Intratumor transforming growth factor-ß signaling with extracellular matrix-related gene regulation marks chemotherapy-resistant gastric cancer.

Drug-tolerant persister (DTP) cells remain following chemotherapy and can cause cancer relapse. However, it is unclear when acquired resistance to chemotherapy emerges. Here, we compared the gene expression profiles of gastric cancer patient-derived cells (GC PDCs) and their respective xenograft tumors with different sensitivities to 5-fluorouracil (5-FU) by using immunodeficient female BALB/c-nu mice. RNA sequencing analysis of 5-FU-treated PDCs demonstrated that DNA replication/cell cycle-related genes were transiently induced in the earlier phase of DTP cell emergence, while extracellular matrix (ECM)-related genes were sustainably upregulated during long-term cell survival in 5-FU-resistant residual tumors. NicheNet analysis, which uncovers cell-cell signal interactions, indicated the transforming growth factor-ß (TGF-ß) pathway as the upstream regulator in response to 5-FU treatment. This induced ECM-related gene expression in the 5-FU-resistant tumor model. In the 5-FU-resistant residual tumors, there was a marked upregulation of cancer cell-derived TGF-ß1 expression and increased phosphorylation of SMAD3, a downstream regulator of the TGF-ß receptor. By contrast, these responses were not observed in a 5-FU-sensitive tumor model. We further found that TGF-ß-related upregulation of ECM genes was preferentially observed in non-responders to chemotherapy with 5-FU and/or oxaliplatin among 22 patient-derived xenograft tumors. These observations suggest that chemotherapy-induced activation of the TGF-ß1/SMAD3/ECM-related gene axis is a potential biomarker for the emergence of drug resistance in GCs.

CAF-associated genes putatively representing distinct prognosis by in silico landscape of stromal components of colon cancer.

Comprehensive understanding prognostic relevance of distinct tumor microenvironment (TME) remained elusive in colon cancer. In this study, we performed in silico analysis of the stromal components of primary colon cancer, with a focus on the markers of cancer-associated fibroblasts (CAF) and tumor-associated endothelia (TAE), as well as immunological infiltrates like tumor-associated myeloid cells (TAMC) and cytotoxic T lymphocytes (CTL). The relevant CAF-associated genes (CAFG)(representing R index = 0.9 or beyond with SPARC) were selected based on stroma specificity (cancer stroma/epithelia, cS/E = 10 or beyond) and expression amounts, which were largely exhibited negative prognostic impacts. CAFG were partially shared with TAE-associated genes (TAEG)(PLAT, ANXA1, and PTRF) and TAMC-associated genes (TAMCG)(NNMT), but not with CTL-associated genes (CTLG). Intriguingly, CAFG were prognostically subclassified in order of fibrosis (representing COL5A2, COL5A1, and COL12A1) followed by exclusive TAEG and TAMCG. Prognosis was independently stratified by CD8A, a CTL marker, in the context of low expression of the strongest negative prognostic CAFG, COL8A1. CTLG were comprehensively identified as IFNG, B2M, and TLR4, in the group of low S/E, representing good prognosis. Our current in silico analysis of the micro-dissected stromal gene signatures with prognostic relevance clarified comprehensive understanding of clinical features of the TME and provides deep insights of the landscape.

Pharmacologic Targeting of Histone H3K27 Acetylation/BRD4-dependent Induction of ALDH1A3 for Early-phase Drug Tolerance of Gastric Cancer.

Anticancer drug-tolerant persister (DTP) cells at an early phase of chemotherapy reshape refractory tumors. Aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is commonly upregulated by various anticancer drugs in gastric cancer patient-derived cells (PDC) and promotes tumor growth. However, the mechanism underlying the generation of ALDH1A3-positive DTP cells remains elusive. Here, we investigated the mechanism of ALDH1A3 expression and a combination therapy targeting gastric cancer DTP cells. We found that gastric cancer tissues treated with neoadjuvant chemotherapy showed high ALDH1A3 expression. Chromatin immunoprecipitation (ChIP)-PCR and ChIP sequencing analyses revealed that histone H3 lysine 27 acetylation was enriched in the ALDH1A3 promoter in 5-fluorouracil (5-FU)-tolerant persister PDCs. By chemical library screening, we found that the bromodomain and extraterminal (BET) inhibitors OTX015/birabresib and I-BET-762/molibresib suppressed DTP-related ALDH1A3 expression and preferentially inhibited DTP cell growth. In DTP cells, BRD4, but not BRD2/3, was recruited to the ALDH1A3 promoter and BRD4 knockdown decreased drug-induced ALDH1A3 upregulation. Combination therapy with 5-FU and OTX015 significantly suppressed in vivo tumor growth. These observations suggest that BET inhibitors are efficient DTP cell-targeting agents for gastric cancer treatment. SIGNIFICANCE: Drug resistance hampers the cure of patients with cancer. To prevent stable drug resistance, DTP cancer cells are rational therapeutic targets that emerge during the early phase of chemotherapy. This study proposes that the epigenetic regulation by BET inhibitors may be a rational therapeutic strategy to eliminate DTP cells.

Equal short-term outcomes of intracorporeal mechanical gastrogastrostomy in laparoscopic pylorus-preserving gastrectomy for cT1N0 gastric cancer in the middle stomach compared with the extracorporeal hand-sewing method.

BACKGROUND: Intracorporeal mechanical gastrogastrostomy (IMG) techniques have recently been developed and their short-term safety was presented in their initial evaluation. However, whether they are comparable to extracorporeal hand-sewing gastrogastrostomy (EHG) remains unclear. The aim of the study is to establish the safety of IMG in totally laparoscopic pylorus-preserving gastrectomy (TLPPG) compared to EHG in laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG). METHODS: We retrospectively analyzed the short-term outcomes of patients with middle-third early gastric cancer who underwent LAPPG or TLPPG between 2005 and 2022. The primary objective of this study was to evaluate the non-inferiority of IMG to EHG in terms of safety, with the primary endpoint being the risk difference in anastomosis-related complications (ARCs). The sample size required to achieve a statistical power of 80% for the non-inferiority test was 971 with a one-sided alpha level of 5% and non-inferiority of 5%. RESULTS: The analysis included a total of 1,021 patients who underwent LAPPG or TLPPG during the study period. Among them, 488 patients underwent EHG, while 533 underwent IMG. The incidences of ARCs were 11.3% and 11.4% in EHG and IMG, respectively. The observed difference in incidence was 0.0017 (90% confidence interval - 0.0313 to 0.0345), which statistically demonstrated the non-inferiority of IMG to EHG in the incidence of ARCs. Among other complications, the incidence of wound infection in IMG was lower than that in EHG. CONCLUSION: IMG is safe regarding ARCs compared with EHG. These results will encourage surgeons to introduce IMG for patients with early middle gastric cancer.

Impact of Olfactory Change on Postoperative Body Weight Loss in Patients with Gastric Cancer after Gastrectomy.

Patients undergoing gastrectomy for gastric cancer may experience alterations in olfaction, yet the association between olfactory changes and postoperative weight loss remains uncertain. This study aimed to elucidate the relationship between olfactory changes and postoperative weight loss in patients with gastric cancer. Patients who underwent radical gastrectomy for gastric cancer between February 2022 and August 2022 were included in the study. Those experiencing a higher Visual Analog Scale (VAS) score postoperatively compared to preoperatively were deemed to have undergone olfactory changes. Postoperative weight loss was determined using the 75th percentile as a cutoff value, designating patients surpassing this threshold as experiencing significant weight loss. Multivariate logistic regression analysis was employed to identify risk factors for postoperative weight loss, with statistical significance set at p < 0.05. Out of 58 patients, 10 (17.2%) exhibited olfactory changes. The rate of postoperative weight loss at one month was markedly higher in the group with olfactory changes compared to those without (9.6% versus 6.2%, respectively; p = 0.002). In addition, the group experiencing olfactory changes demonstrated significantly lower energy intake compared to the group without such changes (1050 kcal versus 1250 kcal, respectively; p = 0.029). Logistic regression analysis revealed olfactory changes as an independent risk factor for significant weight loss at one month postoperatively (odds ratio: 7.64, 95% confidence interval: 1.09-71.85, p = 0.048). In conclusion, olfactory changes emerged as an independent risk factor for postoperative weight loss at one month in patients with gastric cancer following gastrectomy.

Impact of preoperative prealbumin levels on long-term prognosis in patients with gastric cancer after gastrectomy: a retrospective cohort study.

BACKGROUND: The relationship between preoperative prealbumin levels and long-term prognoses in patients with gastric cancer after gastrectomy has not been fully investigated. This study clarified the effect of preoperative prealbumin levels on the long-term prognosis of patients with gastric cancer after gastrectomy. METHODS: This retrospective cohort study included consecutive patients who underwent radical gastrectomy for primary pStage I-III gastric cancer and whose preoperative prealbumin levels were measured between May 2006 and March 2017. Participants were categorized according to their preoperative prealbumin levels into high (≥22 mg/dL), moderate (15-22 mg/dL), and low (<15 mg/dL) groups. The overall survival (OS) in the three groups was compared using the log-rank test, and prognostic factors were identified using Cox proportional hazards regression analysis. RESULTS: The median follow-up duration was 66 months. Of 4732 patients, 3649 (77.2%) were classified as high, 925 (19.6%) as moderate, and 158 (3.3%) as low. Lower prealbumin levels were associated with poorer prognoses (P < 0.001). Multivariate analysis showed that prealbumin levels of 15-22 mg/dL [hazard ratio (HR): 1.576, 95% confidence interval (CI): 1.353-1.835, P < 0.001] and <15 mg/dL (HR: 1.769, 95% CI: 1.376-2.276, P < 0.001) were independent poor prognostic factors for OS. When analyzed according to the cause of death, prealbumin levels were associated with other-cause survival, but not cancer-specific survival. CONCLUSIONS: Preoperative prealbumin levels correlated with OS in patients with gastric cancer after gastrectomy; the lower the prealbumin level, the worse is the prognosis. Prealbumin levels may be associated with other-cause survival.

Risk factors for early recurrence after radical gastrectomy followed by adjuvant chemotherapy for stage II or III gastric cancer: a multicenter, retrospective study.

BACKGROUND: Radical gastrectomy followed by adjuvant chemotherapy is the standard treatment for stage II or III gastric cancer in Asian countries. Early recurrence during or after adjuvant chemotherapy is associated with poor prognosis; however, risk factors for early recurrence remain unclear. METHODS: In this multicenter, retrospective cohort study including six institutions, we evaluated the clinicopathological factors of 553 patients with gastric cancer undergoing gastrectomy followed by adjuvant chemotherapy between 2012 and 2016. Patients were divided into the following groups: early recurrence (recurrence during adjuvant chemotherapy or within 6 months after adjuvant chemotherapy completion) and non-early recurrence, which was further divided into late recurrence and no recurrence. Early-recurrence risk factors were investigated using multivariate Cox proportional hazard model. The chronological changes in the recurrence hazard were also examined for each factor. RESULTS: Early recurrence and late recurrence occurred in 83 (15.0%) and 73 (13.2%) patients, respectively. Based on the Cox proportional hazards model, a postoperative serum carcinoembryonic antigen level of ≥5 ng/mL (hazard ratio: 2.220, 95% confidence interval: 1.089-4.526) and a neutrophil-to-lymphocyte ratio of >1.8 (hazard ratio: 2.408, 95% confidence interval: 1.479-3.92) were identified as independent risk factors of early recurrence, but not late recurrence. The recurrence hazard ratios for neutrophil-to-lymphocyte ratio significantly decreased over time (P < 0.001) and carcinoembryonic antigen also had the same tendency (P = 0.08). CONCLUSIONS: A carcinoembryonic antigen level of ≥5 ng/mL and a neutrophil-to-lymphocyte ratio of >1.8 are predictors of early recurrence after radical gastrectomy and adjuvant chemotherapy for stage II or III gastric cancer.

Impact of Perioperative Immunonutrition on Postoperative Outcomes for Patients Undergoing Head and Neck or Gastrointestinal Cancer Surgeries: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To clarify whether perioperative immunonutrition is effective in adult patients with or without malnutrition undergoing elective surgery for head and neck (HAN) or gastrointestinal (GI) cancers. BACKGROUND: It is important to avoid postoperative complications in patients with cancer as they can compromise clinical outcomes. There is no consensus on the efficacy of perioperative immunonutrition in patients with or without malnutrition undergoing HAN or GI cancer surgery. MATERIALS AND METHODS: We searched MEDLINE (PubMed), MEDLINE (OVID), EMBASE, Cochrane Central Register of Controlled Trials, Web of Science Core Selection, and Emcare from 1981 to 2022 using search terms related to immunonutrition and HAN or GI cancer. We included randomized controlled trials. Intervention was defined as immunonutritional therapy including arginine, n-3 omega fatty acids, or glutamine during the perioperative period. The control was defined as standard nutritional therapy. The primary outcomes were total postoperative and infectious complications, defined as events with a Clavien-Dindo classification grade ≥ II that occurred within 30 days after surgery. RESULTS: Of the 4825 patients from 48 included studies, 19 had upper GI cancer, 9 had lower, and 8 had mixed cancer, whereas 12 had HAN cancers. Immunonutrition reduced the total postoperative complications (relative risk ratio: 0.78; 95% CI, 0.66-0.93; certainty of evidence: high) and infectious complications (relative risk ratio: 0.71; 95% CI, 0.61-0.82; certainty of evidence: high) compared with standard nutritional therapy. CONCLUSIONS: Nutritional intervention with perioperative immunonutrition in patients with HAN and GI cancers significantly reduced total postoperative complications and infectious complications.

Long-term impact of sarcopenia in older patients undergoing gastrectomy for gastric cancer: a systematic review and meta-analysis.

Background: Sarcopenia is an inevitable problem in older patients. After gastrectomy, patients often have an inadequate dietary intake and easily fall into sarcopenia. However, the impact of preoperative sarcopenia on long-term outcomes after gastrectomy has not been analyzed. Methods: A systematic review was conducted for all relevant articles identified on PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov until April 2023. Adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the fixed or random effects model according to the heterogeneity. The Newcastle-Ottawa Scale was used to quantify study quality. Results: Seven studies involving 1,831 patients aged ≥65 years who underwent gastrectomy for gastric cancer were analyzed. Four hundred twelve patients (22.5%) were diagnosed with sarcopenia. The analysis showed that preoperative sarcopenia was significantly associated with poor overall survival (OS) (HR =1.93; 95% CI:1.60-2.34; P<0.001). Two of the included studies also showed that preoperative sarcopenia was significantly correlated with disease-related survival: one with disease-specific survival (DSS) (HR =4.00; 95% CI: 1.20-13.3, P=0.024) and the other with non-cancer specific survival (HR =3.27; 95% CI: 1.61-6.67; P=0.001). Furthermore, sarcopenic patients experienced more severe complications than non-sarcopenic patients (OR =1.80; 95% CI: 1.10-2.95; P=0.019). Conclusions: This meta-analysis suggested that preoperative sarcopenia is useful as a prognostic factor of impaired OS in older patients after gastrectomy. Preoperative evaluation and intervention for skeletal muscle loss should be considered. Further studies of sarcopenic impact on disease-related survival are required.

Optimal resection of gastric bronchogenic cysts based on anatomical continuity with adherent gastric muscular layer: A case report.

BACKGROUND: Bronchogenic cysts are congenital lesions requiring radical resection because of malignant potential. However, a method for the optimal resection of these cysts has not been completely elucidated. CASE SUMMARY: Herein, we presented three patients with bronchogenic cysts that were located adjacent to the gastric wall and resected laparoscopically. The cysts were detected incidentally with no symptoms and the preoperative diagnosis was challenging to obtain via radiological examinations. Based on laparoscopic findings, the cyst was attached firmly to the gastric wall and the boundary between the gastric and cyst walls was difficult to identify. Consequently, resection of cysts alone caused cystic wall injury in Patient 1. Meanwhile, the cyst was resected completely along with a part of the gastric wall in Patient 2. Histopathological examination revealed the final diagnosis of bronchogenic cyst and revealed that the cyst wall shared the muscular layer with the gastric wall in Patients 1 and 2. In Patient 3, the cyst was located adjacent to the gastric wall but histopathologically originated from diaphragm rather than stomach. All the patients were free from recurrence. CONCLUSION: The findings of this study state that a safe and complete resection of bronchogenic cysts required the adherent gastric muscular layer or full-thickness dissection, if bronchogenic cysts are suspected via pre- and/or intraoperative findings.

Relationship between antithrombotic drugs and postoperative outcomes in patients with gastric cancer after gastrectomy: a propensity matching analysis.

BACKGROUND: As there is no consensus on the impact of antithrombotic drugs on post-gastrectomy outcomes in gastric cancer patients, this study aimed to investigate the impact of antithrombotic drugs on postoperative outcomes in these patients after gastrectomy. METHODS: Patients with Stage I-III primary gastric cancer who underwent radical gastrectomy between April 2005 and May 2022 were included. We performed propensity score matching to adjust for patient background and compared bleeding complications. Multivariate analysis with logistic regression analysis was performed to identify risk factors associated with bleeding complications. RESULTS: Of the 6798 patients, 310 (4.6%) were in the antithrombotic group and 6488 (95.4%) were in the non-antithrombotic group. Twenty-six patients (0.38%) experienced bleeding complications. After matching, the number of patients in each group was 300, with insignificant differences in any factor. A comparison of postoperative outcomes showed no difference in bleeding complications (P = 0.249). In the antithrombotic group, 39 (12.6%) continued drugs, and 271 (87.4%) discontinued them before surgery. After matching, there were 30 and 60 patients, respectively, with no differences in patient background. A comparison of postoperative outcomes showed no differences in bleeding complications (P = 0.551). In multivariate analysis, antithrombotic drug use and continuation of antiplatelet agents were not risk factors for bleeding complications. CONCLUSION: Antithrombotic drugs and its continuation may not worsen bleeding complications in patients with gastric cancer after radical gastrectomy. Bleeding complications were rare, and further studies are needed on risk factors for bleeding complications in larger databases.

Oncological impact of unexpected horizontal tumor spread in gastric cancer that requires total gastrectomy.

BACKGROUND: Gastric cancer often exhibits discrepancies between the gross and pathological tumor boundaries, and the degree of discrepancy may be a tumor characteristic. However, whether these discrepancies influence oncological outcomes remains unclear. METHODS: The data of patients who underwent total gastrectomy for gastric cancer from 2005 to 2018 were collected. A new parameter, ΔPM, which corresponds to the length of the discrepancy between the gross and pathological proximal boundaries, was calculated and the patients were divided into two groups: patients with long ΔPM and those with short ΔPM. Oncological outcomes were compared between the two groups. RESULTS: A length of 8 mm was determined as the cutoff value for long or short ΔPM. Tumor size, growth pattern, pathological type, depth, and esophageal invasion were associated with ΔPM > 8 mm. Overall survival of the ΔPM > 8 mm group was significantly worse than that of the ΔPM ≤ 8 mm group (5-year overall survival: 58% vs 78%; p < 0.0001). Multivariate analysis revealed that ΔPM > 8 mm was an independent risk factor for poor survival and peritoneal metastasis. The likelihood ratio test revealed a significant interaction between pT status and ΔPM (p = 0.0007). Circumferential involvement and gross esophageal invasion were poorer survival factors in the ΔPM > 8 mm group. CONCLUSIONS: ΔPM > 8 mm is related to several clinicopathological characteristics and is an independent risk factor for poorer survival and peritoneal metastasis but not local recurrence. ΔPM > 8 mm combined with circumferential involvement or esophageal invasion is associated with relatively poor survival outcomes.

Advantages of Function-Preserving Gastrectomy for Older Patients With Upper-Third Early Gastric Cancer: Maintenance of Nutritional Status and Favorable Survival.

PURPOSE: The incidence of early gastric cancer is increasing in older patients alongside life expectancy. For early gastric cancer of the upper third of the stomach, laparoscopic function-preserving gastrectomy (LFPG), including laparoscopic proximal gastrectomy (LPG) and laparoscopic subtotal gastrectomy (LSTG), is expected to be an alternative to laparoscopic total gastrectomy (LTG). However, whether LFPG has advantages over LTG in older patients remains unknown. MATERIALS AND METHODS: We retrospectively analyzed data of consecutive patients aged ≥75 years who underwent LTG, LPG, or LSTG for cT1N0M0 gastric cancer between 2005 and 2019. Surgical and nutritional outcomes, including blood parameters, percentage body weight (%BW) and percentage skeletal muscle index (%SMI) were compared between LTG and LPG or LSTG. Survival outcomes were also compared between LTG and LFPG groups. RESULTS: A total of 111 patients who underwent LTG (n=39), LPG (n=48), and LSTG (n=24) were enrolled in this study. To match the surgical indications, LTG was further categorized into "LTG for LPG" (LTG-P) and "LTG for LSTG" (LTG-S). No significant differences were identified in the incidence of postoperative complications among the procedures. Postoperative nutritional parameters, %BW and %SMI were better after LPG and LSTG than after LTG-P and LTG-S, respectively. The survival outcomes of LFPG were better than those of LTG. CONCLUSIONS: LFPG is safe for older patients and has advantages over LTG in terms of postoperative nutritional parameters, body weight, skeletal muscle-sparing, and survival. Therefore, LFPG for upper early gastric cancer should be considered in older patients.

A sandwiching method that simplifies hepatic left lateral segment inversion to secure an optimal surgical view around the esophageal hiatus in laparoscopic and robotic gastrectomy for upper gastric and esophagogastric junction cancers.

PURPOSE: In laparoscopic surgery for upper gastric and esophagogastric junction (EGJ) cancer, it is important to achieve optimal exposure of the esophageal hiatus to secure an appropriate workspace. In recent years, hepatic left lateral segment (HLLS) inversion has been used to achieve an optimal surgical field. We present a simple technique to perform a modified HLLS inversion. METHODS: As a simple modified method, suturing a 2-0 straight needle to the peritoneum of the round ligament and pulling it to the outside of the abdominal cavity, the falciform, left triangular, and coronary ligaments were dissected. The HLLS was inverted by moving it to the right through the space of the transected falciform ligament. By ligating the thread through the round ligament, the HLLS was sandwiched between the rest of the liver and abdominal wall. The short-term surgical outcomes of patient who underwent simple modified HLLS inversion were retrospectively reviewed. RESULTS: This study investigated consecutive 24 patients who underwent laparoscopic proximal and total gastrectomies using the simple modified HLLS inversion technique between June 2021 and April 2022. This series of procedures could be completed in approximately 16 min. A Nathanson liver retractor was used in three patients due to difficulties in completing the HLLS inversion in our institution. Postoperative serum liver enzyme levels indicated there was a small effect on the liver. CONCLUSIONS: The simple modified HLLS inversion technique may be a safe and useful procedure and can provide an enhanced surgical field during laparoscopic surgery for upper gastric and EGJ cancers.

Perioperative TAS-118 plus oxaliplatin in patients with locally advanced gastric cancer: APOLLO-11 study.

BACKGROUND: We investigated the feasibility of perioperative chemotherapy with S-1 and leucovorin (TAS-118) plus oxaliplatin in patients with locally advanced gastric cancer. METHODS: Patients with clinical T3-4N1-3M0 gastric cancer received four courses of TAS-118 (40-60 mg/body, orally, twice daily for seven days) plus oxaliplatin (85 mg/m2, intravenously, day one) every two weeks preoperatively followed by gastrectomy with D2 lymphadenectomy, followed by postoperative chemotherapy with either 12 courses of TAS-118 monotherapy (Step 1) or eight courses of TAS-118 plus oxaliplatin (Step 2). The primary endpoints were completion rates of preoperative chemotherapy with TAS-118 plus oxaliplatin and postoperative chemotherapy with TAS-118 monotherapy (Step 1) or TAS-118 plus oxaliplatin (Step 2). RESULTS: Among 45 patients enrolled, the preoperative chemotherapy completion rate was 88.9% (90% CI 78.0-95.5). Major grade ≥ 3 adverse events (AEs) were diarrhoea (17.8%) and neutropenia (8.9%). The R0 resection rate was 95.6% (90% CI 86.7-99.2). Complete pathological response was achieved in 6 patients (13.3%). Dose-limiting toxicity was not observed in 31 patients receiving postoperative chemotherapy (Step 1, n = 11; Step 2, n = 20), and completion rates were 90.9% (95% CI 63.6-99.5) for Step 1 and 80.0% (95% CI 59.9-92.9) for Step 2. No more than 10% of grade ≥ 3 AEs were observed in patients receiving Step 1. Hypokalaemia and neutropenia occurred in 3 and 2 patients, respectively, receiving Step 2. The 3-year recurrence-free and overall survival rates were 66.7% (95% CI 50.9-78.4) and 84.4% (95% CI 70.1-92.3), respectively. CONCLUSIONS: Perioperative chemotherapy with TAS-118 plus oxaliplatin with D2 gastrectomy is feasible.

Anatomical Position of the Pancreas as a Risk Factor for Pancreatic Fistula after Laparoscopic Gastrectomy for Gastric Cancer.

BACKGROUND: Laparoscopic gastrectomy is more frequently associated with postoperative pancreatic fistula than is open gastrectomy. We assumed that compression of the pancreas with various devices to obtain a proper operative view is associated with the higher incidence of PF in LG and that the extent of the compression differs depending on the anatomical position of the pancreas. The present study aimed to elucidate the correlation between the anatomical position of the pancreas and PF after LG for gastric cancer. METHODS: Patients who underwent LG for gastric cancer from 2005 to 2019 were retrospectively reviewed. Two anatomical parameters representing the height of the slope looking down the celiac artery from the top of the pancreas (P-A length) and the steepness of the slope (UP-CA angle) were measured in computed tomography sagittal projections. The correlation between PF and (1) P-A length, (2) UP-CA angle, and (3) other clinicopathological factors was analyzed using a logistic regression model. RESULTS: Among 3485 patients, grade ≥ II PF was observed in 140 (4.0%) patients. The UP-CA angle [odds ratio (OR), 2.472; 95% confidence interval (CI), 1.725-3.543; P < 0.001], a high BMI (OR 2.339; 95% CI 1.634-3.348; P < 0.001), and male sex (OR 2.602; 95% CI 1.590-4.257; P < 0.001) were independently correlated with grade ≥ II PF. CONCLUSIONS: The present study identified a significant correlation between anatomical position of the pancreas and PF after LG. High BMI and male sex were also significantly correlated with PF after LG.

Required esophageal resection length beyond the tumor boundary to ensure a negative proximal margin for gastric cancer with gross esophageal invasion or esophagogastric junction cancer.

BACKGROUND: To obtain a pathologically negative proximal margin (PM) for gastric cancer with gross esophageal invasion (EI) or esophagogastric junction (EGJ) cancer, we should transect the esophagus beyond the proximal boundary of gross EI with a safety margin because of a discrepancy between the gross and pathological boundaries of cancer. However, recommendations regarding the esophageal resection length for these cancers have not been established. METHODS: Patients who underwent proximal or total gastrectomy for gastric cancer with gross EI or EGJ cancer were enrolled. A parameter ΔPM, which corresponded to the length of a discrepancy between the gross and pathological proximal boundary of the tumor, was evaluated. The maximum ΔPM, which corresponded to the minimum length ensuring a pathologically negative PM, was first determined in all patients. Then subgroup analyses according to factors associated with ΔPM ≥ 10 mm were performed to identify alternative maximum ΔPMs. RESULTS: A total of 289 patients with gastric cancer with gross EI or EGJ cancer were eligible and analyzed in this study. The maximum ΔPM was 25 mm. Clinical tumor (cTumor) size and growth and pathological types were independently associated with ΔPM ≥ 10 mm. In subgroup analyses, the maximum ΔPM was 15 mm for cTumor size ≤ 40 mm and superficial growth type. Furthermore, the maximum ΔPM was 20 mm in the expansive growth type. CONCLUSIONS: Required esophageal resection lengths to ensure a pathologically negative PM for gastric cancer with gross EI or EGJ cancer are proposed.

Nutritional counseling for patients with incurable cancer: Systematic review and meta-analysis.

BACKGROUND & AIMS: This systematic review aims to determine whether nutritional counseling by registered dietitians and/or nutritional specialists is recommended for adult patients with incurable advanced or recurrent cancer who are refractory to or intolerant of anticancer therapy. METHODS: This systematic review analyzed randomized controlled trials (RCTs) of nutritional counseling in cancer patients older than 18 years, primarily those with stage 4 cancer. Nutrition counseling was performed by registered dietitians and/or nutritional specialists using any method, including group sessions, telephone consultations, written materials, and web-based approaches. We searched the Medline (PubMed), Medline (OVID), EMBASE (OVID), CENTRAL, Emcare, and Web of Science Core Collection databases for articles published from 1981 to 2020. Two independent authors assessed the risk of bias used the Cochrane Risk of Bias 2 tool. Meta-analysis was performed for results and outcomes that allowed quantitative integration. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (ID: CRD42021288476) and registered in 2021. RESULTS: The search yielded 2376 studies, of which 7 assessed 924 patients with cancer aged 24-95 years. Our primary outcome of quality of life (QoL) was reported in 6 studies, 2 of which showed improvement with nutritional counseling. Our other primary outcome of physical symptoms was reported in two studies, one of which showed improvement with nutritional counseling. Quantitative integration of both QoL and physical symptoms was difficult. A meta-analysis of energy and protein intake and body weight was performed for secondary outcomes. Results showed that nutrition counseling increased energy and protein intake, but total certainty of evidence (CE) was low. Bodyweight was not improved by nutrition counseling. CONCLUSIONS: Nutrition counseling is shown to improve energy and protein intake in patients with incurable cancer. Although neither nutrient intake can be strongly recommended because of low CE, nutrition counseling is a noninvasive treatment strategy that should be introduced early for nutrition intervention for patients with cancer. This review did not find sufficient evidence for the effect of nutrition counseling on QoL, a patient-reported outcome. Overall, low-quality and limited evidence was identified regarding the impact of nutrition counseling for patients with cancer, and further research is needed.

Evaluating the efficacy of post-operative chemotherapy after curative resection of stage IV gastric cancer with synchronous oligo metastasis: a multicenter retrospective study.

BACKGROUND: Surgical resection of oligo-metastasis in gastric cancer (GC) is weakly recommended for patients without other incurable factors in the Japanese GC Treatment Guidelines. While post-operative chemotherapy is the standard treatment in patients with stage II or III GC, its efficacy for resected stage IV GC is unclear. This study aimed to evaluate the efficacy of post-operative chemotherapy after curative resection of GC with oligo-metastasis. METHODS: We retrospectively reviewed the medical records of patients with GC who were diagnosed with synchronous oligo-metastasis at 20 institutions in Japan between 2007 and 2012. The selection criteria were: adenocarcinoma, stage IV with oligo-metastasis at liver or lymph node without other distant metastasis, curative resection including synchronous oligo-metastasis, and no prior treatment of GC before surgery. RESULTS: A total of 110 patients were collected. Of the 94 eligible patients, 84 underwent gastrectomy with surgical resection of oligo-metastasis (39 [41%] liver metastasis and 55, [59%] distant lymph node metastasis), followed by post-operative chemotherapy with S-1 (S1: n = 55), S1 plus cisplatin (CS: n = 22), or Others (n = 7). Moreover, 10 patients did not receive post-operative chemotherapy (Non-Cx). The median overall survival (OS) was 35.2 and 11.1 months in the post-operative chemotherapy and Non-Cx groups (hazard ratio, 3.56; 95% confidence interval, 1.74-7.30; p < 0.001), respectively. In multivariable analysis, Non-Cx and age over 70 years were identified as poor prognostic factors for OS (p < 0.05). CONCLUSIONS: Curative resection followed by post-operative chemotherapy in patients with GC with synchronous oligo-metastasis showed favorable survival.

Reflux Esophagitis After Laparoscopic Pylorus-Preserving Gastrectomy for Gastric Cancer.

BACKGROUND: Laparoscopic pylorus-preserving gastrectomy (LPPG) is performed for cT1N0 gastric cancer as a function-preserving surgery, but reflux esophagitis can develop as a mid- to long-term complication postoperatively. We aimed to clarify the incidence rate of this complication and the factors correlated with it. METHODS: Patients with gastric cancer who underwent LPPG between 2005 and 2017 were analyzed. Postoperative reflux esophagitis was evaluated with esophagogastroduodenoscopy; patients were diagnosed as having reflux esophagitis with erosive esophagitis using the modified Los Angeles classification. The incidence rate of postoperative reflux esophagitis was estimated; factors correlated with postoperative reflux esophagitis were analyzed using the logistic regression model. RESULTS: During the study period, 813 patients underwent LPPG for gastric cancer, and 127 (15.6%) of them developed grade B or more severe postoperative reflux esophagitis. The factors correlated with postoperative reflux esophagitis were male sex (odds ratio, 2.68; 95% confidence interval, 1.77-4.05; P < 0.001), preoperative grade A reflux esophagitis (odds ratio, 3.05; 95% confidence interval, 1.28-7.27; P = 0.012), body mass index of ≥ 23 kg/m2 at 1 year postoperatively (odds ratio, 2.18; 95% confidence interval, 1.34-3.53; P = 0.002), postoperative hiatal hernia (odds ratio, 4.35; 95% confidence interval, 2.35-8.04; P < 0.001), and long-term stasis (odds ratio, 1.58; 95% confidence interval, 1.01-2.47; P = 0.044). CONCLUSIONS: Careful attention should be paid in performing LPPG and in postoperative management after LPPG for gastric cancer patients with those risk factors.