tbuckley/cabot-search huggingface dataset:
Improving outcomes in high-grade goblet cell adenocarcinomas: The interplay of complete cytoreduction, HIPEC and fibrosis.
Authors: Panagiota Chrysovalanto Koukoutsidi, Francis W. Nugent, Thomas Schnelldorfer, Jennifer L. Sabo, Martin D. Goodman
Journal: Journal of Clinical Oncology (2024)

e16379 Background: High-grade goblet cell adenocarcinomas (GCA), including signet-ring cell type (SRC) and poorly differentiated, behave more aggressively compared to typical GCA and are associated with poor prognosis. Due to GCA’s rarity, the treatment aligns with colon cancer guidelines, including surgery, chemotherapy and/or cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for peritoneal carcinomatosis (PC). In our case series, we assessed the outcome of patients with high grade GCA tumors and PC, who underwent either CRS with HIPEC or tumor debulking. Methods: A prospectively maintained database of patients treated at the Division of Surgical Oncology for Peritoneal Carcinomatosis (PC) from 2007 to 2022 was reviewed retrospectively. Patient selection was based on the primary tumor’s original pathology report and scheduling to undergo CRS/HIPEC for PC. We calculated median overall survival from the time of diagnosed peritoneal carcinomatosis, with focus on the attainment of complete cytoreduction (CC) and HIPEC administration. Results: 385 records were screened and 21 cases of GCA were identified. Thirteen (13) patients had a diagnosis of high-grade GCA with PC. Complete cytoreduction (CC0/CC1) with HIPEC was achieved in 7/13 patients, and 6/13 patients underwent tumor debulking. The median overall survival after diagnosing peritoneal carcinomatosis was 53 months for the patients who underwent CC/HIPEC and 20 months for the patients who received debulking. Of note, in the debulking group, 5/6 patients had a poorly differentiated GCA and exhibited intraoperatively tumor characteristics of infiltration, thickening and fibrosis, confirmed by the pathology report, which rendered CC unsuccessful. In contrast, within the CC/HIPEC group, pathology reported localized fibrosis as a chemotherapy response in only 2/7 patients, which did not impede the achievement of CC. Preoperative 5-FU based chemotherapy was administered to 4/7 patients in the CC/HIPEC group and to 5/6 patients in the debulking group. Conclusions: Our results demonstrate that CC with HIPEC may improve overall survival in patients with high grade GCA with PC. Notably, poorly differentiated GCA and the presence of fibrotic tissue, stemming from the tumor and/or preoperative chemotherapy, influences CC success. Considering the potential impact of fibrosis on surgical outcomes, pathological assessment of fibrosis preoperatively and/or use of fibrosis-specific biomarkers could guide cytoreduction strategies and treatment choices in patients diagnosed with high-grade GCA.
Phase 1/2 randomized, open-label, multicenter, Simon two-stage study of pelareorep combined with modified FOLFIRINOX +/- atezolizumab in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Dirk Arnold, Houra Loghmani, Karol Cheetham, Richard Trauger, Thomas Charles Heineman
Journal: Journal of Clinical Oncology (2024)

TPS4203 Background: Immune therapies benefit only the small subset of metastatic pancreatic ductal adenocarcinoma (mPDAC) patients who have microsatellite instability-high (MSI-H) tumors (approximately 1%). Most PDAC tumors are microsatellite stable (MSS) and have an immunologically “cold” phenotype with fewer genetic mutations, reduced immune cell infiltration, and downregulated immune checkpoint proteins. These attributes make most mPDAC tumors resistant to conventional immunotherapy including checkpoint inhibitors. Pelareorep is a naturally occurring, non-genetically modified reovirus that selectively infects cancer cells following intravenous administration. Upon infection, pelareorep’s double-stranded RNA genome stimulates a pro-inflammatory response that primes tumors for immunologic killing. This includes increased T cell infiltration into tumors, expansion of tumor-infiltrating lymphocyte clones, increased PD-L1 expression, and stimulation of tumor-directed innate and adaptive immune responses. Pelareorep combined with chemotherapy, checkpoint inhibitors, or both has shown promising efficacy in several malignancies, including mPDAC. This study is designed to evaluate pelareorep plus modified FOLFIRINOX with or without the PD-L1 inhibitor atezolizumab as first-line therapy in patients with mPDAC. Methods: This trial represents a new cohort within the ongoing GOBLET signal finding platform study in gastrointestinal cancers. This is a phase 1/2 randomized, open-label study that uses a screened selection design within a Simon two-stage approach. Eligible patients must be 18 years or older and have newly diagnosed, radiologically evaluable mPDAC with no prior chemotherapy and an ECOG performance status of 0 or 1. Patients are randomized 1:1 to receive either pelareorep + mFOLFIRINOX orpelareorep + mFOLFIRINOX + atezolizumab. The first stage enrolls 15 evaluable patients into each arm. If pre-specified efficacy criteria are met in Stage 1, one or both arms may be expanded to Stage 2 and enroll 17 additional evaluable patients per arm. The first 3-6 patients enrolled into both arms comprise a safety run-in that must be successfully concluded prior to enrolling additional patients. The treatment period consists of 4-week treatment cycles. The primary objectives are 1) safety and tolerability of pelareorep + mFOLFIRINOX with or without atezolizumab and 2) efficacy based on objective response rate per RECIST v1.1. Secondary objectives include duration of response, progression-free survival, and overall survival. In addition, tumor and blood samples are being collected to evaluate the immunological effects of treatment and to explore potential biomarkers of response. Clinical trial information: Eudra-CT: 2020-003996-16.
Exploring racial disparities and tumor characteristics of CA19-9 producer and non-producer among patients with advanced pancreatic ductal adenocarcinoma (PDAC): Implications for survival and personalized treatment strategies.
Authors: Ibrahim Omore, Sonal Gandhi, Linda Wu, Deirdre J. Cohen
Journal: Journal of Clinical Oncology (2024)

e16309 Background: Despite substantial progress in cancer treatment, PDAC remains a highly lethal disease. CA19-9 plays a crucial role in PDAC diagnosis and therapeutic response assessment. We aimed to evaluate racial differences, tumor characteristics, and outcomes between CA19-9 non-producers and producers among advanced PDAC patients (pts) at an academic teaching hospital. Methods: A retrospective analysis was conducted in patients with unresectable or metastatic PDAC treated at Mount Sinai Health System between January 2012 and December 2021. Pts were categorized into two groups based on CA19-9 levels, using a threshold of 37 U/mL: CA19-9 non-producers (≤37 U/mL) and CA19-9 producers ( &gt; 37 U/mL). Demographic and clinical data were compared between the two groups, and the association between CA19-9 levels and overall survival (OS) was assessed using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Results: A total of 238 pts were included in the analysis, with a median age of 67 years and a balanced gender distribution (52% male). The cohort comprised locally advanced (29.8%) and metastatic (70.2%) cases, with a diverse ethnic composition including non-Hispanic whites (37%), non-Hispanic blacks (25%), and Hispanics (18%). Among the pts, 23.5% were CA19-9 non-producers, while 76.5% were CA19-9 producers. Significant racial differences were observed, with non-Hispanic blacks more likely to be CA19-9 non-producers compared to non-Hispanic whites ( P&lt; 0.001). However, no statistically significant differences were found in age, smoking status, tumor location, size, or site of metastasis between the two groups. Median overall survival (OS) was 13m for CA19-9 producers and 16m for non-producers, but this difference was not statistically significant in both univariate and multivariate analyses (HR 1.09, 95% CI 0.74-1.58, P = 0.66; HR 1.06, 95% CI 0.72-1.58, P 0.8). Hispanic ethnicity was correlated with improved OS (HR 0.59, 95% CI 0.36-0.95, P = 0.029), while larger tumor size predicted worse OS (HR 1.17, P &lt; 0.001). Conclusions: This study highlights racial disparities in CA19-9 production among locally advanced and metastatic PDAC patients. Despite observed differences, CA19-9 levels alone did not emerge as a statistically significant predictor of OS. Future research should delve deeper into the racial disparities observed in CA19-9 production, exploring underlying biological mechanisms and potential implications for diagnostic and therapeutic approaches as this could refine our understanding of PDAC, facilitating targeted interventions for improved patient outcomes.
Factors associated with surgical intervention in Native American patients with hepatocellular carcinoma.
Authors: Vikram Murugan, Aidan Becken, Christopher Reese Bine, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2024)

e16279 Background: Hepatocellular carcinoma (HCC) is the prevailing type of primary liver cancer, exhibited at a higher frequency in individuals afflicted by chronic liver conditions. Past literature has demonstrated the impact certain socioeconomic factors have on the prognosis of HCC. Native American patients often face late-stage cancer diagnoses and have the lowest survival rates among racial and ethnic groups. While surgery offers potential for cure, factors related to surgical interventions in liver cancer for Native American patients remain largely unexplored. Through the NCDB, this study analyzed factors associated with surgical intervention and survival trends in Native American patients with HCC. Methods: The National Cancer Database (NCDB) was used to identify Native American patients diagnosed with Hepatocellular Carcinoma from 2004 to 2019 using the histology code 8170 and race code 03 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Cox Proportional Hazards tests were performed. Data was analyzed using SPSS version 27, and statistical significance was set at α = 0.05. Results: Of 1193 Native American patients included in this sample, 172 (14.4%) patients received surgical treatment for HCC, while 1021 (85.6%) patients did not receive surgical treatment for HCC. Native American patients who received surgery for HCC experienced a greater mean overall survival (90 months) when compared to the mean overall survival (24 months) in HCC Native American patients who did not receive surgical treatments (p &lt; 0.001). When controlling for age, year of diagnosis, stage, grade, facility type and income status, receiving surgery showed an independent decrease in hazard (HR = 0.245; p &lt; 0.05). HCC Native American patients who received surgery were more likely to be treated an at academic facility, have stage I disease, and have less aggressive tumors (grade) (p &lt; 0.05). Native American patients who did not receive surgery were more likely to be older (62 vs 60 years old), have larger tumors, and have brain, bone, lung, and liver metastases (p &lt; 0.05). No associations of surgical versus non-surgical treatment were seen in Charlson-Deyo score, urban or rural residence, and primary payor at diagnosis. Conclusions: Native American patients with HCC who received surgical intervention experienced improved overall survival compared to non-surgical treatment groups. Native American patients undergoing surgical intervention more often received care at academic or private institutions and had lower stages of HCC. These results follow previous trends, where cancer patients receiving adequate surgical intervention generally survive longer. Further research is needed to examine other treatment differences among Native American patients and how these findings compare across other disadvantaged groups.
Claims-based analysis of treatment practices of patients with metastatic gastroenteropancreatic neuroendocrine tumors (mGEP-NET) in the USA.
Authors: Marianne Pavel, Ivo Abraham, Thorvardur Ragnar Halfdanarson, Nicole Princic, Dirk Bernhardt
Journal: Journal of Clinical Oncology (2024)

e16286 Background: GEP-NET is a rare disease with variable tumor biology. An indolent disease course with subtle symptoms renders timely diagnosis difficult; 2/3 of patients (pts) are diagnosed at locally advanced or metastasized stage. In clinical decision-making, disease-specific factors, patient (pt) age and long-term disease control must be balanced against the aggressiveness of therapies. NCCN, NANETS and ENETS guidelines recognize the diversity of mGEP-NET by recommending individualized treatment approaches. We aimed to describe treatment (Tx) utilization patterns in mGEP-NET. Methods: Retrospective cohort study using MarketScan® Commercial and Medicare Databases spanning 07/01/2017-01/31/2023. Eligible were GEP-NET pts with ≥1 inpatient or ≥2 outpatient claims, a subsequent new diagnosis of metastatic disease (index), no secondary malignancy, and follow-up time of ≥12 months (m) after index. Results: Of 16218 GEP-NET pts, 2002 (mean age 60y; 50% female) met inclusion criteria. Mean follow-up time after index was 17m, with 49%, 27% and 15% followed up for ≥12, 24 and 36m, resp. Medical history (12m baseline before index) included mean Charlson Comorbidity Index of 2.62, with hypertension (HTN), type 2 diabetes (T2DM), chronic liver disease (CLD), asthma/COPD, cardiovascular disease (CVD), and chronic kidney disease (CKD) present in 56, 26, 22, 18, 17 and 10% of pts, resp.; 5% had carcinoid syndrome. In total, 949 pts (47.4%) received first-line (1L) systemic Tx: somatostatin analogs (SSA; 61.6%) of either very short or long duration (median 116d vs 775d), chemotherapy (38.8%), targeted therapies (3.4%) and PRRT (0.5%). Relative to NCCN cancer surveillance guidelines, 49.5% received more and 36.8% received fewer than 4 scans in the first year of treatment. Conversely, 1053 (52.6%) did not receive any 1L systemic Tx. With the exception of CLD, pts with vs without 1L Tx had similar proportions of medical conditions during the 12m baseline and during follow-up (HTN 72.4 vs 66.5%; T2DM 34.0 vs 30.3%; asthma/COPD 16.5 vs 19.3%; CVD 27.3 vs 36.9%; CKD 18.9 vs 17.9%; however, CLD 54.0 vs 36.7%). See Table comparing both cohorts on insurance, treatments, and health care utilization during follow-up. Conclusions: This claims analysis reveals treatment differences among mGEP-NET pts that cannot be explained by the parameters assessed herein. Further research should investigate factors influencing diagnosis and treatment decision-making, applying also pt-level health record data; and analyze economic barriers to diagnosis and treatment. [Table: see text]
The relationship of preoperative frailty with short- and long-term surgical outcomes among octogenarians with hepatocellular carcinoma: A multicenter comprehensive analysis.
Authors: Yi-Fan Yang, Ping Zhang, Bo Wu, Si-Yuan Wang, Hong-Wei Guo, Qi-Xuan Zheng, Ting-Hao Chen, Jie Li, Xian-Ming Wang, Ying-Jian Liang, Hong Wang, Xiao-Chang Wu, Wei-Min Gu, Ya-Hao Zhou, Yong-Yi Zeng, Ming-Da Wang, Zhong Chen, Feng Shen, Guo-Yue Lv, Tian Yang
Journal: Journal of Clinical Oncology (2024)

e16269 Background: Hepatocellular carcinoma (HCC) management in very elderly individuals, particularly those considering hepatectomy, demands a balanced evaluation of surgical safety and survival outcomes. This multicenter study aims to elucidate the influence of preoperative frailty, as determined by the Clinical Frailty Scale (CFS), on both short-term and long-term outcomes in octogenarians undergoing hepatectomy for HCC. Methods: We conducted a retrospective analysis of a cohort of octogenarians (≥ 80 years) who underwent hepatectomy for HCC from 2010 to 2022 across 16 hepatobiliary centers. Patients were categorized into frail and non-frail groups based on their preoperative CFS scores, with a CFS score of ≥ 5 indicating frailty. We primarily focused on overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS). Secondary endpoints included perioperative outcomes such as postoperative morbidity and mortality. Results: The study encompassed 240 octogenarians, with 105 (43.8%) classified as frail. Frail patients exhibited significantly higher postoperative 30-day morbidity (61.0% vs. 43.0%, P = 0.006) and mortality at both 30-day (5.8% vs. 0.7%, P = 0.045) and 90-day (6.7% vs. 1.5%, P = 0.044) intervals compared to their non-frail counterparts. Furthermore, 5-year OS, RFS, and CSS were markedly lower in frail patients (25.1%, 15.6%, and 43.7% respectively) as opposed to non-frail patients (51.4%, 36.2%, and 66.7%; all P &lt; 0.001). Both univariable and multivariable analyses identified preoperative frailty as an independent risk factor for postoperative 30-day morbidity (OR: 2.060, 95% CI: 1.215-3.494, P = 0.007), as well as for OS (HR: 2.384, 1.682-3.380, P &lt; 0.001), RFS (HR: 2.190, 1.588-3.019, P &lt; 0.001), and CSS (HR: 2.203, 1.397-3.472, P = 0.001). Conclusions: Preoperative frailty emerges as a significant independent predictor of both short-term and long-term outcomes in octogenarians undergoing hepatectomy for HCC. Integrating frailty assessment into preoperative evaluations could substantially enhance patient selection and optimize perioperative management strategies.
Epigenetic silencing of LDHB to promote hepatocellular carcinoma by remodeling the tumor microenvironment.
Authors: Peng Zhang, Chengsheng Zhang
Journal: Journal of Clinical Oncology (2024)

e16220 Background: Hepatocellular carcinoma (HCC) is a deadly disease with limited therapeutic options. Low expression of the LDHB has been associated with poor prognosis of HCC patients, but the role and underlying mechanism remains unclear. Methods: The HCC dada from The Cancer Genome Atlas (TCGA) and GEO were obtained to analyze the LDHB expression and DNA methylation levels. Next, the correlation between LDHB and Hallmark gene sets was analyzed by GO and KEGG. RNA-seq, Western blotting, Immunohistochemistry, and Bisulfite DNA sequencing were performed to explore the relationship between DNA methylation and LDHB expression. CCK8 and colony formation assay were used to evaluate the effect of overexpression of LDHB on the proliferation of hepatocellular carcinoma cells in vitro. Finally, the role of LDHB in HCC tumor immunity was assessed in multiple mouse models in vivo. Results: Here, we found that down-regulation of LDHB was coupled with the promoter hypermethylation and knocking down the DNMT 3A restored LDHB expression levels in HCC cell lines. Bioinformatics analysis of the HCC cohort from The Cancer Genome Atlas revealed a significant positive correlation between LDHB expression and immune regulatory signaling pathways and immune cell infiltrations. Notably, HCC patients with high LDHB expression responded better to immune checkpoint inhibitors. Finally, we demonstrated that there was no difference in the tumor growth rate between the LDHB-expressing tumors and the control tumors in immunodeficient BALB/c nude mice. However, the LDHB-expressing tumors were significantly inhibited in immunocompetent C57BL/6 mice, suggesting that the host immune system was involved in the LDHB-medicated tumor suppression. Moreover, as compared with the LDHB +/+ mice, LDHB -/- mice showed promoted tumor growth in an NRAS/shp53 plasmid-induced primary liver tumor model. Conclusions: Overall, our findings indicate that DNMT3A-mediated epigenetic silencing of LDHB may contribute to HCC progression through remodeling the tumor immune microenvironment, and LDHB may become a potential prognostic biomarker and target for HCC immunotherapy.
Preoperative BMI and long-term survival in NAFLD-associated hepatocellular carcinoma: A multicenter study revealing a paradox.
Authors: Wei Zhang, Zi-Qiang Li, Yong-Kang Diao, Xing-Kai Liu, Hong-Wei Guo, Xiao-Chang Wu, Hong Wang, Si-Yuan Wang, Ya-Hao Zhou, Jun Lu, Wei-Min Gu, Ting-Hao Chen, Jie Li, Ying-Jian Liang, Ming-Da Wang, Zhong Chen, Guo-Yue Lv, Tian Yang
Journal: Journal of Clinical Oncology (2024)

e16262 Background: As non-alcoholic fatty liver disease (NAFLD) emerges as a key factor in hepatocellular carcinoma (HCC) development, exacerbated by the global obesity epidemic, the prognostic role of body mass index (BMI) in NAFLD-HCC patients undergoing surgical resection remains unclear. This study aims to elucidate the impact of preoperative BMI on long-term outcomes after hepatectomy in patients with NAFLD-HCC, offering insights for more personalized treatment strategies. Methods: In this multicenter retrospective study, patients with early-stage (BCLC stage 0/A) NAFLD-HCC who underwent curative hepatectomy between 2009 and 2022 were analyzed. Based on preoperative BMI, patients were classified into lean ( &lt; 23.0 kg/m 2 ), overweight (23.0-27.4 kg/m 2 ), and obese (≥ 27.5 kg/m 2 ) categories. The primary endpoints, overall survival (OS) and recurrence-free survival (RFS), were compared across these BMI groups. Results: This large multicenter cohort comprised 309 early-stage NAFLD-HCC patients: 66 lean, 176 overweight, and 67 obese. Liver-, tumor-, and surgery-related characteristics were similar across groups. Lean patients exhibited significantly lower 5-year OS and RFS (55.4% and 35.1%, respectively) compared to overweight patients (71.3% and 55.6%, P = 0.017 and P = 0.002), with outcomes comparable to obese patients (48.5% and 38.2%, P = 0.939 and P = 0.442). Multivariable Cox-regression analysis revealed lean BMI, but not obese BMI, as an independent predictor of decreased OS (HR: 1.69; 95%CI: 1.06-2.71; P = 0.029) and RFS (HR: 1.72; 95% CI: 1.17-2.52; P = 0.006). Conclusions: This study challenges conventional perceptions of BMI in cancer prognosis, revealing that lean NAFLD-HCC patients have poorer long-term surgical outcomes compared to their overweight and obese counterparts. These findings underscore the need for a nuanced understanding of BMI’s role in NAFLD-HCC management and prompt further investigation into the underlying biological mechanisms of this paradox.