tbuckley/cabot-search huggingface dataset:
A comparative study of double track anastomosis and tubular esophagogastric anastomosis in laparoscopic radical proximal gastrectomy for upper gastric carcinoma.
Authors: Meng Wei, Wenbin Yu, Zepeng Yan
Journal: Journal of Clinical Oncology (2024)

e16117 Background: For the upper gastric cancer, especially adenocarcinoma at the esophagogastric junction, the optimal surgical method is still controversial. The purpose of the study is to evaluate the safety and clinical effect of double track (DT) anastomosis in laparoscopic radical proximal gastrectomy (LRPG). Methods: A retrospective analysis was conducted involving 243 patients who underwent LRPG in the Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University from Jan. 2017 to Dec. 2020. Patients were divided into tubular esophagogastric (TG) anastomosis group and double track (DT) anastomosis group, according to the digestive tract reconstruction. Their intraoperative conditions, perioperative recovery and postoperative follow-up were compared. Patients were divided into ≥60 and &lt; 60 groups according to age, to analysis the pros and cons of the two surgical methods in different age groups. According to whether or not indocyanine green (ICG) tracer technology was used during the operation, DT group was also divided into ICG group and non-ICG group. Results: Compared with the TG group, the DT group had less volume of gastric tube drainage, shorter gastric tube drainage time and proton pump inhibitors application time, and lower reuse rate of proton pump inhibitors. However, the DT group had more total operation time and lymph node dissection time. The median follow-up time of the patients was 36.0 months. At the end of study, the 1-year OS rate and DFS rate were 94.2% and 92.6% in the TG group and 95.8% and 93.7% in the DT group. The 3-year OS rate and DFS rate were 90.2% and 85.2% in the TG group and 91.9% and 87.7% in the DT group. And there was no significant difference in survival outcomes between the two groups. The DT group had a lower anastomotic stenosis at 3rd month after surgery. Moreover, the incidence of reflux esophagitis and Gerd Q score in the DT group were lower compared with the TG group at 3rd month, 1st year and 3rd year after surgery. In addition, elderly patients had a higher incidence of short-term complications in DT group compared with TG group. In the ICG analysis, the ICG DT group had significantly shorter total operation time and lymph node dissection time, less intraoperative blood loss and more lymph nodes obtained compared with the non-ICG DT group. Conclusions: DT anastomosis is a safe and effective way in LRPG for upper gastric carcinoma. Although the operation time of it is longer than that of TG anastomosis, it has a better anti-reflux effect and reduces the incidence of dysphagia and anastomotic stenosis. In elderly patients, it is important to minimize operative time and better to use TG anastomosis. The application of ICG tracer technique in LRPG has positive significance.
Clinical validation of Northstar response: A novel methylated ctDNA therapy response monitoring assay in patients with advanced gastrointestinal cancers.
Authors: Ilyas Sahin, Doga Kahramangil, George P. Kim, Sherise C. Rogers, Brian Hemendra Ramnaraign, Pravalika Manda, Matthew Gordon Varga, Gary A. Palmer, Patrick Peiyong Ye, Thomas J. George
Journal: Journal of Clinical Oncology (2024)

e16000 Background: Circulating tumor DNA (ctDNA) offers a non-invasive method to comprehensively assess tumors. While most assays for therapy response monitoring rely on variant allele frequencies, methylated ctDNA has shown promise. However, accuracy has been limited by quantification precision. The CLIA-approved Northstar Response assay quantifies over 550 hyper-methylated loci and has demonstrated a 10-fold increase in detection signal over tissue-informed assays. Methods: We present an interim analysis from an ongoing prospective, observational study designed to assess the clinical validity of Northstar Response as a tool to monitor therapeutic response without prior tumor tissue. Our study aims to include 100 advanced GI cancer patients undergoing systemic therapies for advanced disease. Serial ctDNA measurements are collected at baseline, approximately every 30 days post-treatment initiation, and with imaging assessments. The primary endpoint is concordance between ctDNA and RECISTv1.1 criteria for disease response until progression or death. Results: Baseline ctDNA characteristics were examined from 44 patients, with 23 undergoing at least two longitudinal blood collections and subsequent imaging. The median age in this cohort was 65.5 years, with a male predominance (70.5%) and a majority identifying as White (79.5%). Cancers included esophageal (18.2%), hepatocellular (29.5%), biliary (15.9%) and colorectal (15.9%), among others. A majority (59.1%) had both primary and metastatic lesions. Baseline methylation scores ranged from 280 in biliary cancers to 100,000 in colorectal cancers. Those on second-line treatments had lower scores than first or third-line therapies. Methylation scores decreased in patients responding to treatment, indicating that these scores have the potential to serve as indicators of therapeutic efficacy. Conclusions: Baseline methylation scores differ across GI tumor types, disease burdens, and treatment lines, reflecting the complexity of using methylation as a biomarker. Northstar Response has shown initial promise in monitoring therapy response in GI cancers. More mature data, which will further elucidate the assay's clinical utility, will be presented at the meeting.
High versus standard radiation dose of definitive chemoradiotherapy combined with immunotherapy for inoperable esophageal squamous cell carcinoma: A multicenter propensity score matching analysis.
Authors: Baoqing Chen, Biqi Chen, Hao Zhang, Bingyi Wang, Qi Cheng, Wenyan Chen, Xingyuan Cheng, Peiying Cen, Shiliang Liu, Mian Xi, Qiaoqiao Li
Journal: Journal of Clinical Oncology (2024)

e16118 Background: There is no consensus of the radiation dose for esophageal squamous cell carcinoma (ESCC) in the setting of definitive chemoradiotherapy (dCRT) combined with immunotherapy. This study aimed to compare the efficacy and safety of high-dose (HD) versus standard-dose radiotherapy (SD) for locally inoperable ESCC. Methods: Patients with locally advanced unresectable ESCC or advanced ESCC with supraclavicular lymph node metastases only who received high-dose (≥ 60Gy) or standard-dose (50-50.4Gy) radiation in dCRT combined with anti-PD-1 antibody as the first-line treatment from four academic cancer centers were enrolled. Propensity score matching (PSM) was conducted to minimize the potential confounding effects. Results: Between March 2019 and July 2022, 328 patients were enrolled from four cancer centers in China, with 163 patients in the HD and 165 patients in the SD groups, respectively. The median follow-up time in the HD and SD groups were 28.9 and 25.9 months, respectively. There was no significant difference in overall survival (OS) (median OS: not reached in both, P = 0.080), progression-free survival (PFS) (median PFS: not reached vs. 30.3 months, P = 0.073), locoregional progression-free survival (LRPFS) and distant metastasis survival (DM) between the HD and SD groups. After 1:2 PSM, 156 patients in the HD and 78 patients in the SD groups were selected for further analyses. The results remained consistent and showed that the HD group had no significant benefits in OS (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.50-1.51, P = 0.624), PFS (HR = 0.79, 95%CI = 0.51-1.23, P = 0.300), LRPFS (HR = 0.75, 95%CI = 0.47-1.19, P = 0.228) and DM (HR = 1.05, 95%CI = 0.64-1.73, P = 0.849), compared with the SD group. In terms of failure patterns, the incidences of locoregional failure only (13.5% vs. 16.7%, P = 0.512), distant failure only (10.9% vs. 9.0%, P = 0.648) and synchronous locoregional and distant failure (2.6% vs. 6.4%, P = 0.164) were similar between two groups. No significant difference was found in the incidences of hematological toxicities, esophagitis, pneumonia (12.2% vs. 10.3%, P = 0.664) and fistula (7.1% vs 9.0%, P = 0.603) between the HD and SD groups. Conclusions: Compared with a radiation dose of 50-50.4Gy, the increase in radiation dose (≥60Gy) did not result in survival benefits for inoperable ESCC patients receiving dCRT combined with immunotherapy. Furthermore, similar failure patterns and toxicities were observed between the two treatment groups.
Modifying the gastric tumor microenvironment with tadalafil: A transcriptomic analysis of immune signatures from underserved patients of southern Arizona.
Authors: Junaid Arshad, Lin Ding, Aaron J. Scott, Palash Mallick, Rachna T. Shroff, Juanita L Merchant
Journal: Journal of Clinical Oncology (2024)

e16104 Background: Gastric adenocarcinoma (GAC) is the fifth most common cancer worldwide with significant morbidity and mortality. Recently, southern Arizona has seen a concerning surge in incidence of GAC due to ineffective H. pylori screening and treatment. Moreover, peri-operative chemotherapy treatment in stage IB-III GAC represents an area of unmet need for new targets. Our center serves a catchment area that is 40% Hispanic and sees a high volume of GAC patients, making this our research focus. Our preclinical work in Helicobacter infected mice showed a subset of myeloid derived suppressor cells (MDSCs) expressing Schlafen4 (SLFN4) concurrently with gastric metaplasia, a GAC precursor. SLFN4 + MDSCs exhibit robust transcriptional signatures associated with type I interferon(IFN-I) inducible genes, coupled with T cell suppressor function. Pharmacological inhibition via phosphodiesterase (PDE) 5,6 inhibitor sildenafil resulted in the suppression of SLFN4, reversal of T cell suppression, and mitigation of metaplasia. This is the first clinical study aimed to characterize SLFN12L, the human ortholog of mouse SLFN4, and to analyze the neoplastic and immune signatures in GAC before and after PDE5 inhibition with tadalafil. Methods: Using single-cell RNA sequencing, we examined tissues from GAC patients enrolled in a "Window of Opportunity" study (NCT05709574). The patients receive tadalafil (20mg) for 14 days, followed by combined tadalafil and FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) for 8 weeks. Gastric tissue and blood samples were collected i) before treatment, ii) after 14 days of tadalafil, and iii) after 8 weeks of combined treatment. We have enrolled 3 Hispanic patients to date with ongoing enrollment. Results: Tumors exhibited responses as per radiologic and pathologic criteria. In contrast to SLFN4, primarily expressed in myeloid cells, SLFN12L was found in most CD14 + T lymphocytes and natural killer cells. A prominently activated and expanded myeloid population expressing SLFN12L was identified in the gastric mucosa of GAC patients. These cells exhibited transcriptional signatures associated with IFN-I signaling and immunosuppressive activities, diminishing after tadalafil treatment. Within GAC tissue, a notable increase in exhausted T cells and regulatory T cells was observed, decreasing after tadalafil. Post-tadalafil testing showed tissue PDE5/6 inhibition and higher plasma cGMP. Effector T cells exhibited an upward trend following tadalafil, suggesting a reduction in tumor immunosuppression. Conclusions: Preliminary data of this ongoing study show that tadalafil treatment combined with FLOT, has the potential to decrease SLFN12L + MDSC, to attenuate their immunosuppression, and potentially inhibit tumor progression. The trial is active and further analysis will be presented in due course.
Safety and efficacy of intensified preoperative management of locally advanced gastrorsophageal junction cancer (INPROVE).
Authors: Sara Torresan, Martina Bortolot, Marco de Scordilli, Roberto Innocente, Arianna Fumagalli, Luisa Foltran, Michela Guardascione, Paola Di Nardo, Elena Ongaro, Claudia Noto, Simone Rota, Brenno Pastò, Renato Cannizzaro, Federico Navarria, Massimo Vecchiato, Paolo Ubiali, Claudio Belluco, Roberto Petri, Alessandra Guglielmi, Fabio Puglisi
Journal: Journal of Clinical Oncology (2024)

e16110 Background: The optimal management of locally advanced gastroesophageal junction adenocarcinoma (LAGEJad) is not fully established yet. Both neoadjuvant chemoradiotherapy (CRT) and perioperative taxane-based triplet chemotherapy (CT) are acknowledged treatment options for Siewert I and II cancers. In this retrospective study, we aimed to assess the safety and outcomes of an intensified preoperative regimen combining taxane-based triplet CT and CRT. Methods: We conducted a retrospective analysis of a cohort comprising 16 consecutive HER2 negative patients (pts) with LAGEJad treated at the Centro di Riferimento Oncologico of Aviano between 2019 and 2022. All pts received induction CT (iCT) consisting of fluoropyrimidine, oxaliplatin and docetaxel, followed by CRT (45Gy/25Fr) with simultaneous boost and concomitant CT. Surgery (Ivor-Lewis or McKeown) was performed 8 weeks post-CRT. Clinico-pathological (CP) and treatment features were analyzed using logistic regression to assess their association with response to iCT-CRT. The association of iCT-CRT with survival outcomes was investigated using the Kaplan-Meier method. Results: Key CP data are summarized in Table 1. Median age was 59 years, all pts were male. At diagnosis, 81.2% of pts exhibited cT3+ and cN+ disease. All pts received iCT and CRT. The rate of partial responses was 50% after iCT and 68.8% after CRT. Overall, 12 pts underwent surgery, all achieving R0 resections within a median timeframe of 9 [8.5;11] weeks post-CRT. Among them, 25% had a pathologic complete response, while 62.5% attained a Mandard tumor regression grade (TRG) of 1-2. No new safety signals emerged from iCT (only 2 pts had ≥G3 diarrhea) or CRT (≥G3 mucositis occurred in 6.2% and anemia in 6.2% of pts). No significant surgical delays were observed, although 5 pts experienced post-operative complications (4 grade I, 1 grade IIa). There were no statistically significant associations between CP variables and response to the iCT-CRT. Relapses were seen in 8 pts (2 locoregionally); 3-year survival was 46%. Median event-free survival was 5 [5;11] months, while median overall survival 34 [14;NR] months. Conclusions: The intensification of preoperative treatment in pts with LAGEJad is active and safe: the surgical schedule was not significantly delayed, and the safety profile remained comparable to standard regimens, with no major complications reported. Randomized clinical trials are ongoing to assess the clinical benefits of this approach. [Table: see text]
Short term outcomes of robotic assisted minimally invasive oesophagectomy: A single institutional experience.
Authors: Raj Prakash Chandramohan, Ashwani Sharma, Surender Kumar Dabas, Sandeep Kumar Mohan, Sourabh Mukharjee
Journal: Journal of Clinical Oncology (2024)

e16112 Background: With the aim to decrease the rate of pulmonary complications associated with thoracotomy, minimally invasive esophagectomy (MIE) was introduced. Our purpose is to see the feasibility, safety and short-term outcomes of Robot-Assisted MIE (RAMIE). Methods: Seventy-three patients of carcinoma oesophagus who underwent Robotic Esophagectomy from May 2018 to March 2023 were included. Demographic profiles, neoadjuvant therapy, and operative and postoperative outcomes were evaluated. Results: Fifty-three patients were male while 29 were female, with median age of 60 years. Four patients had a previous history of surgery for cancer, 2 had carcinoma colon, one had carcinoma breast and another had carcinoma thyroid. 71% of patients had clinical stage 3 disease and the most common location of the tumour was the middle third (62.7%). 85.3% of patients received neoadjuvant therapy. Eighty percent of our patients underwent Robotic Mc Keown’s Esophagectomy while 20% had Robotic Ivor-Lewis Operation. The thoracic part in 1 patient was converted to open due to extensive adhesions in the right hemithorax. Mean abdominal console time was 146 min (+ 32 min) and thoracic console time was 120 min (+ 39 min); with a total operative time of 314 min (+ 44 min). Intraoperative blood loss was 300 ml (+ 86 ml). Post-operative and short-term outcomes: Out of 75 patients, 74.7% patients recovered well without any major complications. The most common complications were pulmonary (16%). Anastomotic leakage was found in 8 patients of whom 4 patients were managed conservatively, 1 required oesophageal stenting, other 2 had bedside opening of neck wound and 1 required pectoralis major muscle flap cover. Clinically recurrent laryngeal nerve palsy was found in 2 patients while Chylothorax was found in 2 patients. The median ICU stay was 3 days (range 1-28 days), whereas the median hospital stay was 8 days (range 6-38 days). Our 30-day mortality was 1.3% and this patient died on POD8 due to sepsis and respiratory failure, while 90 day mortality was 4%. Oncological Outcomes: Pathological complete response was seen in 21.3% of patients and median lymph nodal yield was 21 nodes (range 9-68). There was one microscopic margin positivity. Conclusions: RAMIE is a technically feasible and safe procedure with good lymph node yield and R0 resections. Postoperative complications and short-term oncologic results are comparable to other high-volume centres.
SLC7A11 as a prognostic biomarker for hepatocellular carcinoma.
Authors: Yuxi Wang, Xi Li, Ya Zhou, Xiao Meng, Ying Wang, Xiaomei Liu
Journal: Journal of Clinical Oncology (2024)

e16004 Background: Disulfidptosis has been discovered as a mechanism of cell death mediating by SLC7A11. Nonetheless, little is known about the relationship between SLC7A11 and hepatocellular carcinoma (HCC). Methods: The clinical and follow-up data of 84 consecutive HCC cases who met the inclusion criteria from 2016 to 2019 were retrospectively analyzed. The expression level of SLC7A11 in tissue samples was determined by immunohistochemistry. Kaplan-Meier and Cox regression analyses were performed to assess the correlation between survival and SLC7A11 expression in HCC patients. Results: We observed that SLC7A11 expression in HCC tissue is significantly higher than that in corresponding para-cancer tissue. Positive immunostaining SLC7A11 of was mainly located in the cytoplasm of HCC. Univariate analysis indicated that clinical pathological features such as expression level of SLC7A11, cirrhosis and stages were all risk factors affecting OS (P &lt; 0.001). Multivariate COX analysis showed that expression level of SLC7A11 was independent risk factors for OS and high-level expression of SLC7A11 indicated poor overall survival for pHCC (P &lt; 0.001). Conclusions: Our study showed that SLC7A11 might be a potential poor prognostic biomarker in HCC and represents a novel diagnostic marker and therapeutic target for HCC. Keywords: SLC7A11; disulfidptosis; hepatocellular carcinoma; prognostic biomarker.
Childhood myelodysplastic syndromes: Is cytoreductive therapy useful before allogeneic hematopoietic stem cell transplantation?
Authors: Baptiste Le Calvez, Maxime Jullien, Jean H. Dalle, Cécile Renard, Charlotte Jubert, Arthur Sterin, Catherine Paillard, Anne Huynh, Sarah Guenounou, Bénédicte Bruno, Virginie Gandemer, Nimrod Buchbinder, Pauline Simon, Cécile Pochon, Anne Sirvent, Dominique Plantaz, Justyna Kanold, Marie C. Béné, Fanny Rialland, Audrey Grain
Journal: HemaSphere (2024)

Abstract For most patients with childhood myelodysplastic syndrome (cMDS), allogeneic hematopoietic stem cell transplantation (allo‐HSCT) remains the only curative option. In the case of increased blasts (cMDS‐IB), the benefit of pretransplant cytoreductive therapy remains controversial. In this multicenter retrospective study, the outcomes of all French children who underwent allo‐HSCT for cMDS reported in the SFGM‐TC registry between 2000 and 2020 were analyzed ( n = 84). The median age at transplantation was 10.2 years. HSCT was performed from matched sibling donors (MSD) in 29% of the cases, matched unrelated donors (MUD) in 44%, haploidentical in 6%, and cord blood in 21%. Myeloablative conditioning was used in 91% of cases. Forty‐eight percent of patients presented with cMDS‐IB at diagnosis (median BM blasts: 8%). Among them, 50% received pretransplant cytoreductive therapy. Five‐year overall survival (OS), cumulative incidence of nonrelapse mortality (NRM), and relapse were 67%, 26%, and 12%, respectively. Six‐month cumulative incidence of grade II–IV acute graft‐versus‐host disease was 46%. Considering the whole cohort, age under 12, busulfan/cyclophosphamide/melphalan conditioning or MUD were associated with poorer 5‐year OS. In the cMDS‐IB subgroup, pretransplant cytoreductive therapy was associated with a better OS in univariate analysis. This seems to be mainly due to a decreased NRM since no impact on the incidence of relapse was observed. Overall, those data may argue in favor of cytoreduction for cMDS‐IB. They need to be confirmed on a larger scale and prospectively.
The contribution of silencer variants to human diseases
Authors: Di Huang, Ivan Ovcharenko
Journal: Genome biology (2024)

Abstract Background Although disease-causal genetic variants have been found within silencer sequences, we still lack a comprehensive analysis of the association of silencers with diseases. Here, we profiled GWAS variants in 2.8 million candidate silencers across 97 human samples derived from a diverse panel of tissues and developmental time points, using deep learning models. Results We show that candidate silencers exhibit strong enrichment in disease-associated variants, and several diseases display a much stronger association with silencer variants than enhancer variants. Close to 52% of candidate silencers cluster, forming silencer-rich loci, and, in the loci of Parkinson’s-disease-hallmark genes TRIM31 and MAL, the associated SNPs densely populate clustered candidate silencers rather than enhancers displaying an overall twofold enrichment in silencers versus enhancers. The disruption of apoptosis in neuronal cells is associated with both schizophrenia and bipolar disorder and can largely be attributed to variants within candidate silencers. Our model permits a mechanistic explanation of causative SNP effects by identifying altered binding of tissue-specific repressors and activators, validated with a 70% of directional concordance using SNP-SELEX. Narrowing the focus of the analysis to individual silencer variants, experimental data confirms the role of the rs62055708 SNP in Parkinson’s disease, rs2535629 in schizophrenia, and rs6207121 in type 1 diabetes. Conclusions In summary, our results indicate that advances in deep learning models for the discovery of disease-causal variants within candidate silencers effectively “double” the number of functionally characterized GWAS variants. This provides a basis for explaining mechanisms of action and designing novel diagnostics and therapeutics.
The Role of Psychosocial Stress on Cardiovascular Disease in Women
Authors: Imo A. Ebong, Odayme Quesada, Ida T. Fonkoue, Deirdre Mattina, Samaah Sullivan, Glaucia Maria Moraes de Oliveira, Telisa Spikes, Jyoti Sharma, Yvonne Commodore, Modele O. Ogunniyi, Niti R. Aggarwal, Viola Vaccarino
Journal: Journal of the American College of Cardiology (2024)
Racial Differences in Diabetic Cardiomyopathy
Authors: Jose Lopez, Yuxi Liu, Javed Butler, Stefano Del Prato, Justin A. Ezekowitz, Carolyn S.P. Lam, Thomas H. Marwick, Julio Rosenstock, W.H. Wilson Tang, Riccardo Perfetti, Alessia Urbinati, Faiez Zannad, James L. Januzzi, Nasrien E. Ibrahim
Journal: Journal of the American College of Cardiology (2024)