bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying targeted therapy combination for refractory colorectal cancer using micro-organospheres.
Authors: Ding Shengli , Kanikarla Marie Preeti , Zhang Ray , Baro Nicholas , Brown Daniel W , Bohn Alan , Pittman Kelly , Paduch Marcin , Hsu Shiaowen David , Kopetz Scott , Shen Xiling 
Published: January 2023

27 Background: Metastatic colorectal cancer (CRC) patients who have become resistant to standard-of-care (SOC) treatments are often put on targeted therapies. However, patients with targeted mutations still often do not respond to the targeted therapies alone, hence it remains a critically unmet need to explore potential combinatorial regimens that will enhance the efficacy. Using micro-organospheres (MOS) derived from metastatic refractory patients who received targeted therapies, we performed a high-throughput combo screen and compared the response of these patient tumor avatars with their clinical responses. Methods: Biopsies from metastatic CRC patients who became resistant to SOC and were about to receive targeted therapies in clinical trials were molecularly profiled and implanted into immunodeficient mice to generate patient-derived xenografts (PDX). MOS were derived and established from PDX using droplet-based microfluidics for high-throughput 3D screening. Response of the MOS patient avatars to dose-titrated single and combination drug treatments including the available targeted therapies were measured by a fully automated robotic dispensing and imaging pipeline and quantified by AI-based live imaging analytical algorithm to generate drug response curves with IC50 and EC50. Results: MOS were successfully established in all PDX derived from refractory patients with targetable mutations including KRAS G12C and BRAF 600E as well as patients without targetable mutations. We tested both FDA-approved and experimental targeted therapies as single agent or in combination in 5-dose titrations. Longitudinal tracking of each MOS with Live/dead fluorescence dye signals was obtained for 5 days. MOS drug response curves and IC50s show correlation with clinical outcomes. Furthermore, this comprehensive dataset enabled us to assess the potential benefit of different combinations, help deconvolute the efficacy and synergy of individual drugs, and provide insight into patients who fail to response to targeted therapies despite possessing the targeted mutations. As the MOSdiagnostic assay can be completed from a patient biopsy within 10 days and is currently in a registered, multi-site clinical trial (ClinicalTrials.gov # NCT05189171), this study provides proof-of-principle for a potential clinical MOS-based assay to guide refractory patients to the optimal combination regimen. Conclusions: Refractory patients may benefit from a MOS-based high-throughput screen assay to select the optimal combination regimen containing targeted therapy.
The influence of procedural volume on the outcome of endoscopic submucosal dissection for gastric neoplasm: A nationwide population-based study.
Authors: Kim Jae Gyu , Park Jae Yong , Kim Beom Jin , Kim Mi-Sook 
Published: January 2023

285 Background: Endoscopic submucosal dissection (ESD) is a well-established treatment modality for gastric neoplasms. The aim of this study was to investigate the effect of procedural volume on the outcome of endoscopic submucosal dissection (ESD) for gastric cancer or adenoma. Methods: Patients who underwent ESD for gastric cancer or adenoma from November 2011 to December 2017 were identified using the Korean National Health Insurance Service database. Operational definitions to identify target population and post-procedural complications were created by combining the diagnosis and procedure codes, and validated using individual hospital medical record data. The outcomes were the occurrence of post-procedural complications (bleeding, perforation, pneumonia, and 30-day mortality) and additional resection within 180 days after the initial ESD procedure. Hospital volume was categorized into four groups based on the mean annual number of procedures: very high-, high-, low-, very low-volume hospitals (VHVH, HVH, LVH, VLVH). The outcome of ESD was compared in relation to hospital volume. Results: There were 95,411 procedures in 89,780 patients during the study period. There were 5,607 composite events, which included 5,098 bleeding, 601 perforation, and 712 pneumonia cases, respectively. Additional resection within 180days occurred in 7,900 cases. There were significant differences in ESD-related adverse outcomes among the four hospital volume categories. Multiple logistic regression revealed that VHVH, HVH, and LVH were associated with significantly lower relative risk of composite outcome, when compared to VLVH. Similar tendencies were also shown in terms of bleeding, perforation, and pneumonia. This volume-outcome association was not evident in additional resection. Conclusions: Hospital volume was closely associated with adverse clinical outcome in patients with ESD for gastric cancer or adenoma. The outcomes of gastric ESD should be closely and systemically monitored to ensure the safety of patients. [Table: see text]
Survival benefit to immunotherapy according to site of organ involvement in metastatic anal cancer.
Authors: Peddireddy Arjun S , Johnson Benny , Wolff Robert A. , Huey Ryan , Holliday Emma , Das Prajnan , Skibber John Michael , Portier Shaelynn , Foo Wai Chin , Halperin Daniel M. , Morris Van K. 
Published: January 2023

3 Background: For patients with metastatic anal cancer, demonstration of anti-tumor activity by anti-PD-(L)1 antibodies has expanded the treatment landscape. To date, there are no predictive biomarkers associated with clinical benefit to immunotherapy in this setting. In the absence of clinical trials directly comparing chemotherapy and immunotherapy for metastatic anal cancer, the optimal sequencing of therapeutic lines remains undefined because historical series have been limited to cytotoxic chemotherapy. We evaluated the survival outcomes of patients with metastatic anal cancer following treatment with immunotherapy and with chemotherapy. Methods: We reviewed retrospectively the MD Anderson Cancer Center database for patients with unresectable and/or metastatic anal cancer diagnosed between 6/2014 and 11/2021. Median survival was estimated using the Kaplan-Meier method and compared between subpopulations of interest with a log-rank test. Results: Among 82 patients with metastatic anal cancer, 68 (83%) were female, and the median age was 60 years (range, 39-81). With a median follow-up time of 24.6 months, the median lines of systemic therapy were 2 (range, 1-5). 58 (71%) received anti-PD-(L)1 immunotherapy, either alone (N=51) or in combination with bevacizumab or with MEDI-0457 on a clinical trial (N=7). Median progression-free survival times (PFS) for lines 1, 2, and 3 of systemic therapy were 7.2 months (95% CI (Confidence Interval) 5.3-9.1; N=82), 3.6 months (95% CI 2.4-4.8; N=58), and 4.1 months (95% CI 2.8-5.4; N=34), respectively. In the treatment-refractory setting, no difference in median PFS between chemotherapy and immunotherapy was observed (4.7 months vs 2.9 months, respectively; hazard ratio (HR) 0.9, 95% CI 0.5-1.4); p=.17). Median overall survival (OS) was estimated at 33.9 months (95% CI, 24.0-34.8). For patients with metastatic anal cancer treated with immunotherapy, involvement of only distant lymph nodes (N=10/58, 17%) was associated with improved median PFS (11.3 months vs 2.8 months; HR 3.5, 95% CI 1.8-6.6; p=.002) and median OS (45.2 months vs 27.1 months; HR 2.9, 95% CI 1.3-6.5, p=.02) than other sites of distant organ involvement (N=48/58, 83%). Conclusions: In this single-institution retrospective study at a large academic referral center, both chemotherapy and immune checkpoint blockade were effective treatment options for patients with metastatic anal cancer. These data provide historical context in estimating median PFS necessary for future trial design in patients with metastatic anal cancer. Lymph node-only distribution of distant metastatic disease was predictive for improved survival with immunotherapy. Pending further validation, these data provide novel identification of a potential predictive factor associated with benefit to immunotherapy in patients with metastatic anal cancer.
Pre-diagnostic delay among patients with curative esophageal and gastric cancer during the COVID-19 pandemic.
Authors: Wang Xin , Espin-Garcia Osvaldo , Bach Yvonne , Aoyama Hiroko , Ma Lucy Xiaolu , Barron Carly C. , Megid Thais Baccili Cury , Chen Eric Xueyu , Yeung Jonathan , Swallow Carol Jane , Brar Savtaj Singh , Wong Rebecca KS , Mesci Aruz , Kim John , Veit-Haibach Patrick , Kalimuthu Sangeetha , Jang Raymond Woo-Jun , Elimova Elena 
Published: January 2023

302 Background: The majority of esophageal and gastric cancers are diagnosed at an advanced stage with poor overall survival (OS), leading some to propose screening, even in countries with a low incidence. Whether diagnostic delay from symptom onset has any impact on OS is unclear. We investigated this question in the peri-COVID19 pandemic era. Methods: We retrospectively analyzed a cohort of 308 patients with esophageal, gastroesophageal junction, or gastric carcinoma treated with curative intent at the Princess Margaret Cancer Centre from January 2017 to December 2021. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. OS was estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to assess the association between pre-diagnostic interval with OS adjusting for baseline patient characteristics. Results: The median interval from symptom onset to diagnosis was 98 days (IQR 47-169 days). Using a cox proportional hazard model, prolonged pre-diagnostic interval was not associated with worse OS (HR 1.00, P=0.62). Comparing patients diagnosed before and during the COVID19 pandemic, there was a notable increase in diagnostic delay with median pre-diagnostic interval increasing from 92 to 126 days (P=0.007). Median age at time of diagnosis was 69.6 during the pandemic vs 64.7 before the pandemic. Linear regression showed squamous cell histology was significantly associated with increasing time to initial diagnosis (P=0.04). Looking at other delay metrics, there were no changes in time interval from diagnosis to treatment during versus before the pandemic (median = 1.7 weeks for both), and there was no change in time from diagnosis to resection in those patients who underwent surgery. Conclusions: The COVID19 pandemic caused significant diagnostic delay for patients presenting with curative esophageal and gastric cancer. We found no evidence of pandemic-related health system delays in treatment, once a diagnosis was made. The lack of correlation of pre-diagnostic interval with OS may reflect underlying tumour biology as the driving force that determines prognosis.
Long-term outcomes after laparoscopy-assisted total or proximal gastrectomy with nodal dissection for clinical stage I gastric cancer: Japan Clinical Oncology Group study (JCOG1401).
Authors: Sakuramoto Shinichi , Katai Hitoshi , Katayama Hiroshi , Iwamoto Shintaro , Hasegawa Yasuhiro , Nomura Takashi , Makino Shigeto , Watanabe Masaya , Omori Takeshi , Yoshikawa Takaki , Ojima Toshiyasu , Terashima Masanori 
Published: January 2023

305 Background: JCOG0912 supports the non-inferiority of laparoscopy-assisted distal gastrectomy (LADG) compared with open distal gastrectomy (ODG) for clinical stage I gastric cancer relapse-free survival (RFS), suggesting that LADG should be considered a standard treatment option when performed by experienced surgeons. No prospective study evaluating laparoscopy-assisted total gastrectomy (LATG) and laparoscopy-assisted proximal gastrectomy (LAPG) has been completed in terms of both safety and long-term survival. Considering that the results of the phase III trial to evaluate the long-term outcome of LADG (JCOG0912) could guarantee that of LATG/LAPG, we conducted a single-arm confirmatory trial (JCOG1401) to evaluate the safety of LATG/LAPG for clinical stage I proximal gastric cancer and JCOG1401 confirmed the safety of LATG/LAPG. Long-term outcomes as the secondary endpoints of this study are reported here after 5-year follow-up period. Methods: Laparoscopic operators were limited to credentialed surgeons. The extent of nodal dissection was selected based on the Gastric Cancer Treatment Guidelines in Japan. The primary endpoint was the proportion of grade 2 (CTCAE ver. 4.0) or greater esophageal anastomotic leak. The sample size was determined to be 245 considering a threshold of 8% and expected value of 3% with a one-sided alpha error of 2.5% and statistical power of 90%. The secondary endpoints were overall survival (OS) and RFS. Results: Between April 2015 and February 2017, 245 patients were enrolled. Among them, 1 patient was excluded from safety analysis due to ineligible. LATG/LAPG was performed in 195/49. 170/47/17/8/2 patients had pStage IA/IB/II/IIIA/IIIB disease and 190/31/15/8 patients had pT1/T2/T3/T4 disease, respectively. Grade 2 or greater esophageal anastomotic leak was 2.5% (6/244) (95% CI 0.9-5.3), as previously reported. 5-year OS was 91.2% (95% CI 86.9-94.2). 5-year RFS was 90.0% (95% CI 85.5-93.2). Among 22 deaths, 14 patients died without recurrence and 8 patients died with recurrence. Twelve recurrences were observed in 5/2/4/1 patients for pT1/T2/T3/T4. The sites of recurrence were peritoneal metastasis in 2 cases, hematogenous metastasis in 9 cases (liver: 6, bone: 2, lung: 1), and other in 1 case. Conclusions: The long-term outcomes of LATG/LAPG for Stage I gastric cancer patients were excellent and seem comparable to those of open procedures. Similar to JCOG0912, JCOG1401 guarantee the long-term survival of LATG/LAPG. Clinical trial information: UMIN000017155 .
Long-term quality of life in patients with metastatic esophagogastric cancer receiving first-line systemic therapy.
Authors: Pape Marieke , Vissers Pauline A.J. , Slingerland Marije , Haj Mohammad Nadia , van de Poll-Franse Lonneke , Verhoeven Rob , Van Laarhoven Hanneke W.M. 
Published: January 2023

306 Background: Thus far, evidence that quality of life (QoL) remains stable during 1st line systemic therapy of patients with metastatic esophagogastric cancer (mEGC) originates from randomized clinical trials (RCTs). Outcomes from a population-based study provides inside into the effect of systemic therapy on HRQoL in daily clinical practice. The aim of this study was to assess QoL of patients with mEGC at baseline, during 1st line, at progression and after disease progression. Methods: Patients diagnosed with mEGC (2014-2020) receiving 1st line systemic therapy registered in the Prospective Observational Cohort study of Oesophageal-gastric cancer Patients (POCOP) were included. QoL was measured with the EORTC QLQ-C30 and -OG25 at baseline, during 1st line therapy, at progression and after disease progression. Results: Of the 263 included patients, 123, questionnaires were available at baseline, 161 during 1st line, 77 at progression and 89 after progression. Results of the mixed effect models showed that global health status and four functioning scales deteriorated after progression as compared to baseline. Largest improvements during 1st line treatment were observed for odynophagia (mean change -17.3), anxiety (-14.9), dysphagia (-11.7) and eating restrictions (-11.1). Trouble with taste deteriorated at all three time points. Conclusions: In accordance to RCTs, QoL outcomes remained relatively stable or improved during 1st line therapy in patients with esophagogastric cancer. Deterioration of functioning scales were mainly observed after progression. [Table: see text]
Role of chemotherapy in clinical T2N0M0 gastric cancer.
Authors: Bawek Sawyer , Vedire Yeshwanth , Groman Adrienne , Mukherjee Sarbajit 
Published: January 2023

308 Background: The role of chemotherapy for patients with early stage, node-negative gastric adenocarcinoma (T2N0M0) remains unclear. Possible options are surgery alone, surgery followed by adjuvant chemotherapy, or perioperative chemotherapy. The objective of our study was to investigate the role and sequence of chemotherapy in T2N0M0 gastric adenocarcinoma. Methods: The National Cancer Data Base (2006-2017) was used to identify patients with T2N0M0 gastric adenocarcinoma. Patients were categorized into 3 groups, surgery alone (S), surgery followed by adjuvant chemotherapy (AC), and peri-operative chemotherapy (POC). Univariate and multivariable Cox proportional-hazards models were performed to evaluate treatment differences in overall survival (OS). Patients were further sub-categorized into two subgroups based on the number of regional nodes examined, less than 15 (RNE<15) and greater or equal to 15 (RNE>15). Univariate and multivariable Cox proportional-hazards models were performed on each subgroup to assess the treatment differences within two groups. Results: The retrospective study analyzed 3,142 patients between 2006 to 2017. Surgery alone represented 2,090 patients (66.5%), AC group had 360 patients (11.5%), and the POC group 692 patients (22.0%). The median age of the population was 70 yrs. Mean inpatient stay was 12.5 days in S, 9.2 days in AC and 10.1 days in the POC group (p<0.001). In the multivariable model, surgery followed by adjuvant chemotherapy (HR 0.75, p=0.003), RNE>15 (HR 0.73, p<0.001), patients treated at academic facilities (HR 0.84, p=0.005), female sex (HR 0.84, p=0.004), and Asian race (HR 0.69, p=0.002) had better outcomes. There were 1,526 (49.2%) patients with RNE<15 and 1,577 (50.8%) patients with RNE>15. Subgroup analysis showed that peri-operative chemotherapy for RNE<15 was beneficial (HR 0.74, p= 0.029). Patients with RNE>15 had an improved survival with surgery followed by adjuvant chemotherapy (HR 0.72, p= 0.017) in the multivariable model. Conclusions: Surgery followed by adjuvant chemotherapy was found to be beneficial in patients having a T2N0M0 Gastric Cancer. However, the number of lymph nodes examined during surgery influences this association. Perioperative chemotherapy maybe beneficial for patients who were under staged due to inadequate exploration of lymph nodes during surgery.
Chemotherapy-induced neuropathy in esophagogastric cancer.
Authors: van Velzen Merel , Pape Marieke , van Kleef Jessy Joy , Slingerland Marije , Beerepoot Laurens V. , Mostert Bianca , Haj Mohammad Nadia , Van Laarhoven Hanneke W.M. 
Published: January 2023

309 Background: Treatment of locally advanced and metastatic esophagogastric cancer (EGC) largely depends on systemic treatment including taxanes or platinum compounds – agents which are known to cause chemotherapy induced peripheral neuropathy (CIPN). To date, the extend of CIPN in EGC has not been investigated in real-world data. Methods: We identified patients with EGC from the Netherlands Cancer Registry (NCR) and Prospective Observational Cohort study of Oesophageal-gastric cancer Patients (POCOP) who underwent systemic treatment between 2016 and 2018 and completed at least one EORTC QLQ-CIPN20 questionnaire. Total CIPN scores and scores for the motor, sensory and autonomic scales (ranged 0-100) were calculated, and analyzed over time for patients receiving chemoradiation (CRT), peri-operative chemotherapy (POC) and patients primarily treated with palliative chemotherapy (PC). To gain insight in the differences between CIPN score at baseline and after 3, 6, 9, 12, 18 and 24 months we constructed linear mixed effect models. Results: We included 1052 EGC patients. 769 patients received CRT (response: 76% at baseline, 30% after 24 months), 143 received POC (response: 79% at baseline, 33% after 24 months) and 140 received PC (response: 74% at baseline, 28% after 12 months). Over time, neuropathy scores increased in all scales for patients receiving POC and PC, with a maximum increase of 16.5 points in total CIPN score after 6 months in the PC group compared to baseline. For patients receiving CRT, increase in neuropathy scores was more subtle, with a maximum increase in total CIPN score of 4.3 points after 24 months compared to baseline. Results of mixed effect models showed a significant increase of CIPN scores over time in all three groups compared to baseline, persisting for as long as two years after start of initial treatment. Conclusions: CIPN frequently occurs in EGC patients treated with chemotherapy, especially with PC. Due to the possible irreversibility of CIPN, it is important that clinicians inquire patients about neurotoxicity often, adjust the dose of neurotoxic agents as needed and that more research is done into strategies possibly preventing the occurrence of CIPN. Results of mixed model analysis to assess changes in total CIPN score over time. Each model was adjusted for age, sex, performance status and number of comorbidities. The model for POC and PC was also adjusted for use of oxaliplatin.[Table: see text] *p-value <0.001 aChemoradiotherapy bPeri-operative chemotherapy cPalliative chemotherapy, no estimates were calculated for 18 and 24 months due to the low number of responses.
Anlotinib plus PD-1 inhibitors as chemo-free therapy in advanced or metastatic esophageal cancer: Updated results from a retrospective real-world study.
Authors: Hong Yonggui , Wu Tao , Lu Ping , Chang Zhiwei , Liang Wei , Zhang Guifang , Tian Yongjing , Wang Junsheng 
Published: January 2023

310 Background: Compared to standard chemotherapy, immune checkpoint inhibitors monotherapy and combined with chemotherapy regimens have been shown significant benefits for patients with advanced or metastatic esophageal cancer in both second-line and first-line treatment, respectively. Anlotinib was an effective second-line monotherapy for esophageal squamous cell carcinoma in China and the combination of anlotinib and immunotherapy might be a promising strategy. The study aimed to investigate the efficacy and safety of anlotinib plus PD-1 inhibitors during the treatment of esophageal cancer in the real world setting. Methods: This is a multicenter real-world study in patients with unresectable locally advanced, recurrent or metastatic esophageal cancer, who would benefit from anlotinib plus a PD-1 inhibitor under the doctor's evaluation. The enrolled patients received treatment according to physicians. The primary endpoint was PFS, and secondary endpoints included ORR, DCR and OS. The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: Between May 2020 and Sep 2022, 207 pts were enrolled. 109 comprised the evaluable population. In the full analysis set, 203 patients were squamous cell and 4 were adenocarcinoma histology. 137 of 207 (66.2%) pts were male. 44(21.3%) had an ECOG performance status of 0, 136 (65.7%) status of 1 and 27 (13.0%) status of ≥2. 47 pts had previously used anti-PD-1/PD-L1 antibody or vascular targeting drugs, of which 8 cases had combined anti-PD-1/PD-L1 antibody and vascular targeting drugs. Among the 109 evaluable pts, 17 (15.6%) pts received first-line therapy, 64 (58.7%) second-line and 28(25.7%) third & above line. Of which, 5 patients achieved complete response (CR), 32 pts partial response (PR), 62 pts stable disease (SD), illustrating an ORR of 34.0% (95%CI 25.1-43.6) and a DCR of 90.8%(95%CI 83.8-95.5). In the first line therapy, ORR was 47.1% and DCR was 88.2%. In the second line therapy, ORR was 32.8% and DCR was 96.9%. In the third & above line, ORR with 28.6% and DCR with 78.6% were observed. Median PFS was not reached, 6m-PFS rate was 87.9%. Treatment related adverse events (TRAEs) were reported in 55 pts (50.5%). 6 patients had grade 3 or more TRAEs. Conclusions: Anlotinib plus PD-1 inhibitors for advanced or metastatic esophageal cancer demonstrated a promising clinical benefit and a manageable safety profile. Further investigation in larger cohorts and even randomized controlled studies is warranted. Clinical trial information: NCT04966611 .