Pub Date : 2024-08-12DOI: 10.1007/s10120-024-01541-2
Byungyoon Yun, Juyeon Oh, Heejoo Park, Jinsoo Chung, Juho Sim, Jongmin Lee, Yangwook Kim, Jin-Ha Yoon
Background: The impact of economic engagement on the health of cancer survivors is notable. Our study aims to explore the association between early loss of economic activity (EA) and the risk of all-cause mortality among gastric cancer survivors.
Methods: This retrospective cohort study utilized data from Korea's National Health Insurance Service, focusing on 30-59-year-old gastric cancer patients who received either surgery or endoscopic procedures from January 2009 to December 2013. The primary outcome measure was all-cause mortality. Early loss of EA was identified when a patient's insurance status shifted to dependent within one year following treatment. Adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality were estimated using multivariable Cox proportional hazards models, conducting separate analyses for surgical and endoscopic groups.
Results: Among 24,159 patients (median follow-up, 9.9 years), 2976 (12.3%) experienced all-cause mortality. Specifically, 2835 of these deaths occurred in patients who underwent surgery, while 141 were in the endoscopic procedure group. Early loss of EA was recorded in 14.4% of the surgery group and 7.7% of the endoscopic procedure group. Adjusted HRs (95% CI) for all-cause mortality associated with early loss of EA were 1.39 (1.27-1.54) for the surgery group and 2.27 (1.46-3.52) for the endoscopic procedure group.
Conclusions: This study highlights a significant association between the early loss of EA and an increased risk of all-cause mortality in those who have undergone curative treatments for gastric cancer. It underscores the crucial role of sustaining EA in enhancing the health outcomes of these survivors.
{"title":"Impact of early economic activity loss on all-cause mortality in gastric cancer survivors following curative treatment: a nationwide study in Korea.","authors":"Byungyoon Yun, Juyeon Oh, Heejoo Park, Jinsoo Chung, Juho Sim, Jongmin Lee, Yangwook Kim, Jin-Ha Yoon","doi":"10.1007/s10120-024-01541-2","DOIUrl":"https://doi.org/10.1007/s10120-024-01541-2","url":null,"abstract":"<p><strong>Background: </strong>The impact of economic engagement on the health of cancer survivors is notable. Our study aims to explore the association between early loss of economic activity (EA) and the risk of all-cause mortality among gastric cancer survivors.</p><p><strong>Methods: </strong>This retrospective cohort study utilized data from Korea's National Health Insurance Service, focusing on 30-59-year-old gastric cancer patients who received either surgery or endoscopic procedures from January 2009 to December 2013. The primary outcome measure was all-cause mortality. Early loss of EA was identified when a patient's insurance status shifted to dependent within one year following treatment. Adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality were estimated using multivariable Cox proportional hazards models, conducting separate analyses for surgical and endoscopic groups.</p><p><strong>Results: </strong>Among 24,159 patients (median follow-up, 9.9 years), 2976 (12.3%) experienced all-cause mortality. Specifically, 2835 of these deaths occurred in patients who underwent surgery, while 141 were in the endoscopic procedure group. Early loss of EA was recorded in 14.4% of the surgery group and 7.7% of the endoscopic procedure group. Adjusted HRs (95% CI) for all-cause mortality associated with early loss of EA were 1.39 (1.27-1.54) for the surgery group and 2.27 (1.46-3.52) for the endoscopic procedure group.</p><p><strong>Conclusions: </strong>This study highlights a significant association between the early loss of EA and an increased risk of all-cause mortality in those who have undergone curative treatments for gastric cancer. It underscores the crucial role of sustaining EA in enhancing the health outcomes of these survivors.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Gastric foveolar type neoplasia is a rare histological variant of gastric tumors. It is very difficult to differentiate between benign and malignant intraepithelial foveolar neoplasia (IFN). Although limited molecular alterations have been identified in IFNs, somatic copy number alterations (SCNAs), which are linked to tumor progression, have not been systematically evaluated in IFN.
Methods: The aim of the present study was to comprehensively examine SCNAs using a SNP array in 37 cases of IFN, compared with intestinal type dysplasia, including 39 low grade (LGD) and 32 high grade dysplasia (HGD) cases. In addition, gene mutations were evaluated using a gene panel. Finally, we attempted to determine molecular profiles using a hierarchical clustering analysis.
Results: Two patterns could be categorized according to the SCNAs in 108 tumors examined: high (subgroup 1) and low (subgroup 2) frequencies of SCNAs. Although IFN and LGD were associated with subgroup 2, HGD was found in both subgroups. The median numbers of total SCNAs and copy number gains were higher in IFN or HGD than in LGD. In addition, the IFN genotype was characterized by altered genes located at 4p13-4q35.2, including RAP1GDS1 and LEF1, which may be associated with IFN development. Finally, no significant mutations were found in IFNs using a gene panel.
Conclusions: The current molecular profiles of IFN may help elucidate the mechanisms of IFN development.
{"title":"The molecular profile of gastric intraepithelial foveolar type neoplasia based on somatic copy number alterations and multiple mutation analysis.","authors":"Tamotsu Sugai, Noriyuki Uesugi, Mitsumasa Osakabe, Ryuya Yamamoto, Koichi Hamada, Michitaka Honda, Naoki Yanagawa, Hiromu Suzuki","doi":"10.1007/s10120-024-01543-0","DOIUrl":"https://doi.org/10.1007/s10120-024-01543-0","url":null,"abstract":"<p><strong>Background: </strong>Gastric foveolar type neoplasia is a rare histological variant of gastric tumors. It is very difficult to differentiate between benign and malignant intraepithelial foveolar neoplasia (IFN). Although limited molecular alterations have been identified in IFNs, somatic copy number alterations (SCNAs), which are linked to tumor progression, have not been systematically evaluated in IFN.</p><p><strong>Methods: </strong>The aim of the present study was to comprehensively examine SCNAs using a SNP array in 37 cases of IFN, compared with intestinal type dysplasia, including 39 low grade (LGD) and 32 high grade dysplasia (HGD) cases. In addition, gene mutations were evaluated using a gene panel. Finally, we attempted to determine molecular profiles using a hierarchical clustering analysis.</p><p><strong>Results: </strong>Two patterns could be categorized according to the SCNAs in 108 tumors examined: high (subgroup 1) and low (subgroup 2) frequencies of SCNAs. Although IFN and LGD were associated with subgroup 2, HGD was found in both subgroups. The median numbers of total SCNAs and copy number gains were higher in IFN or HGD than in LGD. In addition, the IFN genotype was characterized by altered genes located at 4p13-4q35.2, including RAP1GDS1 and LEF1, which may be associated with IFN development. Finally, no significant mutations were found in IFNs using a gene panel.</p><p><strong>Conclusions: </strong>The current molecular profiles of IFN may help elucidate the mechanisms of IFN development.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Clinical findings and postoperative follow-up data on remnant gastric cancer (RGC) are limited due to its rarity. Additionally, the preoperative staging, radical surgery, and managing recurrence in RGC present significant clinical challenges.
Methods: We analyzed the clinicopathological findings, adjuvant chemotherapy, and patterns of postoperative recurrence of 313 consecutive patients who underwent curative surgery for RGC at 17 Japanese institutions. This study investigated the optimal management of RGC and the impact of adjuvant chemotherapy (AC) on recurrence-free survival (RFS).
Results: Pathological stages I, II, and III were observed in 55.9% (N = 175), 24.9% (N = 78), and 19.2% (N = 60) of the patients, respectively. The overall concordance rate between clinical and pathological T staging was 58.3%, with a clinical T4 sensitivity of 41.4% for diagnosing pathological T4. During the median follow-up period of 4.6 years, disease recurrence occurred in 24.3% of patients. Most recurrences (over 80%) occurred within 2.5 years, and 96.1% within 5 years after RGC surgery. Peritoneal recurrence was the most common in patients with advanced RGC, accounting for 14.1% in stage II and 28.3% in stage III. Multivariable regression analysis showed that AC was significantly associated with a longer RFS, with a hazard ratio of 0.45 (95% confidence interval: 0.26-0.76).
Conclusions: Our study underscores the importance of early detection, accurate preoperative staging, and postoperative surveillance in managing advanced RGC cases. Despite some limitations, our findings indicate that AC may provide survival benefits comparable to those seen in primary gastric cancer.
{"title":"Management challenges and the role of adjuvant chemotherapy in remnant gastric cancer: an analysis of 313 patients from the KEGG multicenter observational study.","authors":"Ryosuke Okamura, Ryuhei Aoyama, Shigeru Tsunoda, Yoshito Yamashita, Hiroaki Hata, Yosuke Kinjo, Akira Miki, Seiichiro Kanaya, Michihiro Yamamoto, Koichi Matsuo, Dai Manaka, Eiji Tanaka, Hironori Kawada, Masato Kondo, Atsushi Itami, Takatsugu Kan, Yoshio Kadokawa, Tetsuo Ito, Shunpei Jikihara, Keiko Kasahara, Takashi Sakamoto, Shintaro Okumura, Hisatsugu Maekawa, Tatsuto Nishigori, Shigeo Hisamori, Kazutaka Obama","doi":"10.1007/s10120-024-01544-z","DOIUrl":"https://doi.org/10.1007/s10120-024-01544-z","url":null,"abstract":"<p><strong>Background: </strong>Clinical findings and postoperative follow-up data on remnant gastric cancer (RGC) are limited due to its rarity. Additionally, the preoperative staging, radical surgery, and managing recurrence in RGC present significant clinical challenges.</p><p><strong>Methods: </strong>We analyzed the clinicopathological findings, adjuvant chemotherapy, and patterns of postoperative recurrence of 313 consecutive patients who underwent curative surgery for RGC at 17 Japanese institutions. This study investigated the optimal management of RGC and the impact of adjuvant chemotherapy (AC) on recurrence-free survival (RFS).</p><p><strong>Results: </strong>Pathological stages I, II, and III were observed in 55.9% (N = 175), 24.9% (N = 78), and 19.2% (N = 60) of the patients, respectively. The overall concordance rate between clinical and pathological T staging was 58.3%, with a clinical T4 sensitivity of 41.4% for diagnosing pathological T4. During the median follow-up period of 4.6 years, disease recurrence occurred in 24.3% of patients. Most recurrences (over 80%) occurred within 2.5 years, and 96.1% within 5 years after RGC surgery. Peritoneal recurrence was the most common in patients with advanced RGC, accounting for 14.1% in stage II and 28.3% in stage III. Multivariable regression analysis showed that AC was significantly associated with a longer RFS, with a hazard ratio of 0.45 (95% confidence interval: 0.26-0.76).</p><p><strong>Conclusions: </strong>Our study underscores the importance of early detection, accurate preoperative staging, and postoperative surveillance in managing advanced RGC cases. Despite some limitations, our findings indicate that AC may provide survival benefits comparable to those seen in primary gastric cancer.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC.
Methods: We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups.
Results: Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0 months vs. 3.0 months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151-0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy.
Conclusions: Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC.
{"title":"Landscape of homologous recombination deficiency in gastric cancer and clinical implications for first-line chemotherapy.","authors":"Hiroshi Ichikawa, Masaki Aizawa, Yosuke Kano, Takaaki Hanyu, Yusuke Muneoka, Sou Hiroi, Hiroto Ueki, Kazuki Moro, Yuki Hirose, Kohei Miura, Yoshifumi Shimada, Jun Sakata, Hiroshi Yabusaki, Satoru Nakagawa, Takashi Kawasaki, Shujiro Okuda, Toshifumi Wakai","doi":"10.1007/s10120-024-01542-1","DOIUrl":"https://doi.org/10.1007/s10120-024-01542-1","url":null,"abstract":"<p><strong>Background: </strong>Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC.</p><p><strong>Methods: </strong>We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups.</p><p><strong>Results: </strong>Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0 months vs. 3.0 months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151-0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy.</p><p><strong>Conclusions: </strong>Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1007/s10120-024-01540-3
Hea Lim Choi, Danbee Kang, Hyunsoo Kim, Juhee Cho, Keun Hye Jeon, Wonyoung Jung, Dong Wook Shin, Su-Min Jeong
Background: Previous studies have investigated cardiovascular disease (CVD) risks in cancer patients, but there is limited knowledge concerning the CVD risk in adult and young adolescent (AYA) survivors of gastric cancer.
Objectives: This study aims to investigate the incidence of CVD in AYA gastric cancer survivors, analyzing it by treatment type and identifying associated risk factors.
Methods: We conducted a retrospective cohort study using Korean National Health Insurance Service data collected from 2006 to 2019. Propensity score matching (1:3, caliper < 0.1) was performed using the variables age, sex, income, residential area, and presence of comorbidities, and we classified participants into gastric cancer (n = 6562) and non-cancer control (n = 19,678) groups. Cox regression models were used to calculate hazard ratios (HRs) for CVD incidence. The study assessed CVD incidence by cancer treatment and identified risk factors through multivariable Cox regression.
Results: During a median 6.5-year follow-up, AYA gastric cancer survivors consistently exhibited greater CVD incidence. Their risk of CVD was significantly elevated compared to that of controls (HR, 1.18; 95% confidence interval [CI] 1.05-1.33). In particular, deep vein thrombosis (HR, 3.93; 95% CI 3.06-14.67) and pulmonary embolism (HR, 6.58; 95% CI 3.06-14.67) risks were notably increased. Chemotherapy was associated with an increased risk of stroke, heart failure, atrial fibrillation, deep vein thrombosis, and pulmonary embolism. Hypertension (HR, 1.58; 95% CI 1.10-2.26) and dyslipidemia (HR, 1.46; 95% CI 1.06-2.20) emerged as risk factors for CVD development.
Conclusion: This study reports elevated risks of CVD in AYA gastric cancer survivors and emphasizes the need for vigilant monitoring of CVD in this population.
{"title":"Increased cardiovascular disease risk among adolescents and young adults with gastric cancer.","authors":"Hea Lim Choi, Danbee Kang, Hyunsoo Kim, Juhee Cho, Keun Hye Jeon, Wonyoung Jung, Dong Wook Shin, Su-Min Jeong","doi":"10.1007/s10120-024-01540-3","DOIUrl":"https://doi.org/10.1007/s10120-024-01540-3","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have investigated cardiovascular disease (CVD) risks in cancer patients, but there is limited knowledge concerning the CVD risk in adult and young adolescent (AYA) survivors of gastric cancer.</p><p><strong>Objectives: </strong>This study aims to investigate the incidence of CVD in AYA gastric cancer survivors, analyzing it by treatment type and identifying associated risk factors.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study using Korean National Health Insurance Service data collected from 2006 to 2019. Propensity score matching (1:3, caliper < 0.1) was performed using the variables age, sex, income, residential area, and presence of comorbidities, and we classified participants into gastric cancer (n = 6562) and non-cancer control (n = 19,678) groups. Cox regression models were used to calculate hazard ratios (HRs) for CVD incidence. The study assessed CVD incidence by cancer treatment and identified risk factors through multivariable Cox regression.</p><p><strong>Results: </strong>During a median 6.5-year follow-up, AYA gastric cancer survivors consistently exhibited greater CVD incidence. Their risk of CVD was significantly elevated compared to that of controls (HR, 1.18; 95% confidence interval [CI] 1.05-1.33). In particular, deep vein thrombosis (HR, 3.93; 95% CI 3.06-14.67) and pulmonary embolism (HR, 6.58; 95% CI 3.06-14.67) risks were notably increased. Chemotherapy was associated with an increased risk of stroke, heart failure, atrial fibrillation, deep vein thrombosis, and pulmonary embolism. Hypertension (HR, 1.58; 95% CI 1.10-2.26) and dyslipidemia (HR, 1.46; 95% CI 1.06-2.20) emerged as risk factors for CVD development.</p><p><strong>Conclusion: </strong>This study reports elevated risks of CVD in AYA gastric cancer survivors and emphasizes the need for vigilant monitoring of CVD in this population.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-20DOI: 10.1007/s10120-024-01537-y
Ozen Leylek, Megan E Honeywell, Michael J Lee, Michael T Hemann, Gulnihal Ozcan
Background: Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy.
Methods: We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments.
Results: Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR.
Conclusion: In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.
{"title":"Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.","authors":"Ozen Leylek, Megan E Honeywell, Michael J Lee, Michael T Hemann, Gulnihal Ozcan","doi":"10.1007/s10120-024-01537-y","DOIUrl":"10.1007/s10120-024-01537-y","url":null,"abstract":"<p><strong>Background: </strong>Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy.</p><p><strong>Methods: </strong>We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments.</p><p><strong>Results: </strong>Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR.</p><p><strong>Conclusion: </strong>In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: The significance of reinforcement of the duodenal stump with seromuscular sutures and the effectiveness of reinforced staplers in preventing duodenal stump leakage remain unclear. We aimed to explore the importance of duodenal stump reinforcement and determine the optimal reinforcement method for preventing duodenal stump leakage.
Methods: This retrospective cohort study was conducted between January 1, 2012 and December 31, 2021, with data analyzed between December 1, 2022 and September 30, 2023. This multicenter study across 57 institutes in Japan included 16,475 patients with gastric cancer who underwent radical gastrectomies. Elective open or minimally invasive (laparoscopic or robotic) gastrectomy was performed in patients with gastric cancer.
Results: Duodenal stump leakage occurred in 153 (0.93%) of 16,475 patients. The proportions of males, patients aged ≥ 75 years, and ≥ pN1 were higher in patients with duodenal stump leakage than in those without duodenal stump leakage. The incidence of duodenal stump leakage was significantly lower in the group treated with reinforcement by seromuscular sutures or using reinforced stapler than in the group without reinforcement (0.72% vs. 1.19%, p = 0.002). Duodenal stump leakage incidence was also significantly lower in high-volume institutions than in low-volume institutions (0.70% vs. 1.65%, p = 0.047). The rate of duodenal stump leakage-related mortality was 7.8% (12/153). In the multivariate analysis, preoperative asthma and duodenal invasion were identified as independent preoperative risk factors for duodenal stump leakage-related mortality.
Conclusions: The duodenal stump should be reinforced to prevent duodenal stump leakage after radical gastrectomy in patients with gastric cancer.
{"title":"Importance of duodenal stump reinforcement to prevent stump leakage after gastrectomy: a large-scale multicenter retrospective study (KSCC DELICATE study).","authors":"Akihiko Sano, Yoshiro Imai, Takahisa Yamaguchi, Takeo Bamba, Naoki Shinno, Yoshiyuki Kawashima, Masanori Tokunaga, Yasuaki Enokida, Tomoya Tsukada, Satoru Hatakeyama, Tadashi Koga, Shirou Kuwabara, Naoki Urakawa, Junichi Arai, Manabu Yamamoto, Itaru Yasufuku, Hironori Iwasaki, Masahiro Sakon, Takuya Honboh, Yoshihiko Kawaguchi, Tetsuya Kusumoto, Kazunori Shibao, Naoki Hiki, Nobuhiro Nakazawa, Makoto Sakai, Makoto Sohda, Ken Shirabe, Eiji Oki, Hideo Baba, Hiroshi Saeki","doi":"10.1007/s10120-024-01538-x","DOIUrl":"https://doi.org/10.1007/s10120-024-01538-x","url":null,"abstract":"<p><strong>Background: </strong>The significance of reinforcement of the duodenal stump with seromuscular sutures and the effectiveness of reinforced staplers in preventing duodenal stump leakage remain unclear. We aimed to explore the importance of duodenal stump reinforcement and determine the optimal reinforcement method for preventing duodenal stump leakage.</p><p><strong>Methods: </strong>This retrospective cohort study was conducted between January 1, 2012 and December 31, 2021, with data analyzed between December 1, 2022 and September 30, 2023. This multicenter study across 57 institutes in Japan included 16,475 patients with gastric cancer who underwent radical gastrectomies. Elective open or minimally invasive (laparoscopic or robotic) gastrectomy was performed in patients with gastric cancer.</p><p><strong>Results: </strong>Duodenal stump leakage occurred in 153 (0.93%) of 16,475 patients. The proportions of males, patients aged ≥ 75 years, and ≥ pN1 were higher in patients with duodenal stump leakage than in those without duodenal stump leakage. The incidence of duodenal stump leakage was significantly lower in the group treated with reinforcement by seromuscular sutures or using reinforced stapler than in the group without reinforcement (0.72% vs. 1.19%, p = 0.002). Duodenal stump leakage incidence was also significantly lower in high-volume institutions than in low-volume institutions (0.70% vs. 1.65%, p = 0.047). The rate of duodenal stump leakage-related mortality was 7.8% (12/153). In the multivariate analysis, preoperative asthma and duodenal invasion were identified as independent preoperative risk factors for duodenal stump leakage-related mortality.</p><p><strong>Conclusions: </strong>The duodenal stump should be reinforced to prevent duodenal stump leakage after radical gastrectomy in patients with gastric cancer.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-19DOI: 10.1007/s10120-024-01536-z
Chiara Molinari, Leonardo Solaini, Francesca Rebuzzi, Gianluca Tedaldi, Davide Angeli, Elisabetta Petracci, Dusan Prascevic, Jan Ewald, Erhard Rahm, Matteo Canale, Martinelli Giovanni, Anna Tomezzoli, Maria Bencivenga, Maria Raffaella Ambrosio, Daniele Marrelli, Paolo Morgagni, Giorgio Ercolani, Paola Ulivi, Luca Saragoni
Background: The purpose of the study was to conduct a comprehensive genomic characterization of gene alterations, microsatellite instability (MSI), and tumor mutational burden (TMB) in submucosal-penetrating (Pen) early gastric cancers (EGCs) with varying prognoses.
Methods: Samples from EGC patients undergoing surgery and with 10-year follow-up data available were collected. Tissue genomic alterations were characterized using Trusight Oncology panel (TSO500). Pathway instability (PI) scores for a selection of 218 GC-related pathways were calculated both for the present case series and EGCs from the TCGA cohort.
Results: Higher age and tumor location in the upper-middle tract are significantly associated with an increased hazard of relapse or death from any cause (p = 0.006 and p = 0.032). Even if not reaching a statistical significance, Pen A tumors more frequently present higher TMB values, higher frequency of MSI-subtypes and an overall increase in PI scores, along with an enrichment in immune pathways. ARID1A gene was observed to be significantly more frequently mutated in Pen A tumors (p = 0.006), as well as in patients with high TMB (p = 0.027). Tumors harboring LRP1B alterations seem to have a higher hazard of relapse or death from any cause (p = 0.089), being mutated mainly in relapsed patients (p = 0.093).
Conclusions: We found that the most aggressive subtype Pen A is characterized by a higher frequency of ARID1A mutations and a higher genetic instability, while LRP1B alterations seem to be related to a lower disease-free survival. Further investigations are needed to provide a rationale for the use of these markers to stratify prognosis in EGC patients.
研究背景该研究旨在对不同预后的粘膜下穿透性早期胃癌(EGC)的基因改变、微卫星不稳定性(MSI)和肿瘤突变负荷(TMB)进行全面的基因组学分析:方法:收集接受过手术且有10年随访数据的EGC患者样本。采用 Trusight Oncology 面板(TSO500)对组织基因组改变进行表征。针对本病例系列和TCGA队列中的EGC,计算了218条GC相关通路的通路不稳定性(PI)评分:结果:较高的年龄和肿瘤位于中上部与复发或死于任何原因的风险增加有显著相关性(p = 0.006 和 p = 0.032)。即使未达到统计学意义,Pen A 型肿瘤也更常出现较高的 TMB 值、较高的 MSI 亚型频率和 PI 评分的整体增加,以及免疫通路的富集。据观察,ARID1A 基因在 Pen A 型肿瘤(p = 0.006)和高 TMB 患者(p = 0.027)中的突变频率明显更高。携带LRP1B基因改变的肿瘤似乎有更高的复发或死于任何原因的风险(p = 0.089),主要在复发患者中发生突变(p = 0.093):我们发现,最具侵袭性的亚型 Pen A 的特点是 ARID1A 突变频率较高和遗传不稳定性较高,而 LRP1B 的改变似乎与较低的无病生存率有关。还需要进一步研究,为使用这些标记物对EGC患者的预后进行分层提供依据。
{"title":"Genomic events stratifying prognosis of early gastric cancer.","authors":"Chiara Molinari, Leonardo Solaini, Francesca Rebuzzi, Gianluca Tedaldi, Davide Angeli, Elisabetta Petracci, Dusan Prascevic, Jan Ewald, Erhard Rahm, Matteo Canale, Martinelli Giovanni, Anna Tomezzoli, Maria Bencivenga, Maria Raffaella Ambrosio, Daniele Marrelli, Paolo Morgagni, Giorgio Ercolani, Paola Ulivi, Luca Saragoni","doi":"10.1007/s10120-024-01536-z","DOIUrl":"https://doi.org/10.1007/s10120-024-01536-z","url":null,"abstract":"<p><strong>Background: </strong>The purpose of the study was to conduct a comprehensive genomic characterization of gene alterations, microsatellite instability (MSI), and tumor mutational burden (TMB) in submucosal-penetrating (Pen) early gastric cancers (EGCs) with varying prognoses.</p><p><strong>Methods: </strong>Samples from EGC patients undergoing surgery and with 10-year follow-up data available were collected. Tissue genomic alterations were characterized using Trusight Oncology panel (TSO500). Pathway instability (PI) scores for a selection of 218 GC-related pathways were calculated both for the present case series and EGCs from the TCGA cohort.</p><p><strong>Results: </strong>Higher age and tumor location in the upper-middle tract are significantly associated with an increased hazard of relapse or death from any cause (p = 0.006 and p = 0.032). Even if not reaching a statistical significance, Pen A tumors more frequently present higher TMB values, higher frequency of MSI-subtypes and an overall increase in PI scores, along with an enrichment in immune pathways. ARID1A gene was observed to be significantly more frequently mutated in Pen A tumors (p = 0.006), as well as in patients with high TMB (p = 0.027). Tumors harboring LRP1B alterations seem to have a higher hazard of relapse or death from any cause (p = 0.089), being mutated mainly in relapsed patients (p = 0.093).</p><p><strong>Conclusions: </strong>We found that the most aggressive subtype Pen A is characterized by a higher frequency of ARID1A mutations and a higher genetic instability, while LRP1B alterations seem to be related to a lower disease-free survival. Further investigations are needed to provide a rationale for the use of these markers to stratify prognosis in EGC patients.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-06DOI: 10.1007/s10120-024-01533-2
Muhammad Irfan, Misaal Fatima, Maryam Shehzadi
{"title":"Comment on \"a machine learning model for predicting the lymph node metastasis of early gastric cancer not meeting the endoscopic curability criteria\".","authors":"Muhammad Irfan, Misaal Fatima, Maryam Shehzadi","doi":"10.1007/s10120-024-01533-2","DOIUrl":"https://doi.org/10.1007/s10120-024-01533-2","url":null,"abstract":"","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-04DOI: 10.1007/s10120-024-01531-4
Kuan-Fu Liao, Shih-Wei Lai
{"title":"Comment on \"Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors for new-onset gastric cancer and gastric diseases in patients with type 2 diabetes mellitus: a population-based cohort study\".","authors":"Kuan-Fu Liao, Shih-Wei Lai","doi":"10.1007/s10120-024-01531-4","DOIUrl":"https://doi.org/10.1007/s10120-024-01531-4","url":null,"abstract":"","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}