TTD and OS were longer for HER2+:ERBB2+ (concordant; n = 93) v HER2+:ERBB2- pts (discordant; n = 30): TTD, 5.2 v 0.8 months, aHR 0.46 (0.29-0.70); OS 14.8 v 7.5 months, aHR 0.38 (0.21-0.68). Median OS was 22.0 vs 8.4 months for 1L T-treated pts with ERBB2 CN &gt; 30 (median) v CN ≤30 (aHR 0.69 [0.37-1.27]). Conclusions: In this large real-world clinico-genomic dataset, HER2:ERBB2 agreement was high in tested pts with adv GE cancer. 1L T-treated pts with discordant tests (HER2+:ERBB2-) had significantly shorter TTD and OS. Pts with higher ERBB2 CN had longer OS, but this finding was not significant after adjusting for covariates. Further research is needed to explore associations between HER2:ERBB2 agreement and clinical outcomes in this population.
Revisiting the value of drains after low anterior resection for rectal cancer: An analysis of 996 patients.
Authors: Rachel M. Lee, Adriana C. Gamboa, Michael K. Turgeon, Sanjana Prasad, Gifty Kwakye, Katherine Hrebinko, Jennifer Holder-Murray, Sherif Abdel-Misih, Charles Kimbrough, Mosope Soda, Alexander Hawkins, William C. Chapman, Matthew Silviera, Shishir K. Maithel, Glen C. Balch
Journal: Journal of Clinical Oncology (2020)

45 Background: Although potentially associated with increased infections, intraoperative pelvic drains are often placed during low anterior resection (LAR) to evacuate postoperative fluid collections and identify/control potential anastomotic leaks. Our aim was to assess the validity of this practice in a large dataset of patients undergoing LAR for rectal cancer. Methods: Patients from the US Rectal Cancer Consortium (2007-17) who underwent curative-intent LAR for a primary rectal cancer were included. Patients were categorized as receiving a closed suction drain intraoperatively or not. Primary outcomes were superficial surgical site infection(SSI), deep SSI, intraabdominal abscess, anastomotic leak, and need for secondary drain placement. Three subgroup analyses were conducted in patients who received neoadjuvant chemoradiation, had a diverting loop ileostomy (DLI), and had low tumors &lt;6cm from the anal verge. Results: Of 996 pts, average age was 58 yrs, 61% were male, and 67% (n=551) received a drain. Drain patients were more likely to be male (64vs54%), have a smoking history (25vs19%), have received neoadjuvant chemoradiation (73vs61%), have low tumors within 6cm of the anal verge (56vs36%), and have received a DLI (80vs71%) (all p&lt;0.05). Drains were associated with an increased anastomotic leak rate (14vs8%, p=0.041), although there was no difference in the need for a secondary drainage procedure to control the leak (82vs88%, p=0.924). These findings persisted in all subset analyses. Drains were not associated with increased superficial SSI, deep SSI, or intraabdominal abscess in the entire cohort or each subset analysis. Reoperation (12vs10%, p=0.478) and readmission rates (28vs31%, p=0.511) were similar. Conclusions: Although not associated with increased infectious complications, intraoperatively-placed pelvic drains after low anterior resection for rectal cancer are associated with an increase in anastomotic leak rate and no reduction in the need for secondary drain placement or reoperation. Routine drainage should be abandoned.