tbuckley/cabot-search huggingface dataset:
Reply: Concerns regarding the use of Fatty Liver Index in studies of lean NAFLD
Authors: Oumarou Nabi, Nathanaël Lapidus, Jerome Boursier, Victor de Ledinghen, Jean-Michel Petit, Sofiane Kab, Adeline Renuy, Marie Zins, Karine Lacombe, Lawrence Serfaty
Journal: Hepatology (2024)

We appreciate the opportunity to respond to Frhaan et al,1 and we express our gratitude for their insightful comments on our manuscript.2 Their concerns regarding the use of the Fatty Liver Index (FLI) as a diagnostic tool for NAFLD in lean individuals highlight the potential introduction of selection bias by emphasizing individuals with elevated gamma-glutamyl transferase (GGT) or triglycerides, and potentially excluding lean NAFLD with normal GGT. In this setting, our lean NAFLD population might predominantly consist of individuals with a higher degree of liver fibrosis due to elevated GGT rather than representing all lean NAFLD.3 We acknowledge the importance of this observation, which indeed requires further clarification. We conducted an in-depth analysis within our study population of NAFLD, which was defined by an FLI ≥ 60, including the 3664 lean NAFLD (body mass index < 25 kg/m2). Contrary to the notion of selection bias, we found that a significant proportion (68.91%, n = 2,525) of these lean NAFLD had normal GGT levels (≤ 55 IU/L in men, ≤45 IU/L in women). Moreover, our analysis revealed a higher prevalence of liver advanced fibrosis in the lean NAFLD subset with normal GGT compared with those with elevated GGT (4.86% vs. 2.34%, respectively, p < 0.0001). Finally, in alignment with disease severity, our data illustrated that lean NAFLD with normal GGT experienced poorer clinical outcomes as compared to non-lean NAFLD, in a similar way than in those with elevated GGT. In this setting, the risks (HR) of hepatic events and overall mortality were 4.50 (95% CI 3.28–6.16) vs. 2.77 (95% CI 1.45–5.29) and 2.75 (95% CI 2.13–3.54) vs. 2.49 (95% CI 1.58–3.93), respectively. Building upon existing literature, we explored the role of waist circumference, which is part of the calculation of FLI and a better reflection of visceral adipose tissue than body mass index, as a predictor of liver steatosis and fibrosis, as demonstrated in prior studies.4 Notably, in our study population, we observed that lean NAFLD with normal GGT exhibited a significantly higher waist circumference (81.1 vs. 76.8, p < 0.00001) compared to those with elevated GGT. Moreover, the severity of fibrosis demonstrated a positive correlation with waist circumference (data not shown). In summary, we believe our study population is representative of lean individuals with NAFLD and that FLI through waist circumference rather than GGT is associated with the severity of fibrosis in lean individuals. We remain committed to ongoing research and discussions that contribute to better understand the physiopathology of steatotic liver disease in this specific population.
Impact of Canagliflozin on Kidney and Cardiovascular Outcomes by Type 2 Diabetes Duration: A Pooled Analysis of the CANVAS Program and CREDENCE Trials
Authors: Sheldon W. Tobe, Thomas A. Mavrakanas, Harpreet S. Bajaj, Adeera Levin, Navdeep Tangri, April Slee, Brendon L. Neuen, Vlado Perkovic, Kenneth W. Mahaffey, Wally Rapattoni, Fernando G. Ang
Journal: Diabetes Care (2024)

OBJECTIVE The study was undertaken because it was unknown whether the duration of type 2 diabetes modifies the effects of sodium–glucose cotransporter 2 inhibitor canagliflozin on cardiovascular (CV) and kidney outcomes. RESEARCH DESIGN AND METHODS This post hoc analysis of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program (N = 10,142) and Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial (N = 4,401) evaluated hazard ratios and 95% CIs using Cox proportional hazards for the effects of canagliflozin on CV and kidney outcomes, including progression and regression of albuminuria over 5-year intervals of disease duration. RESULTS Canagliflozin had ranges of benefit across intervals of diabetes duration, with no heterogeneity for major adverse CV events, CV death or heart failure hospitalization, and kidney failure requiring therapy or doubling serum creatinine. Furthermore, canagliflozin reduced albuminuria progression and increased albuminuria regression with no interaction across all diabetes duration subgroups. CONCLUSIONS Our findings suggest that earlier treatment with canagliflozin confers consistent cardiorenal benefits to individuals with type 2 diabetes.
Lenvatinib plus hepatic arterial infusion chemotherapy with cisplatin for advanced hepatocellular carcinoma.
Authors: Makoto Yamamoto, Takeshi Terashima, Tatsuya Yamashita, Masahiro Yanagi, Hidetoshi Nakagawa, Akihiro Seki, Kouki Nio, Kuniaki Arai, Tadashi Toyama, Taro Yamashita
Journal: Journal of Clinical Oncology (2024)

496 Background: A recent phase II study demonstrated that combination therapy with lenvatinib and hepatic arterial infusion chemotherapy using cisplatin (Lenva+CDDP) had high anti-tumor effects for patients with advanced hepatocellular carcinoma (HCC) with no prior history of systemic chemotherapy; however, whether the efficacy of Lenva+CDDP is superior to lenvatinib monotherapy remains unclear. Methods: We retrospectively reviewed the medical records of patients with advanced HCC and a Child–Pugh score of 5, 6, or 7 who were treated with Lenva+CDDP or lenvatinib, and compared the efficacy between the treatments. Patients in both groups received a once daily dose of lenvatinib (8 mg or 12 mg according to their weight), and the Lenva+CDDP group also received 65 mg/m 2 of CDDP via the hepatic artery every 4 weeks. Treatment was repeated until tumor progression or unacceptable toxicity were observed. Results: A total of 140 patients (40 in the Lenva+CDDP group and 100 in the lenvatinib group) were included in this analysis. Patient backgrounds were comparable between the two groups, and 12 and 19 patients were previously treated with immunotherapy in the Lenva+CDDP group and lenvatinib group, respectively. The objective response rate and tumor control rate, assessed by RECIST ver1.1, in the Lenva+CDDP group were 67.5% and 100%, respectively, which was higher than in the lenvatinib group (17.0% and 87.0%, respectively). Median progression-free survival (PFS) and overall survival (OS) were 8.8 months and 19.6 months, respectively, in the Lenva+CDDP group, and 5.6 months and 20.3 months, respectively, in the lenvatinib group. Among patients who previously received immunotherapy, the median PFS, median OS, and 1-year survival rate were 9.7 months, not reached, and 87.5%, respectively, in the Lenva+CDDP group, and 4.7 months, 15.8 months, and 64.7%, respectively, in the lenvatinib group. Hematological toxicities were the main grade 3–4 adverse events (AEs) more frequently observed in the Lenva+CDDP group compared with the lenvatinib group. However, all grade 3–4 AEs were reversible, and there were no treatment-related deaths in either group. Conclusions: Lenva+CDDP demonstrated a better response and patient outcome than lenvatinib, and was well-tolerated in patients with advanced HCC. We are currently conducting a randomized controlled trial comparing the efficacy of these treatments.
Clinical outcomes of primary esophagectomy and secondary esophagectomy after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma: A propensity-score matched analysis.
Authors: Minjee Kim, Tae Jun Kim, Hyuk Lee, Byung-Hoon Min, Jun Haeng Lee, Poong-Lyul Rhee, Jae J. Kim, Yang Won Min
Journal: Journal of Clinical Oncology (2024)

307 Background: Currently it is unknown whether secondary esophagectomy after endoscopic submucosal dissection (ESD) is comparable to primary esophagectomy considering outcomes in patients with T1 esophageal cancer. We compared short- and long- term clinical outcomes between the two groups. Methods: Primary surgery (esophagectomy) was performed in 191 patients between 2003 and 2014, and 62 patients underwent secondary surgery (esophagectomy) after ESD for T1 esophageal cancer between 2007 and 2019. Propensity matching was performed for age, sex, Charlson Comorbidity Index (CCI), location, pathology, degree of differentiation, tumor size, and invasion depth. Lymph node metastasis (LNM), overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and postoperative complications were compared between groups. Results: Sixty-eight patients were included after propensity score matching, LNM, OS, DSS, and RFS were comparable between the two groups. Comparing primary and secondary surgery, the respective LNM rates were 23.5% and 26.5%, 6-year OS 78.0% and 89.7%, P= 0.15; DSS were 80.4% and 96.8%, P= .057; and RFS 80.8% and 89.7%, P= .069. Multivariate analyses revealed no statistically significant differences between among LNM, OS, and RFS rates. Comparing the adverse events between the two groups, more early complications were observed in the primary surgery group than in secondary surgery group (50% vs. 20.6%, P = .021). Conclusions: Secondary surgery did not increase the risk of LNM. The long-term outcomes were comparable. Therefore, attempts to perform upfront ESD for superficial esophageal squamous cell cancers are justified.
Factors associated with the receipt of surgery in acinar cell carcinoma of the pancreas.
Authors: Jasleen Kaur Chaddha, Christopher Reese Bine, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2024)

668 Background: Acinar cell carcinoma of the pancreas (PACC) accounts for 1-2% of adult pancreatic tumors. Clinically, this malignancy presents as a hypersecretory syndrome as lipase is released into circulation. Median overall survival is 18 to 47 months. Aggressive surgical resection is associated with long-term survival in PACC patients. This appears to be the treatment of choice for most localized pancreatic cancers, however, there are no clear treatment guidelines or standardized protocols for PACC due to its rarity. Further, no significant study has analyzed the factors correlated with receiving this surgery. This study aims to uncover the possible factors associated with the receipt of tumor resection in patients with PACC. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with PACC from 2004 to 2019 using the histology code 8550 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Multilevel Logistic Regression were performed, and data were analyzed using SPSS version 29. Statistical significance was set at α = 0.05. Results: 1430 patients with PACC were queried. 600 (41.95%) patients received surgical resection. Surgical patients experienced longer overall survival than non-surgical patients (87.5 months vs. 25.3 months, P &lt; 0.01). Of the surgical patients, wider surgical margins and complete tumor resection were associated with improved survival (P&lt;0.001). Stage I and II disease, well and moderately differentiated disease, and receiving treatment at an academic/research facility were associated with an increased likelihood of receiving surgery (P&lt;0.001). Metastasis at the time of diagnosis was associated with a decreased likelihood of receiving surgery (P&lt;0.001). Income status, race, insurance status, and age did not appear to be significant predicting factors of surgery. Of the initial sample, 219 (15.31%) patients received adjuvant chemotherapy, 8 (0.55%) patients received adjuvant radiation, and 4 (0.28%) patients received both adjuvant chemotherapy and radiation. Adjuvant therapies did not appear to impact the overall survival of PACC patients. Conclusions: This study confirms that tumor resection is associated with increased survival in patients with PACC. Improved survival with surgery is correlated to wider surgical margins and complete tumor resection. It appears that patients with well or moderately differentiated disease, stage I or II disease, and treatment at an academic/research facility are more likely to receive surgery. PACC patients with metastasis to distant sites are less likely to receive surgery. The efficacy of adjuvant therapy remains unclear. Further studies are needed to better understand the factors involved in receiving surgery and other treatment modalities as part of PACC treatment.
The role of exosomal LINC00853 in gastric cancer progression.
Authors: Sang Kil Lee
Journal: Journal of Clinical Oncology (2024)

378 Background: Examination of various substances contained in exosomes (EXOs) as biomarkers is being actively conducted. Long non-coding RNAs (lncRNAs) are garnering interest in the diagnosis of gastric cancer. In this experiment, we attempted to obtain lncRNAs that drive the onset and recurrence of gastric cancer and elucidate the mechanism to observe their potential as exosomal biomarkers. Methods: LncRNA expression profiling was conducted using ArrayStar Human LncRNA array 2.0 for the patient’s tissues who underwent endoscopic resection that reflected early gastric cancer onset and recurrence. The proliferation, apoptosis, invasion, and migration of AGS and MKN74 cells were measured after treatment with pcDNA over expressing vector and two different siRNAs. To observe the interaction between lncRNA and MAP17, RNA immunoprecipitation (IP) and electrophoretic mobility shift assay were conducted. EXOs were extracted from patient samples and gastric cancer cell lines, which were then administered to gastric cancer cells. Results: Five target lncRNAs (LINC00853, LINC00634, LINC01535, GAPLINC, and AC017002.1) were selected by performing a lncRNA microarray analysis. The validation results showed that LINC00853 was upregulated in gastric cancer tissues compared to that in paired adjacent non-cancer tissues. LINC00853 induced proliferation and suppressed apoptotic signaling of AGS and MKN74 cells. LINC00853 promoted the invasion and migration of AGS and MKN74 cells. LINC00853 bound with its neighbor gene MAP-17 and activated it via the downstream PDZK1/AKT signaling pathway. LINC00853 and MAP-17 cooperatively acted as oncogenes in gastric cancer. EXOs derived from patients with gastric cancer and those from gastric cancer cell lines (AGS, MKN74) contained LINC00853. Knock-down of LINC00853 decreased LINC00853 expression in EXOs, which, in turn, reduced the oncogenicity of LINC00853 exosome in AGS cells. Cellular and exosomal LINC00853 exert an oncogenic effect via MAP-17-related cell signaling in gastric cancer. Conclusions: Exosomal LINC00853 can be a candidate biomarker of occurrence of recurrence of gastric cancer.
Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4 year (yr) follow-up of CheckMate 649.
Authors: Kohei Shitara, Markus H. Moehler, Jaffer A. Ajani, Lin Shen, Marcelo Garrido, Carlos Gallardo, Lucjan S. Wyrwicz, Kensei Yamaguchi, James M. Cleary, Elena Elimova, Ricardo Elias Bruges Maya, Michalis Karamouzis, Tomasz Skoczylas, Arinilda Bragagnoli, Tianshu Liu, Mustapha Tehfe, Kynan Feeney, Rui Wang, Raheel Nathani, Yelena Y. Janjigian
Journal: Journal of Clinical Oncology (2024)

306 Background: NIVO + chemo demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit vs chemo and an acceptable safety profile in previously untreated, advanced non-HER2+ GC/GEJC/EAC, leading to approvals in many countries. NIVO + chemo continued to demonstrate clinically meaningful improvement in efficacy at 2 and 3-yr follow-ups. We present 4-yr follow-up results for NIVO + chemo vs chemo from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. HER2+ patients (pts) were excluded. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 1581 pts were randomized to NIVO + chemo or chemo. At the 48-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table) OS benefit with NIVO + chemo was observed in most prespecified subgroups. Objective response rates (ORR) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). In the exploratory analysis of OS by response at the 18-week landmark timepoint, there were numerically more pts achieving response with NIVO + chemo vs chemo, and median OS (95% CI) with NIVO + chemo was numerically longer in responders vs non-responders both in pts with PD-L1 CPS ≥ 5 (20.5 [17.5–25.0] vs 14.0 [11.6–15.7]) and all randomized pts (19.4 [17.5–21.7] vs 13.1 [11.6–14.4]). No new safety signals were identified, consistent with the 3-yr follow-up. Conclusions: NIVO + chemo is the first PD-1 inhibitor/chemo combination to demonstrate long-term efficacy and acceptable safety after 4 yrs of follow up in previously untreated advanced GC/GEJC/EAC. These results are consistent with earlier follow-ups, further supporting NIVO + chemo as a standard 1L treatment in these pts. Clinical trial information: NCT02872116 .[Table: see text]
Paclitaxel protein bound (A) plus gemcitabine (G) plus cisplatin (C) and hydroxychloroquine (HCQ) neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC).
Authors: Erkut Hasan Borazanci, Gayle S. Jameson, Courtney Edwards Snyder, Amar Thosani, Steven Sckolnik, Ronald Lee Korn, Syed Rahmanuddin, Dan Mocan, Shelby Pearse, Michael S. Gordon, Daniel D. Von Hoff, Aryan Modasi, Albert Amini
Journal: Journal of Clinical Oncology (2024)

667 Background: Neoadjuvant therapy has become the consensus treatment for individuals with locally advanced (LA) and borderline resectable (BR) PDAC. Neoadjuvant therapy for resectable (R) PDAC has been in greater use due to concerns over micro metastases at diagnosis. Typical therapies involve the use of multiagent systemic chemotherapy with or without radiation therapy. In retrospective studies, Cancer Antigen 19-9 (CA 19-9) normalization in borderline resectable (BR) and locally advanced (LA) PDAC has been associated with greater OS. The addition of cisplatin (C) to gemcitabine (G) and paclitaxel protein bound (A), has shown promising clinical data in a previously reported study in advanced PDAC [JAMA Oncol. 2020;6(1):125-132]. HCQ has been shown to target autophagy in PDAC and has demonstrated higher response in combination with GA. We conducted a prospective, phase 2 clinical trial of patients with R, BR, and LA PDAC utilizing a regimen combining A + G + C + HCQ with the primary endpoint of CA 19-9 normalization (NCT04669197). Methods: Eligibility criteria include patients with histologically confirmed R, BR, or LA PDAC, elevated CA 19-9, and a KPS ≥ 70% with normal end organ function. Doses are A 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2 on days 1, 8 of a 21-day cycle (IV) along with HCQ 600 mg po bid. Primary objective is to evaluate CA 19-9 normalization with the neoadjuvant chemotherapy. Secondary objectives are to assess R0 rate, pathologic complete response (pCR), safety and tolerability, radiologic response rate (by RECIST 1.1), and 2 year overall survival (OS) from date of study entry. Exploratory objectives include evaluating imaging biomarkers and vascular involvement by tumor in relation to therapy. Results: To date all planned 12 patients have been enrolled, 11 evaluable. 8 male, 4 female; age range 50 to 76 yo. Patient classifications is 3 R; 4 BR; 5 LAPC. Most common drug related grade (gr) 3-4 adverse events (AEs) are: thrombocytopenia gr 3 27%, gr 4 27%, anemia gr 3 36%, and neuropath gr 3 36%. CA 19-9 normalization occurred in 36% (4/11) who have completed at least 1 cycle of treatment. To date, 3 individuals went to surgery, with 3 achieving R0. Overall response rate in measurable patients is 45% (1CR, 4 PR). Median OS and 2-year survival data are not yet matured. Conclusions: In patients with non-metastatic PDAC, the use of A+G+C+HCQ resulted in a CA 19-9 normalization rate in 36% of individuals. Most patients did not go to surgery. The OS data is maturing. Supported by grants from the HonorHealth Foundation and Marley Foundation. Clinical trial information: NCT04669197 .
A novel classification of small bowel adenocarcinoma based on a hidden genome classifier: A multi-institutional study.
Authors: Lauren E. Schleimer, Cecilia Grace Ethun, Colin Court, Joanne F. Chou, Sarah Margaret Helena McIntyre, Henry S. Walch, Carlie S. Sigel, Jeremy Sharib, Sabran Masoud, Wei Chen, Victoria Aveson, Huamin Wang, Matthew H. G. Katz, Michael J. Overman, Michael Lidsky, Shishir K. Maithel, George A. Poultsides, Ryan Fields, Mithat Gonen, William R. Jarnagin
Journal: Journal of Clinical Oncology (2024)

724 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy with poor prognosis. Data describing the clinical and pathologic characteristics of this disease are sparse, and few studies examine the genetic footprint of SBAs within the continuum of the gastrointestinal tract. Methods: All patients with small bowel adenocarcinoma for whom primary tumor tissue was available from 1993 to 2021 at six institutions were included. A hidden genome classifier (HGC) was developed based on genomic features from 286 gastroesophageal cancers (foregut) and 286 colorectal cancers (hindgut) using targeted tumor sequencing. The SBA samples were run through the HGC to obtain the predicted probability of either foregut or hindgut lineage. For patients submitted to curative intent resection, overall survival (OS) was calculated from 90 days post resection until date of last follow up. Cox regression was used to examine factors associated with OS and to construct the multivariable model. Results: Of a total of 243 patients with SBA, 60% were male. The most common anatomic locations were duodenum (53%), jejunum (28%), and ileum (12%). HGC prediction of foregut lineage was higher for duodenal (55%) and intestinal-type periampullary (64%) tumors, while prediction of hindgut lineage was higher for ileal (68%) and jejunal (54%) tumors. Patients were then divided into three HGC prediction groups based on the lowest-, highest-, and inter-quartile ranges: foregut (n=61), characterized by gene amplification of CDK12, CD3, EGFR, and KRAS and cytoband segmentation of chromosomes 8-p21.1 and 15-q26.3; hindgut (n=61), characterized by APC and KRAS mutations; and mixed-type (n=121) with elements of both. Among those undergoing curative-intent surgery (n=160), median OS was 73 months. On multivariable analysis, HGC prediction group (hindgut vs mixed-type, HR 3.22, 95%CI 1.54-6.73), age (HR 1.03, 95%CI 1.01-1.05) and positive lymph node status (HR 1.96, 95%CI 1.02-3.76) were associated with decreased survival (Table). Neither anatomic site nor the presence of other driver mutations was associated with survival. Conclusions: Small bowel adenocarcinomas display genomic heterogeneity. A novel hidden genome classifier that stratifies SBAs based on homology to foregut or hindgut genomic alterations may be superior to anatomic location for characterizing disease biology. Additional studies are needed to validate and further explore these findings. [Table: see text]