Serum NY-ESO-1 antibody as a predictive biomarker for postoperative recurrence of gastric cancer: a multicenter prospective observational study.

BACKGROUND: No reliable marker has been identified to predict postoperative recurrence of gastric cancer. We designed a clinical trial to investigate the utility of serum NY-ESO-1 antibody responses as a predictive marker for postoperative recurrence in gastric cancer. METHODS: A multicenter prospective study was conducted between 2012 and 2021. Patients with resectable cT3-4 gastric cancer were included. Postoperative NY-ESO-1 and p53 antibody responses were serially evaluated every 3 months for 1 year in patients with positive preoperative antibody responses. The recurrence rate was assessed by the positivity of antibody responses at 3 and 12 months postoperatively. RESULTS: Among 1001 patients, preoperative NY-ESO-1 and p53 antibody responses were positive in 12.6% and 18.1% of patients, respectively. NY-ESO-1 antibody responses became negative postoperatively in non-recurrent patients (negativity rates; 45% and 78% at 3 and 12 months, respectively), but remained positive in recurrent patients (negativity rates; 9% and 8%, respectively). p53 antibody responses remained positive in non-recurrent patients. In multivariate analysis, NY-ESO-1 antibody positivity at 3 months (P < 0.03) and 12 months (P < 0.001) were independent prognostic factors for a shorter recurrence-free interval. CONCLUSIONS: Serum NY-ESO-1 antibodies may be a useful predictive marker for postoperative recurrence in gastric cancer. CLINICAL TRIAL REGISTRATION: UMIN000007925.

Long-Term Effects of Oral Nutritional Supplements After Gastrectomy for Gastric Cancer: A Survival Analysis from a Multicenter, Open-Label, Randomized Controlled Trial.

BACKGROUND: Weight loss (WL) after gastrectomy for gastric cancer is associated with both decreased compliance with adjuvant chemotherapy and impaired survival. This study examined the effects of administering oral nutritional supplements (ONS) for 3 months after gastrectomy in terms of compliance with adjuvant chemotherapy and survival outcomes. METHODS: This large-scale, multicenter, open-label, randomized controlled trial enrolled 1,003 gastric cancer patients undergoing curative gastrectomy. Patients were assigned to the control group (n = 503) or ONS group (n = 500). In the ONS group, 400 kcal/day of ONS was recommended in addition to a regular diet for 3 months after gastrectomy. Compliance with adjuvant chemotherapy and survival outcomes were compared between the two groups. RESULTS: Compared with the control group, the ONS group showed significantly decreased WL at 3 months after gastrectomy (8.6 ± 6.1 vs. 7.2 ± 5.7%, respectively, P = 0.0004). The control and ONS groups did not differ regarding the induction rate of adjuvant chemotherapy (84.9 vs. 82.8%, respectively, P = 0.614) or the continuation rate at 3 months postoperatively (75.3 vs. 76.6%, respectively, P = 0.809). Oral nutritional supplements for 3 months showed no survival benefit; the 3- and 5-year overall survival (OS) rates were 91.3% and 87.6% in the control group and 89.6% and 86.4% in the ONS group, respectively, indicating no significant difference (P = 0.548). Subgroup analysis could not detect a population in which ONS administration increased OS. CONCLUSIONS: Administration of ONS for 3 months after gastrectomy was not associated with increased compliance with adjuvant chemotherapy or with improved prognosis.

The impact of contour maps on estimating the risk of gastrointestinal stromal tumor recurrence: indications for adjuvant therapy: an analysis of the Kinki GIST registry.

INTRODUCTION: Contour maps enable risk classification of GIST recurrence in individual patients within 10 postoperative years. Although contour maps have been referred to in Japanese guidelines, their usefulness and role in determining indications for adjuvant therapy is still unclear in Japanese patients. The aims of this study are to investigate the validity of contour maps in Japanese patients with GIST and explore the new strategy for adjuvant therapy. MATERIALS AND METHODS: A total of 1426 Japanese GIST patients who were registered to the registry by the Kinki GIST Study Group between 2003 and 2012 were analyzed. Patients who had R0 surgery without perioperative therapy were included in this study. The accuracy of contour maps was validated. RESULTS: Overall, 994 patients have concluded this study. Using contour maps, we validated the patients. The 5-year recurrence-free survival rates of patients within the GIST classification groups of 0-10%, 10-20%, 20-40%, 40-60%, 60-80%, 80-90%, and 90-100% were 98.1%, 96.6%, 92.3%, 48.0%, 37.3%, 41.0% and 42.4%, respectively. We confirmed that this classification by contour maps was well reflected recurrence prediction. Further, in the high-risk group stratified by the modified National Institutes of Health consensus criteria (m-NIHC), the 10-year RFS rate was remarkably changed at a cutoff of 40% (0-40% group vs. 40-100% group: 88.7% vs. 50.3%, p < 0.001). CONCLUSION: Contour maps are effective in predicting individual recurrence rates. And it may be useful for the decision of individual strategy for high-risk patients combined with m-NIHC.

Lipolysis-stimulated lipoprotein receptor promote lipid uptake and fatty acid oxidation in gastric cancer.

BACKGROUND: Lipolysis-stimulated lipoprotein receptor (LSR), a lipid receptor, is associated with cancer progression. However, detailed effects on intracellular metabolism are unclear. We aimed to elucidate the mechanism of LSR-mediated lipid metabolism in gastric cancer. METHODS: We investigated lipid metabolic changes induced by lipoprotein administration in gastric cancer cells and evaluated the significance of LSR expression and lipid droplets formation in gastric cancer patients. The efficacy of inhibiting ß-oxidation in gastric cancer cells was also examined in vitro and vivo. RESULTS: In gastric cancer cells, LSR promoted cellular uptake of lipoprotein and cell proliferation. Furthermore, the inhibition of LSR in gastric cancer cells expressing high levels of LSR counteracted both effects. Immunohistochemical analysis of human gastric cancer tissues showed that the increase in lipid droplets via LSR is a factor that influences prognosis. Lipidomics analysis of LSR-high-expressing gastric cancer cells revealed an increase in ß-oxidation. Based on these results, we used etomoxir, a ß-oxidation inhibitor, and found that it inhibited cell proliferation as well as the suppression of LSR. Similarly, in a mouse xenograft model of LSR-highly expressing gastric cancer cells, the tumor growth effect of high-fat diet feeding was counteracted by etomoxir, consistent with the Ki-67 labeling index. CONCLUSIONS: We demonstrated that lipids are taken up into gastric cancer cells via LSR and cause an increase in ß-oxidation, resulting in the promotion of cancer progression. Controlling LSR-mediated lipid metabolism may be a novel therapeutic strategy for gastric cancer.

Short-term outcomes of preoperative chemotherapy with docetaxel, oxaliplatin, and S-1 for gastric cancer with extensive lymph node metastasis (JCOG1704).

BACKGROUND: The prognosis for marginally resectable gastric cancer with extensive lymph node metastasis (ELM) remains unfavorable, even after R0 resection. To assess the safety and efficacy of preoperative docetaxel, oxaliplatin, and S-1 (DOS), we conducted a multicenter phase II trial. METHODS: Eligibility criteria included histologically proven HER2-negative gastric adenocarcinoma with bulky nodal (bulky N) involvement around major branched arteries or para-aortic node (PAN) metastases. Patients received three cycles of docetaxel (40 mg/m2, day 1), oxaliplatin (100 mg/m2, day 1), and S-1 (80-120 mg/body, days 1-14), followed by gastrectomy with D2 plus PAN dissection. Subsequently, patients underwent postoperative chemotherapy with S-1 for 1 year. The primary endpoint was major (grade ≥ 2a) pathological response rate (pRR) according to the Japanese Classification of Gastric Carcinoma criteria. RESULTS: Between October 2018 and March 2022, 47 patients (bulky N, 20; PAN, 17; both, 10) were enrolled in the trial. One patient was ineligible. Another declined any protocol treatments before initiation. Among the 45 eligible patients who initiated DOS chemotherapy, 44 (98%) completed 3 cycles and 42 (93%) underwent R0 resection. Major pRR and pathological complete response rates among the 46 eligible patients, including the patient who declined treatment, were 57% (26/46) and 24% (11/46), respectively. Common grade 3 or 4 toxicities were neutropenia (24%), anorexia (16%), febrile neutropenia (9%), and diarrhea (9%). No treatment-related deaths occurred. CONCLUSIONS: Preoperative chemotherapy with DOS yielded favorable pathological responses with an acceptable toxicity profile. This multimodal approach is highly promising for treating gastric cancer with ELM.

5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer.

BACKGROUND: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is the standard treatment for pathological stage II gastric cancer. The phase III trial (JCOG1104) investigating the non-inferiority of four courses of S-1 to eight courses was terminated due to futility at the first interim analysis. To confirm the primary results, we reported the results after a 5-years follow-up in JCOG1104. METHODS: Patients histologically diagnosed with stage II gastric cancer after radical gastrectomy were randomly assigned to receive S-1 for eight or four courses. In detail, 80 mg/m2/day S-1 was administered for 4 weeks followed by a 2-week rest as a single course. RESULTS: Between February 16, 2012, and March 19, 2017, 590 patients were enrolled and randomly assigned to 8-course (295 patients) and 4-course (295 patients) regimens. After a 5-years follow-up, the relapse-free survival at 3 years was 92.2% for the 8-course arm and 90.1% for the 4-course arm, and that at 5 years was 87.7% for the 8-course arm and 85.6% for the 4-course arm (hazard ratio 1.265, 95% CI 0.846-1.892). The overall survival at 3 years was 94.9% for the 8-course arm, 93.2% for the 4-course arm, and that at 5 years was 89.7% for the 8-course arm, and 88.6% for the 4-course arm (HR 1.121, 95% CI 0.719-1.749). CONCLUSIONS: The survival of the four-course arm was slightly but consistently inferior to that of the eight-course arm. Eight-course S-1 should thus remain the standard adjuvant chemotherapy for pathological stage II gastric cancer.

A real-world survey on expensive drugs used as first-line chemotherapy in patients with HER2-negative unresectable advanced/recurrent gastric cancer in the stomach cancer study group of the Japan clinical oncology group.

BACKGROUND: Molecular-targeted drugs and immune checkpoint inhibitors have been developed for various malignant diseases, thereby improving clinical outcomes. However, these drugs are expensive, and few studies have assessed their actual use and costs in Japan. This study aimed to survey the use and costs of first-line chemotherapy for advanced/recurrent gastric cancer (AGC) in real-world settings. METHODS: The survey included patients with human epidermal growth factor receptor type2 (HER2)-negative AGC who initiated first-line chemotherapy from January 2022 to December 2022 at the participating 92 institutions in the Japan Clinical Oncology Group. Data on the regimens were collected using Google Forms. A regimen that costs >500 000 Japanese yen (JPY) per month was defined as expensive. RESULTS: Data on chemotherapy regimens were collected from 2173 patients at all 92 institutions between March 2023 and May 2023. We analyzed 2113 patients who underwent the chemotherapy with recommended regimens and conditionally recommended regimens according to the Japanese Gastric Cancer Treatment Guidelines sixth edition. The expensive regimens were triplet chemotherapy with fluoropyrimidine (S-1 or capecitabine or 5-fluorouracil/levofolinate), oxaliplatin, and nivolumab. Their monthly costs ranged from 767 648 to 771 046 JPY. Nivolumab-containing regimens cost more than 20 times the price of conventional chemotherapy with fluoropyrimidine and oxaliplatin. These regimens were used in 1416 (67%) of 2113 patients: in 71% of patients aged ≤74 years and in 59% of patients aged ≥75 years. CONCLUSION: The regimens with >20-fold cost of conventional chemotherapy were used as first-line chemotherapy in two-thirds of patients and more than half even in the elderly population with HER2-negative AGC. This finding is important for future health economic studies on drug cost-efficacy.

Protocol digest of a randomized controlled adaptive Phase II/III trial of neoadjuvant chemotherapy for Japanese patients with oesophagogastric junction adenocarcinoma: Japan Clinical Oncology Group Study JCOG2203 (NEO-JPEG).

Treatment strategies for oesophagogastric junction adenocarcinoma have not been standardized despite its poor prognosis due to differences in the incidence rates between Western countries and Asia. This randomized Phase II/III trial was initiated in June 2023 to determine which neoadjuvant chemotherapy regimen, docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel, is a more promising treatment in Phase II and confirm the superiority of neoadjuvant chemotherapy with docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel followed by surgery and postoperative chemotherapy over upfront surgery and postoperative chemotherapy in terms of overall survival in patients with Clinical Stage III or IVA oesophagogastric junction adenocarcinoma in Phase III. A total of 460 patients, including 150 patients in Phase II and 310 patients in Phase III, are planned to be enrolled from 85 hospitals in Japan over 5 years. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230182 (https://jrct.niph.go.jp/latest-detail/jRCTs031230182).

Association between fibrosis around the tumor and postoperative infectious complication in patients with esophageal cancer who underwent preoperative therapy.

BACKGROUND: Multidisciplinary treatment combining chemotherapy, chemo radiation therapy (CRT), and surgery has been utilized for advanced esophageal cancer. However, preoperative treatment could cause postoperative inflammation and complications. We hypothesized that fibrosis surrounding tumor tissue caused by preoperative treatment could induce postoperative systemic inflammation and influence postoperative complications. METHODS: Surgical specimens from patients with thoracic esophageal cancer who underwent preoperative CRT (38 cases) or chemotherapy (77 cases) and those who received no preoperative treatment (49 cases) were evaluated to measure the fibrotic area adjacent to the tumor (10 mm from the tumor edge) by applying Azan staining. Pleural effusion and peripheral blood serum interleukin-6 levels were analyzed to evaluate local and systemic postoperative inflammation in 37 patients. RESULTS: The fibrotic areas around the tumors were significantly larger in patients who underwent preoperative CRT than in patients who underwent chemotherapy (p < 0.001) or who had received no preoperative therapy (p < 0.001). Infectious complications were higher in patients who underwent preoperative CRT than chemotherapy (p = 0.047) or surgery alone (p < 0.001). The patients with larger fibrotic areas had more infectious complications (p = 0.028). Multivariate analysis showed that both a large fibrotic area and preoperative CRT were correlated with infectious complications, but not significantly. Pleural effusion interleukin-6 was significantly higher in patients who underwent preoperative CRT than in patients who received no preoperative therapy (p = 0.013). CONCLUSIONS: A large fibrotic peritumoral esophageal tissue area after preoperative treatment could cause postoperative inflammatory response and infectious complications.

Phase II study of S-1 plus docetaxel as first-line treatment for older patients with advanced gastric cancer (OGSG 0902).

BACKGROUND: Although there is insufficient evidence for the treatment of older patients with advanced gastric cancer, fluorouracil combined with platinum chemotherapy has been recognized as a standard first-line treatment for such populations in Japan despite the lack of efficacy and toxicity data. METHODS: Patients aged 75 years or older with advanced gastric cancer were enrolled. S-1 plus docetaxel (docetaxel: 40 mg/m2, day 1; S-1: 80 mg/m2, days 1-14; q21 days) was repeated every 3 weeks. The primary endpoint was overall response rate. Secondary endpoints were safety, progression-free survival, time to treatment failure, and overall survival. The sample size was calculated as 30 under the hypothesis of an expected response rate of 40% and a threshold response rate of 20%, at a power of 90% and a two-sided alpha value of 5%. RESULTS: From February 2010 to January 2015, 31 patients were enrolled and assessed for efficacy and toxicity. The response rate was 45.2% (95% CI 27.3%-64.0%; p = 0.001) and it exceeded the expected response rate set at 40%. Median progression-free survival was 5.8 months, the 1-year survival rate was 58.1%, and the median survival time was 16.1 months. The major grade 3/4 adverse events were neutropenia (58%), febrile neutropenia (13%), anemia (10%), anorexia (10%), and fatigue (6%). CONCLUSIONS: These findings indicate that S-1 plus docetaxel as first-line treatment for older patients is feasible and that it has promising efficacy against advanced gastric cancer.

English version of Japanese Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) issued by the Japan Society of Clinical Oncology.

The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients' wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries.

Indications for neoadjuvant chemotherapy in older patients undergoing esophagectomy for esophageal cancer.

PURPOSE: To investigate the indications for neoadjuvant chemotherapy (NAC) in esophageal cancer patients aged 75 years or older. METHODS: We analyzed data, retrospectively, from 155 patients over 75 years old, who underwent esophagectomy for esophageal cancer between 2010 and 2020. Forty-one patients underwent upfront surgery (US group) and 114 were treated with NAC followed by surgery (NAC group). We compared the patient backgrounds and perioperative outcomes including prognosis, between the two groups. RESULTS: The NAC group patients were significantly younger and had significantly more advanced clinical stage disease than the US group patients. The incidence of postoperative complications was similar in the two groups. Patients with a good pathological response to NAC had a significantly better prognosis than those with a poor response and those in the US group. Among patients with a performance status (PS) of 0, the 5-year OS rate was 56.5% in the NAC group and 38.1% in the US group (HR = 0.63, 95% CI 0.35-1.12). Among those with a PS of 1-2, the 5-year OS rates were 28.1% and 57.1%, respectively (HR = 1.69, 95% CI 0.99-2.89; P = 0.037 for interaction). CONCLUSIONS: NAC did not improve the postoperative prognosis of older esophageal cancer patients with a PS of 1 or higher.

The role of anterior gastropexy in elderly Japanese hiatal hernia patients.

PURPOSE: As Japanese society ages, the number of surgeries performed in elderly patients with hiatal hernia (HH) is increasing. In this study, we examined the feasibility, safety, and potential effectiveness of the addition of anterior gastropexy to hiatoplasty with or without mesh repair and/or fundoplication in elderly Japanese HH patients. METHODS: We retrospectively evaluated 39 patients who underwent laparoscopic HH repair between 2010 and 2021. We divided them into 2 groups according to age: the "younger" group (< 75 years old, n = 21), and the "older" group (≥ 75 years old, n = 18). The patient characteristics, intraoperative data, and postoperative results were collected. RESULTS: The median ages were 68 and 82 years old in the younger and older groups, respectively, and the female ratio was similar between the groups (younger vs. older: 67% vs. 78%, p = 0.44). The older group had more type III/IV HH cases than the younger group (19% vs. 83%, p < 0.001). The operation time was longer in the older group than in the younger group, but there was no significant difference in blood loss, perioperative complications, or postoperative length of stay between the groups. The older group had significantly more cases of anterior gastropexy (0% vs. 78%, p < 0.001) and less fundoplication (100% vs. 67%, p = 0.004) than the younger group. There was no significant difference in HH recurrence between the groups (5% vs. 11%, p = 0.46). CONCLUSIONS: The addition of anterior gastropexy to other procedures is feasible, safe, and potentially effective in elderly Japanese patients with HH.

Pancreas-left gastric artery angle predicts difficulty of suprapancreatic lymph node dissection in gastrectomy for gastric cancer: a cross-sectional study.

PURPOSE: Suprapancreatic lymph node dissection is one of the most challenging procedures performed in the treatment of gastric cancer. This study aimed to investigate whether the pancreas-left gastric artery angle (PLA) can be used to predict the difficulty of the procedure. METHODS: This was a single-center cross-sectional study. Before gastrectomy, the patients were classified according to the size of the PLA into the small PLA (s-PLA; < 30°) and large PLA (l-PLA; ≥ 30°) groups in a surgeon-blinded manner. After gastrectomy, a surgeon evaluated suprapancreatic lymph node dissection as hard, normal, or easy to perform. RESULTS: Seventy-three patients were enrolled in the study. Surgeons evaluated lymph node dissection as hard in 43.8 and 8.7% of patients in the s-PLA and l-PLA groups, respectively (p = 0.002). The time taken for suprapancreatic lymph node dissection was also significantly longer in the s-PLA group than in the l-PLA group (p = 0.040). In patients who underwent laparoscopic gastrectomy, the time for node dissection in the s-PLA group was also significantly longer than that in the s-PLA group (p = 0.021), while there was no difference in those who underwent robotic surgery (p = 0.815). CONCLUSION: PLA is useful for predicting the degree of difficulty of suprapancreatic lymph node dissection during gastrectomy for gastric cancer.

Prognostic factors and significance of postoperative adjuvant chemotherapy in patients with advanced gastric cancer undergoing neoadjuvant chemotherapy followed by gastrectomy.

PURPOSE: In Japan, gastrectomy with D2 lymph node dissection and postoperative adjuvant chemotherapy are the standard treatments for locally advanced gastric cancer. Neoadjuvant chemotherapy (NAC) is not affected by postgastrectomy syndromes or postoperative complications. This multicenter retrospective study investigated the prognostic factors and significance of postoperative adjuvant chemotherapy in patients with advanced gastric cancer who underwent NAC followed by gastrectomy. METHODS: Consecutive patients (n = 221) with advanced gastric cancer who underwent NAC followed by curative surgery were enrolled in this study. Prognostic factors including postoperative adjuvant chemotherapy were investigated using univariate and multivariate analyses. RESULTS: A multivariate analysis revealed that pathological lymph node metastasis (ypN) status and postoperative adjuvant chemotherapy were independent prognostic factors for the overall and relapse-free survival. Forty-five patients (20.4%) did not receive postoperative adjuvant chemotherapy. There were no significant differences between patients with and without adjuvant chemotherapy for all factors, except age. The most common reason for not undergoing postoperative adjuvant chemotherapy was a poor condition (n = 23). CONCLUSIONS: ypN status and postoperative adjuvant chemotherapy were independent prognostic factors in gastric cancer patients who underwent NAC followed by curative gastrectomy. It is important to maintain the patient's condition during NAC and the perioperative period so that they can receive postoperative adjuvant chemotherapy.

A new scope warmer/cleaner for laparoscopic surgery: a disposable hot pack.

BACKGROUND: Fogging and staining of a laparoscope lens negatively impact surgical visualization. We hypothesized that the disposable hot pack could not only warm but also clean laparoscopes. Hence, this study verified and developed the disposable hot pack with anti-fogging and cleaning function. MATERIAL AND METHODS: The laparoscope was inserted into a swine abdominal cavity for five minutes. Then, the laparoscopic tip was heated with 65 °C saline or the folded disposable hot pack with nonwoven fabric coated surfactant for ten seconds (n = 15). Also, a laparoscopic tip with dirt was wiped with the prototype or conventional gauze for 10 s (n = 10). The dirt, fogging, and temperature of the laparoscopic tip were respectively evaluated after the laparoscope was inserted into the abdominal cavity. RESULTS: The laparoscopic tip temperature five minutes after insertion into the abdominal cavity was similar (31.1 °C vs 31.2 °C, p = 0.748) and there was no fogging in both methods. The conventional gauze had significantly less temperature of the laparoscopic tip after cleaning and higher fogging occurrence than the prototype (29.5 °C vs 34.0 °C, p < 0.001, 30% vs 0%, p = 0.030, respectively), although there was no dirt left after both methods. CONCLUSION: The disposable hot pack has a strong potential as an anti-fogging and cleaning device for use during laparoscopic surgery.

Innovative device for surgical wound irrigation: a preclinical testing and pilot clinical validation study.

INTRODUCTION: Surgical site infection (SSI) poses a substantial postoperative challenge, affecting patient recovery and healthcare costs. While surgical wound irrigation is pivotal in SSI reduction, consensus on the optimal method remains elusive. We developed a novel device for surgical wound irrigation and conducted preclinical and clinical evaluations to evaluate its efficacy and safety. METHODS: Two preclinical experiments using swine were performed. In the washability test, two contaminated wound model were established, and the cleansing rate between the device and the conventional method were compared. In the contamination test, the irrigation procedure with a fluorescent solution assessed the surrounding contamination of drapes. Subsequently, a clinical trial involving patients undergoing abdominal surgery was conducted. RESULTS: The washability test demonstrated significantly higher cleansing rates with the device method (86.4% and 82.5%) compared to the conventional method (65.2% and 65.1%) in two contamination models. The contamination test revealed a smaller contaminated region with the device method than the conventional method. In the clinical trial involving 17 abdominal surgery cases, no superficial SSIs or adverse events related to device use were observed. CONCLUSIONS: Our newly developed device exhibits potential for achieving more effective and safe SSI control compared to conventional wound irrigation.

Efficacy and survival of nivolumab treatment for recurrent/unresectable esophageal squamous-cell carcinoma: real-world clinical data from a large multi-institutional cohort.

BACKGROUND: Real-world clinical outcomes of and prognostic factors for nivolumab treatment for esophageal squamous-cell carcinoma (ESCC) remain unclear. This study aimed to evaluate real-world outcomes of nivolumab monotherapy in association with relevant clinical parameters in recurrent/unresectable advanced ESCC patients. METHODS: This population-based multicenter cohort study included a total of 282 patients from 15 institutions with recurrent/unresectable advanced ESCC who received nivolumab as a second-line or later therapy between 2014 and 2022. Data, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively collected from these patients. RESULTS: Objective response and disease control rates were 17.0% and 47.9%, respectively. The clinical response to nivolumab treatment significantly correlated with development of overall immune-related adverse events (P < .0001), including rash (P < .0001), hypothyroidism (P = .03), and interstitial pneumonia (P = .004). Organ-specific best response rates were 20.6% in lymph nodes, 17.4% in lungs, 15.4% in pleural dissemination, and 13.6% in primary lesions. In terms of patient survival, the median OS and PFS was 10.9 and 2.4 months, respectively. Univariate analysis of OS revealed that performance status (PS; P < .0001), number of metastatic organs (P = .019), C-reactive protein-to-albumin ratio (CAR; P < .0001), neutrophil-lymphocyte ratio (P = .001), and PMI (P = .024) were significant. Multivariate analysis further identified CAR [hazard ratio (HR) = 1.61, 95% confidence interval (CI) 1.15-2.25, P = .0053)] in addition to PS (HR = 1.65, 95% CI 1.23-2.22, P = .0008) as independent prognostic parameters. CONCLUSIONS: CAR and PS before nivolumab treatment are useful in predicting long-term survival in recurrent/unresectable advanced ESCC patients with second-line or later nivolumab treatment. TRIAL REGISTRATION: UMIN000040462.

Combination of pimitespib (TAS-116) with sunitinib is an effective therapy for imatinib-resistant gastrointestinal stromal tumors.

Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.

Phase I study of the irreversible fibroblast growth factor receptor 1-4 inhibitor futibatinib in Japanese patients with advanced solid tumors.

This phase I study was designed to: (1) determine the maximum tolerated dose (MTD) and recommended dose (RD) of the fibroblast growth factor receptor (FGFR) inhibitor futibatinib in Japanese patients with advanced solid tumors, and (2) examine the antitumor activity of the RD in patients with gastric cancer (GC) or other advanced solid tumors who have FGFR or FGF/FGFR abnormalities, respectively. In the dose-escalation phase, patients were assigned to 21-day cycles of oral futibatinib 8-160 mg three times a week (TIW) or 16 or 20 mg once daily (QD). In the expansion phase, patients received oral futibatinib 56, 80, or 120 mg TIW, or 16 or 20 mg QD. Eighty-three patients received futibatinib TIW (n = 40) or QD (n = 43). No dose-limiting toxicities were observed according to the final study protocol definition, and the MTD was not reached. The most common adverse events with both regimens were hyperphosphatemia (TIW, 82.5%; QD, 100.0%) and decreased appetite (TIW, 40.0%; QD, 58.1%). Hyperphosphatemia was asymptomatic, not leading to futibatinib discontinuation. The overall response rate (ORR) was 11.5% in patients with FGF/FGFR abnormalities. Notably, in GC patients harboring FGFR2 copy number (CN) ≥10, the ORR was 36.4% versus 0 in patients with CN <10. Therefore, futibatinib had a generally predictable and manageable safety profile in patients with advanced solid tumors. Antitumor activity was seen in patients with FGF/FGFR abnormalities, particularly those with GC and high FGFR2 CNs. Thus, futibatinib 20 mg QD was chosen as the RD for phase II studies.