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Background: This randomized phase II study explored the superiority of trastuzumab plus S-1 plus cisplatin (SP) over SP alone as neoadjuvant chemotherapy (NAC) for HER2-positive resectable gastric cancer with extensive lymph node metastasis. Methods: Eligible patients with HER2-positive gastric or esophagogastric junction cancer and extensive lymph node metastasis were randomized to receive three or four courses of preoperative chemotherapy with SP (arm A) or SP plus trastuzumab (arm B). Following gastrectomy, adjuvant chemotherapy with S-1 was administered for 1 year in both arms. The primary endpoint was overall survival, and the sample size was 130 patients in total. The trial is registered with the Japan Registry of Clinical Trials, jRCTs031180006. Results: This report elucidates the early endpoints, including pathological findings and safety. The study was terminated early due to slow patient accruals. In total, 46 patients were allocated to arm A (n = 22) and arm B (n = 24). NAC was completed in 20 patients (91%) in arm A and 23 patients (96%) in arm B, with similar incidences of grade 3–4 hematological and non-hematological adverse events. Objective response rates were 50% in arm A and 84% in arm B (p = 0·065). %R0 resection rates were 91% and 92%, and pathological response rates (≥ grade 1b in Japanese classification) were 23% and 50% (p = 0·072) in resected patients, respectively. Conclusions: Trastuzumab can be safely added to platinum-containing doublet chemotherapy as NAC, and it has the potential to contribute to higher antitumor activity against locally advanced, HER2-positive gastric or esophagogastric junction cancer with extensive nodal metastasis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Capecitabine plus oxaliplatin (CapeOX) is a standard treatment option for advanced gastric cancer (AGC). We conducted a prospective multicenter phase II study to evaluate the efficacy and safety of CapeOX as a first-line therapy for AGC in older patients. Methods: Chemotherapy-naive patients aged ≥ 70 years with AGC were eligible. Initial treatment comprised capecitabine (2000 mg/m2 on days 1–14) and oxaliplatin (130 mg/m2 on day 1) every 3 weeks. After the initial feasibility assessment, the dose was reduced considering toxicity (capecitabine, 1500 mg/m2 on days 1–14; and oxaliplatin, 100 mg/m2 on day 1 every 3 weeks). The primary endpoint was overall survival (OS). Results: In total, 108 patients were enrolled, of whom 104 were evaluated. Thirty-nine patients received the original-dose treatment, whereas 65 received the reduced-dose treatment. The median OS, progression-free survival (PFS), and time to treatment failure (TTF) were 12.9 (95% CI 11.6–14.8), 5.7 (95% CI 5.0–7.0), and 4.3 (95% CI 3.9–5.7) months, respectively, for all patients; 13.4 (95% CI 9.5–16.0), 5.8 (95% CI 4.1–7.8), and 5.3 (95% CI 3.5–7.2) months in the original-dose group; and 12.8 (95% CI 11.3–15.3), 5.7 (95% CI 4.4–7.0), and 4.1 (95% CI 3.7–5.7) months in the reduced-dose group. The most common grade 3/4 toxicities were neutropenia (17.9%), anemia (12.8%), and thrombocytopenia (12.8%) in the original-dose group and neutropenia (13.8%) and anorexia (12.3%) in the reduced-dose group. Conclusions: These findings demonstrate CapeOX's efficacy and safety in older AGC patients. [ABSTRACT FROM AUTHOR]

Background: Elevated preoperative serum C-reactive protein (CRP) levels are reportedly associated with a poor prognosis for patients with various types of malignant tumors. However, the impact of postoperative CRP levels on the prognosis of patients with esophageal cancer remains unknown. The present study aims to clarify the prognostic significance of postoperative CRP levels on the survival of patients with esophageal cancer. Methods: We reviewed the records of consecutive 202 patients with thoracic esophageal squamous cell carcinoma who underwent transthoracic esophagectomy. We measured serum CRP levels on postoperative days (PODs) 1, 2, 3, 5 and 7 and evaluated the relationships between postoperative CRP levels and survival. Results: The findings of Cox regression analyses suggested that elevated CRP levels on POD 3, 5 and 7 were associated with poor recurrence-free survival (RFS). We divided CRP levels on POD 7 into three tertiles and found that RFS could be clearly stratified, being the poorest ( p < 0.001) in the highest tertile (high CRP). The trend was similar even in patients with or without infectious complications and with or without advanced pathological stage. Multivariate analysis showed that pathologically advanced stage (Hazard ratio [HR], 5.14; 95% confidence interval [CI] 2.67-9.87; p < 0.001) and high CRP (HR, 2.27; 95% CI 1.3-3.96; p = 0.004) were independent predictors of RFS. Conclusion: Postoperative CRP levels could predict the prognosis of patients with esophageal cancer. We propose that the clinical course of postoperative CRP level should be carefully monitored as a predictor of survival. [ABSTRACT FROM AUTHOR]

Objectives: Few studies have evaluated the mechanism of serious injury in acute hospitalization. Thus, the association between fall-related serious injury and activity during falls in acute care hospital remains unclear. Herein, we investigated the relationship between serious injury caused by fall and activity at the time of the fall in an acute care hospital. Methods: This retrospective cohort study was conducted at Asa Citizens Hospital. All inpatients aged 65 years and older were eligible for the study, which was conducted from April 1, 2021, through March 31, 2022. The magnitude of the association between injury severity and activity during the fall was quantified using odds ratio. Results: Among the 318 patients with reported falls, 268 (84.3%) had no related injury, 40 (12.6%) experienced minor injury, 3 (0.9%) experienced moderate injury, 7 (2.2%) experienced major injury. Moderate or major injuries caused by a fall was associated with the activity during the fall (odds ratio: 5.20; confidence intervals: 1.43–18.9, p = 0.013). Conclusion: This study recognizes that falling during ambulation caused moderate or major injuries in an acute care hospital. Our study suggests that falls while ambulating in an acute care hospital were associated not only with fractures, but also with lacerations requiring sutures and brain injuries. Among the patients with moderate or major injuries, more falls occurred outside the patient's bedroom as compared with patients with minor or no injuries. Therefore, it is important to prevent moderate or major injuries related to falls that occur while the patient is walking outside their bedroom in an acute care hospital. [ABSTRACT FROM AUTHOR]

Morgagni hernia is a rare form of diaphragmatic hernia. It is located at the anterior edge of the diaphragm and does not have an anterior rim. It is difficult to achieve a secure closure and maintain the tension of closure with laparoscopic surgery. We have performed laparoscopic resection of colorectal cancer and hernia repair simultaneously. An 89-year-old woman underwent laparoscopic hernia repair and ileocecal resection simultaneously. Regarding hernia repair, we considered that it would be difficult to use a mesh from the viewpoint of infection due to the colectomy. Therefore, we have done the extra-abdominal suture method. After laparoscopic ileocecal resection, a small incision was made in the epigastric region, and Morgagni hernia repair was performed with extra-abdominal sutures. She had no recurrence of either colon cancer or hernia for 22 months post-operatively. The extra-abdominal suture method can provide secure closure of the hernia orifice for Morgagni hernia. [ABSTRACT FROM AUTHOR]

A gastro-bronchial fistula (GBF) is a rare complication after esophageal reconstruction using a gastric tube, but it can cause severe pneumonia, and the surgical procedure is challenging. We herein describe a patient who was successfully managed using a two-stage operation for a GBF. Because the patient had life-threatening pneumonia and respiratory failure caused by the GBF, we first transected the duodenum, established a cervical esophagostomy and gastrostomy and placed a decompression catheter in the gastric tube without a thoracotomy. The patient recovered from pneumonia after the resolution of the salivary inflow and digestive juice reflux into the lungs through the GBF. Two months later, an esophageal bypass was achieved by reconstructing the esophagus using a long segment of pedicled jejunum. The patient was discharged 38 days thereafter. Appropriate treatment for GBF should be tailored to individual patients based on their current status and disease severity. [ABSTRACT FROM AUTHOR]

Distal gastrectomy (DG) with lymph node dissection is considered as the standard treatment for gastric cancer. Ischemic necrosis of the gastric remnant is a rare but serious complication of DG that requires careful consideration for early diagnosis and treatment to lower the associated mortality rate. A 71-year-old male presented to our hospital with hyperglycemia and was evaluated for suspected diabetes. The patient's medical history was otherwise unremarkable. Computed tomography (CT) revealed a thickening of the stomach wall, with follow-up esophagogastroduodenoscopy revealing type 3 gastric cancer in the greater curvature of the antrum. Biopsy specimen confirmed a pathological diagnosis of mucinous adenocarcinoma, with a clinical diagnosis of cT3N0M0, cStageIIB. An open DG with Billroth I reconstruction was performed, without incident. On postoperative day 1, the patient developed a high fever, abdominal pain, and elevated white blood cell count (12,200/μL). On postoperative day 2, his C-reactive protein level increased to >30 mg/dL. CT revealed an edematous thickening of the stomach wall, with poor mucosal enhancement of the remnant stomach and thinning of the anastomosis wall, with air nearby. Emergency surgery was performed for suspected leakage. Intraoperative findings showed no evidence of leakage. Intraoperative endoscopy revealed a necrotic gastric remnant, and we performed a total remnant gastrectomy with Roux-en Y reconstruction. The patient was discharged in a stable condition, 25 days after the first surgery. Although ischemic necrosis of the gastric remnant is a rare complication, its possibility should be carefully considered after DG, for early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Our previous report showed that surgical palliation maintained quality of life (QOL), improved solid food intake, and had an acceptable surgical safety among patients with malignant bowel obstruction (MBO) caused by advanced gastric cancer. This study performed a survival analysis stratified by the patients' QOL to elucidate its impact on survival. Methods: Patients who underwent resection or bypass of the small intestine/colon or ileostomy/colostomy for bowel obstruction caused by peritoneal dissemination of gastric cancer were included. Validated instruments (EuroQoL-5 Dimensions) were used to assess QOL at baseline and 2 weeks, 1 month, and 3 months following surgical palliation. Postoperative improvement in oral intake was also evaluated using the Gastric Outlet Obstruction Scoring System (GOOSS). Univariate and multivariate survival analyses were performed using baseline characteristics and changes in QOL and GOOSS scores 2 weeks after surgery to determine prognostic factors. Results: We enrolled 60 patients with a median survival time of 6.64 (95% CI 4.76–10.28) months. Patients who received postoperative chemotherapy and had lower baseline C-reactive protein (CRP) levels, higher baseline albumin levels, better baseline EuroQoL-5 Dimensions (EQ-5D) scores, and improved oral intake after palliative surgery exhibited significantly better survival. Multivariate analysis identified postoperative chemotherapy, lower baseline CRP levels, and improved oral intake as independent prognostic factors. Conclusions: The current study revealed that baseline QOL and postoperative QOL changes did not affect survival. Moreover, improved oral intake, lower baseline CRP levels, and postoperative chemotherapy were significant prognostic factors in patients who underwent palliative surgery for advanced gastric cancer with MBO. [ABSTRACT FROM AUTHOR]

Background: Patients with peritoneal dissemination of gastric cancer have poor oral intake caused by malignant bowel obstruction (MBO). Palliative surgery has often been undertaken to improve quality of life (QOL), but few prospective studies on palliative surgery in this patient population have been published. Patients and methods: We prospectively investigated the significance of palliative surgery using patient-reported QOL measures. Patients underwent palliative surgery by small intestine/colon resection or small intestine/colon bypass or ileostomy/colostomy for MBO. The primary endpoint was change in QOL assessed at baseline, 14 days, 1 month, and 3 months following palliative surgery using the Euro QoL Five Dimensions (EQ-5D™) questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire gastric cancer module (QLQ-STO22). Secondary endpoints were postoperative improvement in oral intake and surgical complications. Results: Between April 2013 and March 2018, 63 patients were enrolled from 14 institutions. The mean EQ-5D™ utility index baseline score of 0.6 remained consistent. Gastric-specific symptoms mostly showed statistically significant improvement from baseline. Forty-two patients (67%) were able to eat solid food 2 weeks after palliative surgery and 36 patients (57%) tolerated it for 3 months. The rate of overall morbidity of ≥ grade III according to the Clavien–Dindo classification was 16% (10 patients) and the 30-day postoperative mortality rate was 3.2% (2 patients). Conclusions: In patients with MBO caused by peritoneal dissemination of gastric cancer, palliative surgery did not improve QOL while improving solid food intake, with an acceptable postoperative morbidity and mortality rate. [ABSTRACT FROM AUTHOR]

Background: Specific treatment strategies are sorely needed for scirrhous-type gastric cancer still, which has poor prognosis. Based on the promising results of our previous phase II study (JCOG0210), we initiated a phase III study to confirm the efficacy of neoadjuvant chemotherapy (NAC) in type 4 or large type 3 gastric cancer. Methods: Patients aged 20–75 years without a macroscopic unresectable factor as confirmed via staging laparoscopy were randomly assigned to surgery followed by adjuvant chemotherapy with S-1 (Arm A) or NAC (S-1plus cisplatin) followed by D2 gastrectomy plus adjuvant chemotherapy with S-1 (Arm B). The primary endpoint was overall survival (OS). Results: Between October 2005 and July 2013, 316 patients were enrolled, allocating 158 patients to each arm. In Arm B, in which NAC was completed in 88% of patients. Significant downstaging based on tumor depth, lymph node metastasis, and peritoneal cytology was observed using NAC. Excluding the initial 16 patients randomized before the first revision of the protocol, 149 and 151 patients in arms A and B, respectively, were included in the primary analysis. The 3-year OS rates were 62.4% [95% confidence interval (CI) 54.1–69.6] in Arm A and 60.9% (95% CI 52.7–68.2) in Arm B. The hazard ratio of Arm B against Arm A was 0.916 (95% CI 0.679–1.236). Conclusions: For type 4 or large type 3 gastric cancer, NAC with S-1 plus cisplatin failed to demonstrate a survival benefit. D2 surgery followed by adjuvant chemotherapy remains the standard treatment. [ABSTRACT FROM AUTHOR]

Background: This prospective observational study evaluated the real-world effectiveness of nivolumab monotherapy in previously treated advanced gastric cancer (GC). A preplanned 2-year final analysis was performed to confirm survival and tumor behavior with nivolumab monotherapy., Patients and Methods: The primary endpoint was overall survival (OS). The data regarding tumor size were prospectively collected and evaluated using the RECIST criteria. Exploratory analyses were performed for survival according to the tumor response and depth of response (DpR) in patients with measurable lesions who were receiving nivolumab monotherapy as third- or later-line therapy., Results: In 487 patients, the median OS and progression-free survival (PFS) were 5.8 (95% CI 5.3-6.9) months and 1.8 (95% CI 1.7-2.0) months, respectively. The response rate (RR) was 14.5% in 282 patients with measurable lesions. In 234 patients treated with third- or later-line, the DpR was found to be associated with PFS and OS in the Spearman analysis (r = 0.55 and 0.44, respectively) as well as using a discrete variable. When the DpR was divided into 5 groups (-20%≥DpR; -20%

Background: Laparoscopic gastrectomy (LG) is considered a standard treatment for clinical stage I gastric cancer. Nevertheless, LG has some drawbacks, such as motion restriction and difficulties in spatial perception. Robot-assisted gastrectomy (RG) overcomes these drawbacks by using articulated forceps, tremor-filtering capability, and high-resolution three-dimensional imaging, and it is expected to enable more precise and safer procedures than LG for gastric cancer. However, robust evidence based on a large-scale randomized study is lacking., Methods: We are performing a randomized controlled phase III study to investigate the superiority of RG over LG for clinical T1-2N0-2 gastric cancer in terms of safety. In total, 1,040 patients are planned to be enrolled from 46 Japanese institutions over 5 years. The primary endpoint is the incidence of postoperative intra-abdominal infectious complications, including anastomotic leakage, pancreatic fistula, and intra-abdominal abscess of Clavien-Dindo (CD) grade ≥ II. The secondary endpoints are the incidence of all CD grade ≥ II and ≥ IIIA postoperative complications, the incidence of CD grade ≥ IIIA postoperative intra-abdominal infectious complications, relapse-free survival, overall survival, the proportion of RG completion, the proportion of LG completion, the proportion of conversion to open surgery, the proportion of operation-related death, and short-term surgical outcomes. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in January 2020. Approval from the institutional review board was obtained before starting patient enrollment in each institution. Patient enrollment began in March 2020. We revised the protocol to expand the eligibility criteria to T1-4aN0-3 in July 2022 based on the results of randomized trials of LG demonstrating non-inferiority of LG to open surgery for survival outcomes in advanced gastric cancer., Discussion: This is the first multicenter randomized controlled trial to confirm the superiority of RG over LG in terms of safety. This study will demonstrate whether RG is superior for gastric cancer., Trial Registration: The protocol of JCOG1907 was registered in the UMIN Clinical Trials Registry as UMIN000039825 ( http://www.umin.ac.jp/ctr/index.htm ). Date of Registration: March 16, 2020. Date of First Participant Enrollment: April 1, 2020., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Aim: Postoperative small bowel obstruction (SBO) is one of the major complications that is mainly caused by postoperative adhesion. Recently, the antiadhesion membrane has become popular for postoperative SBO prevention. However, its efficacy is yet to be confirmed in the gastric cancer surgery field. Here, we conducted the supplemental analysis of the randomized controlled trial JCOG1001 to investigate the efficacy of the antiadhesion membrane on SBO prevention in patients with open gastrectomy for gastric cancer., Methods: Of the 1204 patients enrolled in JCOG1001, 1200 patients were included. The development of SBO of Grade ≥ IIIa according to the Clavien-Dindo classification was recorded. Univariable and multivariable analyses were performed using the Fine and Gray model to determine the risk factors for SBO., Results: Fifty-one patients developed SBO (median follow-up duration: 5.6 years). Total gastrectomy, combined resection, and blood loss significantly increased the risk for SBO development in the univariable analysis. Large amount of blood loss was independently associated with SBO development in the multivariable analysis (hazard ratio [HR], 3.089; 95% confidence interval [CI], 1.562-6.109, p  = 0.0012). Antiadhesion membrane did not reduce the risk for SBO (HR, 1.299; 95% CI 0.683-2.470; p  = 0.4246). In the patients belonging to subgroup analyses who received distal and total gastrectomy, the antiadhesion membrane was not associated with the incidence of SBO., Conclusions: Antiadhesion membrane did not decrease SBO occurrence rate after open gastrectomy. Therefore, the use of antiadhesion membrane would not be effective for preventing SBO in gastric cancer surgery., Competing Interests: Yuichiro Doki and Yukinori Kurokawa are editorial board members of Annals of Gastroenterological Surgery. Junki Mizusawa has received personal fees from Taiho Pharmaceutical outside the submitted work, and his spouse is employed by Pfizer. Takeshi Sano has received personal fees from Taiho, Chugai, Ono, Lilly, and Daiichi‐Sankyo, outside the submitted work. Mitsuru Sasako has received personal fees from Chugai, Taiho, and Daiichi‐Sankyo outside the submitted work. For the remaining authors (Tetsuro Toriumi, Masanori Terashima, Kohei Uemura, Yukinori Kurokawa, Shuji Takiguchi, Yuichiro Doki, Jun Hihara, Hiroshi Imamura, Akinori Takagane, Seiji Ito, and Takaki Yoshikawa), none were declared., (© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

We report a case of unresectable advanced esophageal cancer with an esophageal fistula that was treated with pembrolizumab plus CDDP plus 5-FU therapy and the fistula was closed. A 73-year-old male was diagnosed with cervical-upper thoracic esophageal cancer and esophago-bronchial fistula on CT and esophagogastroduodenoscopy. He underwent chemotherapy containing pembrolizumab. The fistula was closed after 4 cycles and oral intake became possible. Six months have passed since the first visit and chemotherapy is ongoing. The prognosis of esophago-bronchial fistula is extremely poor, and there is no established treatment, including fistula closure. Chemotherapy containing immune checkpoint inhibitors could considered to be expected not only for local control but also for long-term survival.

Background: This study investigated whether schedule modification of bi-weekly nanoparticle albumin-bound paclitaxel (nab-PTX) plus ramucirumab (RAM) is efficacious against gastric cancer (GC) or gastroesophageal junction cancer (GJC)., Patients and Methods: Patients with unresectable GC or GJC who were previously treated with fluoropyrimidine-containing regimens received nab-PTX (100 mg/m 2 ) on days 1, 8, and 15 and RAM (8 mg/kg) on days 1 and 15 of a 28-day cycle. Based on the incidence of severe adverse events (AEs) during the first cycle, patients were modified to bi-weekly therapy from the second cycle. The primary endpoint was progression-free survival (PFS) in the bi-weekly therapy population. Based on the hypothesis that bi-weekly nab-PTX plus RAM would improve PFS from 4.5 to 7.0 months, 40 patients were required for power of 0.8 with a one-sided α of 0.05., Results: Of the 81 patients enrolled, 47 patients (58%) were assigned to bi-weekly therapy. Patient characteristics were Eastern Cooperative Oncology Group performance status of 1 (19%) and diffuse type (45%). Median PFS was 4.7 months (95% confidence interval [CI] 3.7-5.6 months) and overall response rate was 25% (95% CI 11-39%). Severe AEs of grade 3 or worse were mainly neutropenia (83%) and hypertension (23%). EQ-5D scores were maintained during the treatment. In patients who continued standard-schedule therapy, median PFS was 2.7 months (95% CI 1.8-4.0 months)., Conclusions: The primary endpoint for PFS was statistically not met, but modification of nab-PTX plus RAM to a bi-weekly schedule might be a feasible treatment option as second-line treatment for advanced GC/GJC patients, especially elderly patients, with severe AEs during the first cycle., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

We here report a case of pancreatic duct rupture associated with high-grade pancreatic intraepithelial neoplasia treated by radical resection. A 71-year-old man presented to our hospital because of abdominal bloating. Diagnoses of early-stage pancreatic body cancer with pancreatic duct rupture, pancreatic ascites, and formation of a pseudocyst were made on the basis of blood tests, multidetector dynamic computed tomography, endoscopic ultrasonography, magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography. After achieving control of the ascites by placement of a pancreatic duct stent and aspiration of the pseudocyst, distal pancreatectomy with D2 lymph node dissection was performed. Intraoperative cytologic examination of the ascites was negative. The pathological diagnosis was high-grade pancreatic intraepithelial neoplasia in the pancreatic body. The branched pancreatic duct was occluded and dilated by acute inflammation around the pancreatic neoplasm, the inflammation being in the region of the dilated branched pancreatic duct and having caused its rupture. To the best of our knowledge, this is the first published report of pancreatic duct rupture associated with high-grade pancreatic intraepithelial neoplasia., (© 2022. Japanese Society of Gastroenterology.)

Background: Skeletal muscle loss is a hallmark of malignancies, including advanced gastric cancer (GC). Although programmed death (PD)-1 inhibitors, including nivolumab, have promising anti-cancer effects, there is limited information regarding markers that can predict these therapeutic effects, which include PD-ligand 1 (PD-L1) expression and the tumor mutation burden. Therefore, we evaluated whether the baseline psoas muscle mass index (PMI, a surrogate for skeletal muscle mass) could predict the response of GC to nivolumab treatment, based on progression-free survival (PFS), the objective response rate, and the disease control rate., Methods: This retrospective study evaluated 31 Japanese patients who received nivolumab for advanced GC and underwent imaging analysis between November 2017 and November 2019. The computed tomography results were used to estimate the psoas major muscle mass. Sex-specific cut-off values were used for the PMI, with low PMI values defined as < 3.6 cm 2 /m 2 for male patients and < 2.9 cm 2 /m 2 for female patients., Results: The median PFS interval was 2.3 months for the patients with stage IV GC. Nine patients (29%) had a low baseline PMI, and these patients had significantly shorter median PFS than the group with a non-low baseline PMI (0.5 months vs. 2.4 months, P = 0.004)., Conclusions: As a surrogate marker for skeletal muscle loss, the PMI may be useful for predicting the response to nivolumab among patients with advanced GC.

Background: Gastric cancer (GC) patients with positive peritoneal lavage cytology (CY1) and/or localized peritoneum metastasis (P1a) are defined as stage IV in the 15th edition of the Japanese Classification of Gastric Cancer. In Japan, the most common treatment for patients with CY1 and/or P1a is gastrectomy followed by postoperative chemotherapy., Patients and Methods: Subjects in this multi-institutional retrospective study were GC patients with CY1 and/or P1a who received surgical resection that leaves no macroscopically visible disease. Patients were selected from 34 institutions in Japan between 2007 and 2012. Selection criteria included adenocarcinoma, no distant metastasis except CY1 and P1a, and no prior treatment for GC before surgery., Results: Among 824 patients registered, 506 were identified as eligible, with a background of P0CY1, P1aCY0, or P1aCY1 (72.5%, 16.0%, and 11.5% of subjects, respectively). Sixty-two patients had not received postoperative chemotherapy (no-Cx), whereas 444 patients had received postoperative chemotherapy: S-1 monotherapy (S-1; n = 267, 52.7%), cisplatin plus S-1 (CS; n = 114, 22.5%), and others (n = 63, 12.6%). Overall survival (OS) was 29.5, 24.7, 25.4 and 9.9 months in the S-1, CS, 'others', and no-Cx groups, respectively [CS vs. S-1: hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.89-1.50; p = 0.275]. In multivariate analysis, OS was similar between the S-1 and CS groups (CS vs. S-1: HR 1.19, 95% CI 0.92-1.55; p = 0.18)., Conclusions: Postoperative chemotherapy after gastrectomy that leaves no macroscopically visible disease may have some survival benefits for GC patients with CY1 and/or P1a. In contrast, S-1 plus cisplatin seems to have no additional benefit over S-1 treatment alone.

Background: Invasive micropapillary carcinoma (IMPC) is a relatively rare subtype of gastric adenocarcinoma and has aggressive histopathologic characteristics, including lymphatic and vascular invasion. However, the associated long-term survival outcomes remain unclear. This study aimed to compare the clinicopathological characteristics and prognosis of gastric adenocarcinoma with and without IMPC using propensity score-matched (PSM) analysis., Methods: Patients with gastric adenocarcinoma who underwent gastrectomy between 2006 and 2015 were included in the analysis. PSM analysis was performed to compensate for the background heterogeneity between the groups. The primary endpoint was disease-free survival (DFS) after gastrectomy, and the secondary endpoints were disease-specific survival (DSS) and recurrence pattern., Results: Of 882 patients who underwent gastrectomy for gastric adenocarcinoma, with a follow-up duration greater than 36 months, 35 were diagnosed as having gastric adenocarcinoma with IMPC. After PSM, 70 patients, including 35 with IMPC and 35 without IMPC, were selected. Gastric adenocarcinoma with IMPC is characterized by lymphatic invasion (94% versus 69%, p = 0.012). Patients with IMPC had significantly poorer DFS than those without IMPC, with 3-year DFS rates of 62.2% and 93.4% (p = 0.003), respectively. Furthermore, a significant difference was also observed in DSS (p = 0.016); patients with IMPC more frequently developed liver metastasis (20%) than those without IMPC (3%, p = 0.006)., Conclusions: Resected gastric carcinoma with IMPC was associated with poorer DFS and DSS; furthermore, an increased rate of lymphatic invasion and liver metastasis was noted than in cases without IMPC.

Background: The clinical significance of lymph node (LN) status determined by preoperative 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) has not been investigated in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (NCRT) followed by surgery (trimodal therapy)., Methods: This study reviewed 132 consecutive patients with ESCC who had been preoperatively evaluated using FDG-PET before and after NCRT to analyze associations among LN status according to PET findings, pathologic LN metastasis, and prognosis of ESCC after trimodal therapy., Results: Lymph nodes that were PET-positive both before and after NCRT comprised significant predictive markers of pathologic LN metastasis in station-by-station analyses (sensitivity, specificity, and accuracy respectively 41.7%, 95.0%, and 92.7% before, and 12.0%, 99.4%, and 95.6% after NCRT; both p < 0.0001). The numbers of LNs evaluated using PET before and after NCRT were significantly associated with those of pathologic metastatic LNs. Uni- and multivariable analyses selected LN status determined by PET before NCRT as a significant independent predictor of both recurrence-free [LN-negative vs LN-positive: hazard ratio (HR) 1.90; 95% confidence interval (CI) 1.02-3.23; p = 0.045] and overall survival (HR 2.62; 95% CI 1.29-5.30; p = 0.01)., Conclusions: The status of LN determined by preoperative FDG-PET is significantly associated with pathologic LN status and the prognosis of ESCC with trimodal therapy. Thus, FDG-PET is a useful diagnostic tool for preoperative prediction of pathologic LN metastasis and survival among patients with ESCC.

A 48-year-old man with unresectable gastric cancer and widespread peritoneal dissemination received concentrated ascites reinfusion therapy, followed by systemic chemotherapy. However, leptomeningeal carcinomatosis (LMC) was diagnosed 1 year later. Spinal drainage and ventriculoperitoneal shunting improved the patient's neurological functions for approximately 2 weeks. The patient died 2 months after LMC diagnosis, but these treatments temporarily improved the quality of life during end-of-life care., Competing Interests: Conflict of interestThe authors declare that they have no conflicts of interest.

Background: The evaluation of treatment outcomes and detection of prognostic factors after recurrence are very important for tailoring optimal therapies for individual patients with recurrent esophageal cancer., Methods: We reviewed 133 patients in whom esophageal squamous cell carcinoma (ESCC) recurred after curative surgery, and assessed recurrence patterns, treatment outcomes and prognostic factors., Results: Recurrence in 57 (42.9%), 54 (40.6%) and 22 (16.5%) patients was locoregional, distant and combined, respectively. The median amounts of elapsed time until recurrence and median survival after recurrence for all patients were 9.1 and 8.3 months, respectively. Univariate and multivariate analyses selected time to recurrence (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.97-0.999; p = 0.04), recurrence location (locoregional vs. distant: HR, 1.63; 95% CI, 1.03-2.61; p = 0.04), number of organs with recurrence (1 vs. 3: HR, 3.49; 95% CI, 1.23-9.87; p = 0.02) and treatment after recurrence (best supportive care, [BSC] vs. chemotherapy [CT] or radiation therapy [RT]: HR, 0.37; 95% CI, 0.15-0.94; p = 0.04; BSC vs. CT and RT: HR, 0.50; 95% CI, 0.26-0.94; p = 0.03; BSC vs. surgery: HR, 0.47; 95% CI, 0.25-0.88; p = 0.02) as independent factors for survival after recurrence. Seventeen (12.8%) patients who had localized lymph node recurrence and lung oligometastasis and received multidisciplinary therapy after recurrence survived for >3 years thereafter., Conclusion: Despite the poor survival of patients with ESCC and early or distant recurrence or recurrence in ≥3 recurrent organs, appropriate multimodal therapies should be tailored for individual patients with recurrent ESCC.

Background: Intensive trimodality therapy is needed for locally advanced esophageal squamous cell carcinoma (ESCC). However, some patients develop recurrence and die of cancer even after trimodality therapy., Methods: We evaluated prognostic factors based on data from 125 patients with ESCC who underwent neoadjuvant chemoradiotherapy (NCRT) comprising concurrent chemotherapy and 40 Gy of radiation, followed by curative-intent esophagectomy., Results: Thirty-four (27.2%) patients achieved a pathological complete response (pCR) after NCRT. The 5-year recurrence-free (RFS) and overall survival (OS) rates of all patients were 49.2 and 52.9%, respectively, and were significantly better for patients with pCR than without pCR (p = 0.01 and 0.02, respectively). Univariate and multivariate analyses selected performance status [PS 0 vs. 1: hazard ratio (HR) 2.05; 95% confidence interval (CI) 1.30-4.84; p = 0.01] and ypN (0 vs. 1: HR 2.33; 95% CI 1.12-4.84; p = 0.02; 0 vs. 2/3: HR 3.73; 95% CI 1.68-8.28; p = 0.001) as independent covariates for RFS. Furthermore, PS (0 vs. 1; HR 2.94; 95% CI 1.51-5.72; p = 0.002) and ypN (0 vs. 1; HR 2.26; 95% CI 1.09-4.69; p = 0.03; 0 vs. 2/3: HR 3.90; 95% CI 1.79-8.48; p = 0.001) were also independent covariates for OS., Conclusions: Performance status 1 and ypN+ were significantly associated with a poor prognosis after trimodality therapy for ESCC.

Background: The accurate prediction of a pathologic complete response (ypT0N0M [LYM] 0 ypStage 0) before operation is essential for selecting appropriate strategies for treating esophageal cancer after neoadjuvant chemoradiotherapy., Methods: We reviewed 130 consecutive patients with esophageal squamous cell carcinoma who were evaluated preoperatively using upper gastrointestinal endoscopy, computed tomography, and 18 F-fluorodeoxyglucose-positron emission tomography after neoadjuvant chemoradiotherapy and subsequently underwent esophagectomy. Our aim was to determine the diagnostic abilities of computed tomography, 18 F-fluorodeoxyglucose-positron emission tomography, and endoscopy to predict preoperatively a pathologic complete response of the primary site of the locally advanced esophageal squamous cell carcinoma and associated lymph nodes to trimodal neoadjuvant chemoradiotherapy. Associations between clinical complete response (ycT0N0M [LYM] 0 ycStage 0) and pathologic complete response were investigated preoperatively., Results: Twenty-nine (22.3%) and 43 (33.1%) patients, respectively, achieved clinical complete response and pathologic complete response, which were associated (P=.001). The sensitivity and specificity, as well as the positive and negative predictive values of clinical complete response to define pathologic complete response were 39.5%, 86.2%, 58.6%, and 74.3%, respectively. Univariate and multivariate analyses selected clinical complete response as the sole independent preoperative predictor of pathologic complete response (clinical complete responses versus non-clinical complete responses: odds ratio: 0.26, 95% confidence interval, 0.10-0.65, P=.004). Recurrence-free and overall survival (OS) rates were better in patients with than in those without clinical complete response (5-year recurrence-free and overall survival: 69.0% vs 41.4% and 75.9% vs 45.0%, respectively, both P=.02). Furthermore, clinical complete response was an independent preoperative predictor of recurrence-free survival (clinical complete response versus nonclinical complete response: hazard ratio: 2.20, 95% confidence interval, 1.08-4.45, P=.03)., Conclusion: Although pathologic complete response was predictable preoperatively to some extent, the accuracy was somewhat low. Considerable caution should be exercised when selecting the watch-and-wait approach with operation as needed and omitting planned operative intervention even for patients who achieve clinical complete response after neoadjuvant chemoradiotherapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The prognoses of submucosal esophageal squamous cell carcinoma patients vary. Patients with favorable prognoses may receive less invasive or nonsurgical interventions, whereas patients with poor prognoses or advanced esophageal cancer may require aggressive treatments. We sought to identify prognostic factors for patients with submucosal esophageal squamous cell carcinoma, focusing on lymph node metastasis and recurrence., Methods: We included 137 submucosal esophageal squamous cell carcinoma patients who had undergone transthoracic esophagectomy with systematic extended lymph node dissection. Submucosal tumors were classified as SM1, SM2, and SM3 according to the depth of invasion. Prognostic factors were determined by univariable and multivariable analyses., Results: Lymph node metastasis was observed in 18.8%, 30.5%, and 50.0% of SM1, SM2, and SM3 cases, respectively. The overall 5-year recurrence rate was 21.9%; the rates for SM1, SM2, and SM3 tumors were 9.4%, 18.6%, and 34.8%, respectively. The SM1 tumors all recurred locoregionally; distant metastasis occurred in SM2 and SM3 cases. The 5-year overall survival rates were 83%, 77%, and 59% for SM1, SM2, and SM3 cases, respectively. On univariable analysis, lymph node metastasis, depth of submucosal invasion (SM3 versus SM1/2), and tumor location (upper thoracic versus mid/lower thoracic) were poor prognostic factors for overall survival. Multivariable Cox regression analyses identified depth of submucosal invasion (hazard ratio 2.51, 95% confidence interval: 1.37 to 4.61) and tumor location (hazard ratio 2.43, 95% confidence interval: 1.18 to 4.63) as preoperative prognostic factors., Conclusions: Tumor location (upper thoracic) and infiltration (SM3) are the worse prognostic factors of submucosal esophageal squamous cell carcinoma, but lymph node metastasis is not a predictor of poorer prognosis., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Anal metastasis of colorectal cancer is rare, and no standardized effective therapeutic strategy exists. We report a case of abdominoperineal resection for anal metastasis of rectal cancer. A 65-year-old man underwent laparoscopic low anterior resection for rectal cancer in August 2013. Histopathological examination revealed a moderately differentiated adenocarcinoma( tub2, pSS, ly3, v2, pN1, H0, P0, M0, Stage III a, Cur A). In February 2015, he complained of anal discomfort, and tumor markers were elevated. Enhanced CT revealed a 15-mm high-density solid tumor in the anal canal. The results of needle biopsy indicated a moderately differentiated adenocarcinoma. This tumor was suspected to be metastasis from rectal cancer, and we performed abdominoperineal resection. Histopathological examination revealed a moderately differentiated adenocarcinoma, which was the same histological type as the primary rectal cancer and was covered with normal anal epithelium. Collectively, the findings indicated anal metastasis from rectal cancer. The patient is alive without recurrence for 18 months after resection. Anal metastasis should be considered as a differential diagnosis in patients with anal discomfort who have a history of colon/rectal cancer. Abdominoperineal resection may be an effective treatment modality for this condition.

Background/aim: The TNM staging system for esophageal cancer is designed to predict survival based on pathological stage in patients who have been treated with surgery alone. However, pathological stage can vary considerably after neoadjuvant therapy due to tumor responses., Patients and Methods: We reviewed 110 patients with esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant chemoradiotherapy (nCRT) followed by surgery, and investigated the effects of nCRT on TNM stage and its prognostic significance., Results: A comparison of pre-treatment clinical and pathological stages (cStage and ypStage, respectively) resulted in 75 (68%) of the patients being down-staged. Good responders (over two-thirds of the primary tumor reduced by nCRT) comprised 100%, 83%, 69%, 52% and 50% of patients with ypStages 0, I, II, III and IV, respectively (p=0.001). In addition, 62 (83%) and 20 (57%) of patients with and without down-staged tumors, respectively, were pathological good responders (p=0.004). We found that cStage did not significantly correlate with survival, whereas univariate analysis significantly associated ypStages III/IV (p=0.003) and down-staged tumors (p=0.04) with overall survival (OS). Multivariate analysis selected ypStage III/IV (HR=3.26; 95% CI=1.52-6.99; p=0.002) and no down-staging (HR=2.06; 95%CI=1.16-3.64, p=0.01) as independent covariates for OS., Conclusion: nCRT could lead to down-staged ESCC tumors for many patients and a good prognosis. The correlation between ypStage and pathological response to nCRT indicated that ypStage could stratify survival and serve as a prognostic predictor after trimodal therapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To determine the preoperative ability of [ 18 F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) to predict pathologic tumor invasion and lymph node status in cT1N0M0 esophageal squamous cell carcinoma (ESCC)., Methods: We retrospectively analyzed 40 consecutive patients diagnosed with cT1N0M0 ESCC between February 2006 and April 2011. All patients were treated by esophagectomy with two- or three-field lymphadenectomy without neoadjuvant therapy. We evaluated the relevance between clinical variables including maximum standardized uptake values (SUV max ) of the primary tumor on FDG-PET and pathologic tumor invasion and lymph node status using a logistic regression model., Results: Tumors invaded the middle submucosal layer (SM2) and beyond in 21 (52.5 %) patients, and 6 (15 %) had lymph node metastases. The areas under receiver operating characteristic (ROC) curves for SUV max of the primary tumor used to predict factors involved in tumor infiltration to SM2 or deeper and lymph node metastasis were 0.75 (p = 0.006) and 0.79 (p = 0.025), respectively. The optimal SUV max cutoff was 2.7. The findings of univariate and multivariate analyses identified SUV max as the only significant preoperative predictor associated with tumor infiltration into SM2 or beyond and lymph node metastasis. Furthermore, SUV max  ≥ 2.7 of the primary tumor on FDG-PET was associated with poor recurrence-free and disease-specific survival (p = 0.019 and p = 0.012, respectively)., Conclusions: FDG-PET is helpful for diagnosing tumors that can infiltrate SM2 and beyond as well as occult lymph node metastasis of cT1N0M0 ESCC that are valuable indications in deciding therapeutic strategies for superficial ESCC.

Background: Responses of esophageal cancer to neoadjuvant therapy and patient prognosis are difficult to predict preoperatively. This study aimed to determine the ability of fluorine-18 fluorodeoxyglucose ((18)FDG) positron emission tomography (FDG-PET) to predict outcomes of trimodal therapy on esophageal squamous cell carcinoma (ESCC)., Methods: The responses of 111 patients with ESCC were monitored using FDG-PET before and after neoadjuvant chemoradiotherapy (nCRT) followed by surgical treatment. Associations between the maximum standardized uptake value (SUVmax) and pathologic responses (PRs) and prognosis were analyzed., Results: Responses were significantly associated with SUVmax after nCRT (post-SUVmax) and with the rate of decreases in the SUVmax (%ΔSUVmax) of the primary tumor. The optimal cutoffs for post-SUVmax and %ΔSUVmax determined from receiver operating characteristic (ROC) curves were 2.7 (area under the curve [AUC], 0.68; 95% confidence interval [CI], 0.58-0.78; p = 0.001) and 75 (AUC, 0.64; 95% CI, 0.54-0.75; p = 0.01) for predicting a pathologic complete response (pCR) and 3.7 (AUC, 0.76; 95% CI, 0.63-0.89; p < 0.001) and 70 (AUC, 0.65; 95% CI, 0.52-0.78; p = 0.02) for predicting a good response according to Japan Esophageal Society response criteria. These values reliably separated patients into groups with and without pCR and with and without a good response. Multivariate analysis showed that %ΔSUVmax (≤70 and >70) was an independent prognostic factor for disease-specific survival (hazard ratio [HR], 0.45; 95% CI, 0.21-0.98; p = 0.04)., Conclusions: SUVmax is a valuable preoperative predictor of tumor response and survival among patients who undergo trimodal therapy for ESCC., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Esophageal cancer is most frequently treated with platinum-based chemoradiotherapy (CRT). We previously described a phase I study of definitive CRT with docetaxel (DOC) and 5-fluorouracil (5FU) in patients with advanced esophageal cancer. This regimen had low toxicity and was effective without platinating agents. The present study aims to determine the antitumor effects of neoadjuvant CRT with DOC and 5FU and surgical outcomes., Methods: We reviewed data from 38 patients with locally advanced cancer of the esophagus or esophagogastric junction who underwent trimodality therapy comprising neoadjuvant CRT with DOC and 5FU followed by esophagectomy between 2003 and 2008., Results: Esophagitis was the most common toxicity associated with neoadjuvant CRT (grade 3; 26.3%), and hematologic toxicity was mild. Transthoracic esophagectomy and pharyngolaryngoesophagectomy proceeded in 36 (94.7%) and 2 (5.3%) patients, respectively, and 35 (92.1%) underwent R0 resection. Five (13.2%) patients had complete pathologic responses (pCR) of the primary tumor, and 23 (60.5%) had pathologic reductions of over two-thirds of the primary tumor. The T or N status was also down-staged in 26 (68.4%) patients. Overall postoperative morbidity developed in 21 (55.3%) patients, and mortality due to postoperative morbidity was zero. The 5-year recurrence-free and overall survival rates were 39.5% and 44.7%, respectively., Conclusions: The rates of neoadjuvant CRT toxicity and postoperative complications were acceptable, and the complete resection rate and survival data were favorable. This regimen is promising as neoadjuvant CRT for esophageal cancer and very useful as an alternative regimen for treating patients with esophageal cancer who cannot tolerate cisplatin., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: In T4 esophageal cancer with tracheobronchial invasion, an esophagorespiratory fistula (ERF) often occurs during or after chemoradiotherapy. We have performed esophageal bypass operations prior to definitive chemoradiotherapy for these patients to increase the chemoradiotherapy completion rate by minimizing the potential effect of an ERF. The aim of this study was to examine the clinical outcome of esophageal bypass surgery prior to chemoradiotherapy., Methods: Between 1997 and 2010, 17 patients underwent esophageal bypass surgery followed by definitive chemoradiotherapy for esophageal cancer with tracheobronchial invasion (bypass group). Ten patients in the same circumstances were treated with chemoradiotherapy alone (control group). Overall survival, the clinical effect of chemoradiotherapy, the ERF incidence rate, and the safety of esophageal bypass surgery were assessed., Results: The overall response rate to chemoradiotherapy was 64.7% in the bypass group and 90.0% in the control group. Except for 2 patients with ERF at initial diagnosis, 4 (26.7%) of the 15 patients developed ERF in the bypass group, and 3 (30.0%) of the 10 patients developed ERF in the control group during or after chemoradiotherapy. The 2-year and 3-year overall survival rates were 17.6% and 17.6% in the bypass group and 20.0% and 0% in the control group, respectively (p = 0.924); long-term survival of more than 3 years was seen only in the bypass group., Conclusions: Esophageal bypass surgery prior to definitive chemoradiotherapy could be performed safely, and this strategy contributed to long-term survival in the patients who achieved a good response to chemoradiotherapy but developed an ERF., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background/aim: The status of each patient with advanced esophageal cancer varies widely, and the prognosis is generally poor. We aimed to determine which prognostic factors are involved in the management of locally advanced esophageal cancer with adjacent organ invasion., Patients and Methods: We retrospectively investigated the therapeutic outcomes of 74 patients with thoracic esophageal cancer and clinical evidence of adjacent organ invasion but without distant metastasis. The predictive factors for a chemoradiotherapeutic response and survival were evaluated., Results: Definitive chemoradiotherapy (CRT), bypass surgery and CRT, as well as CRT followed by esophagectomy were carried out in 48 (64.9%), 17 (23.0%), and 9 (12.2%) patients, respectively. The median survival time (MST) of patients overall was 11.3 months. The MST of patients after definitive CRT, bypass surgery plus CRT and CRT followed by esophagectomy was 10.4, 11.0 and 16.4 months, respectively; MST did not differ significantly between patients. MST of patients with a complete response (CR), a partial response (PR) and stable (SD)/progressive (PD) disease as clinical outcomes of CRT was 52.6, 11.3 and 6.7 months, respectively; the MST was considerably longer in patients with, than in those without CR (CR vs. SD/PD, p<0.0001; CR vs. PR, p=0.0004). In multivariate analysis, age <60 years [odds ratio (OR)=7.74; 95% confidence interval (CI)=1.85-32.41; p=0.005] and hemoglobin ≥13 g/dl (OR=11.54; 95% CI=1.29-103.21; p=0.03) were independently associated with CR as an outcome of CRT, and serum albumin level ≥3.5 g/dl (OR=2.11; 95% CI=1.09-4.10; p=0.03) was independently associated with prolonged survival., Conclusion: Pre-treatment hemoglobin and albumin levels were valuable predictors of the outcome of CRT and survival, respectively. A better response to CRT as well as improved nutritional status prolonged the survival of patients with advanced esophageal cancer.

We describe the case of an 80-year-old man with hepatocellular carcinoma (HCC) who developed tracheal obstruction due to peritracheal lymph node metastasis. A metastatic tumor that protruded into the airway was ablated using a neodymium yttrium-aluminium-garnet laser and then a self-expandable metallic stent (SEMS) was deployed in the trachea. Stenting resolved symptoms of severe dyspnea upon mild exertion and in the supine position. Three months later, the patient is alive and has resumed normal activities as an outpatient, despite having metastatic HCC. Peritracheal lymph node metastasis arising from HCC is very rare and a polypoid tumor growing from a metastatic lymph node into the trachea is also extremely unusual. Tracheal obstruction in this patient was successfully treated by airway stenting.

Metabolomics has developed as an important new tool in cancer research. It is expected to lead to the discovery of biomarker candidates for cancer diagnosis and treatment. The current study aimed to perform a comprehensive metabolomic analysis of the intracellular dynamic responses of human gastric cancer cells to 5-fluorouracil (5-FU), referencing the mechanisms of drug action and drug resistance. Small metabolites in gastric cancer cells and 5-FU-resistant cells were measured by liquid chromatography-mass spectrometry. Candidates for drug targets were selected according to the presence or absence of resistance, before and after 5-FU treatment. In addition, the gene expression of each candidate was assessed by reverse transcription-polymerase chain reaction. The number of metabolites in cancer cells dramatically changed during short-term treatment with 5-FU. Particularly, proline was reduced to one-third of its original level and glutamate was increased by a factor of 3 after 3 h of treatment. The metabolic production of glutamate from proline proceeds by proline dehydrogenase (PRODH), producing superoxide. After 5-FU treatment, PRODH mRNA expression was upregulated 2-fold and production of superoxide was increased by a factor of 3. In 5-FU-resistant cells, proline and glutamate levels were less affected than in non-resistant cells, and PRODH mRNA expression and superoxide generation were not increased following treatment. In conclusion, the authors identified a candidate biomarker, PRODH, for drug effects using a meta-bolomic approach, a result that was confirmed by conventional methods. In the future, metabolomics will play an important role in the field of cancer research.

Airway stenting is required for the palliative treatment of advanced esophageal cancer. This study retrospectively analyzes the outcomes of airway stenting for esophageal cancer at our institution. Data from nine patients who underwent airway stenting were reviewed. All patients had poor respiratory status due to esophagorespiratory fistula and/or respiratory stenosis. We retrospectively assessed the results of airway stenting as five grades of respiratory symptoms, regarding stent-related complications and clinical course and survival. Six silicone and six covered self-expandable metallic stents were deployed in five and six patients, respectively. Two types of airway stents were deployed in two patients, and double stents were positioned in the airway and in the esophagus of three other patients. The grade of respiratory symptoms improved in seven patients. The mean dyspnea grade was 3.0±0.9 and 1.3±1.3 before and after airway stenting, respectively. Stent-related complications comprised of chest pain, incomplete closure of the ERF, sputum retention and stent migration. The mean±SD survival of all patients was 103±108 (range, 0 to 325) days, and the survival of patients without relapsed cancer at the time of stenting, who underwent cancer-specific therapy after stenting, was prolonged. Although the airway should be stented according to the status and the prognosis of each patient individually stenting can relieve symptoms and improve the prognosis even when esophageal cancer is at very advanced stages. Airway stenting could play a role in the multidisciplinary management of advanced esophageal cancer.

Purpose: The purpose of this study was to evaluate the efficacy of(adjuvant)surgery following the response to chemotherapy for advanced gastric cancer., Subjects and Methods: The subjects were 20 advanced gastric cancer patients who had undergone gastrectomy following the response to combination chemotherapy with docetaxel and S-1 from September 2003 to December 2008. They consisted of 14 men and 6 women, with a median age of 58. 8, who received combination chemotherapy with docetaxel and S-1 according to the following regimen: S-1, 80 mg/m2, was administered on 14 consecutive days followed by a 7-day rest period, and docetaxel, 40 mg/m2, was administered on day 1., Results: The average treatment was 4. 4 courses. They consisted of 17 PR and 3 SD. The median overall survival was 855 days. 2-year and 3-year survival was seen in 80% and 54. 9% of patients, respectively, following macroscopically curative operation. Median survival of patients with liver metastasis and peritoneal dissemination was 865 days and 510 days, respectively., Conclusion: Adjuvant surgery might be effective in advanced gastric cancer patients except for cases of peritoneal dissemination.

The patient was a 59-year-old man who suffered from discomfort during swallowing. An esophageal small cell carcinoma was pointed out at another clinic by gastrointestinal fiberscopy. He was hospitalized in our hospital on May 15, 2003. He was diagnosed as esophageal small cell carcinoma with mediastinum lymph node, pancreas and multiple liver metastasis by CT scan. Then he was administered CDDP+CPT-11 therapy. CDDP 60 mg/m2 (day 1) and CPT-11 60 mg/m2 (day 1, 8, 15)were infused once a week for 3 weeks followed by 1-week interval as one cycle. At one cycle after the first infusion therapy, primary tumor, pancreas and liver metastasis were markedly reduced. His quality of life was greatly improved. No particular toxic events occurred. Five cycles after the first infusion therapy, he was diagnosed with a lymph node recurrence around the pancreas on January 19, 2004. Then we started CBDCA and VP-16 combination therapy as second-line chemotherapy. But obstructive jaundice and skull metastasis occurred, and he died on July 21, 2004.

The CD4+CD25high regulatory T (Treg) cells have been demonstrated to negatively modulate anti-tumor immune responses in cancer patients. In this study, effects of low dose anti-CD25 antibody (Ab) to attenuate Treg cells were investigated in cancer patients in vitro and in vivo. Peripheral blood mononuclear cells (PBMCs) from cancer patients were cultivated in vitro in the presence of a high-affinity chimeric anti-CD25 Ab (basiliximab). The CD4+CD25high population, interferon-gamma (IFN-gamma) production and FOXP3 expression were analyzed using flow cytometry (FCM), enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, respectively. During in vivo studies, basiliximab was administered intravenously on day 1, followed by AIT using autologous activated lymphocytes on day 8, and the treatment cycle was repeated. Subjective and objective effects were observed, and patients' PBMCs were subjected to FCM and RT-PCR analysis. In vitro analysis revealed that a low concentration of 0.01 microg/ml basiliximab reduced almost all of CD4+CD25high cells, but less of the CD4+ CD25low cells, and augmented IFN-gamma production of activated PBMCs. FOXP3 mRNA expression of PBMCs was not affected with or without basiliximab. An in vivo study of 9 metastatic cancer patients (7 colorectal and 2 esophageal) demonstrated no subjective or objective adverse effects, even under repeated administration of basiliximab. The results suggested that low-dose basiliximab can safely be administered repeatedly, and can target CD4+CD25high Treg cells whilst relatively preserving CD4+CD25low activated T cells. The host conditioning with low-dose basiliximab may augment the efficacy of AIT for cancer using activated autologous lymphocytes.

The purpose of this study was to evaluate the pattern of the expression of orotate phosphoribosyltransferase (OPRT) in several components of colorectal carcinoma (CRC). Fifty-six surgically-resected samples of CRC were subjected to immunohistochemistry with a polyclonal anti-OPRT antibody. Grading was performed independently for several components of CRC, including mucosal carcinoma lesions (n=56), infiltrative lesions (n=53), lymphovascularly invasive lesions (n=34) and metastatic lymph nodes (n=17). The expression of OPRT in mucosal carcinoma and infiltrative lesions correlated significantly only with the presence of lymphovascular invasion (p=0.0007 and <0.0001, respectively). The frequency of OPRT expression in mucosal carcinoma, infiltrative and lymphovascularly invasive lesions as well as metastatic lymph nodes was 32.1, 69.8, 88.2 and 88.8%, respectively. In addition, nuclear staining of OPRT was observed in metastatic lymph nodes and lymphovascularly invasive lesions. Our results suggest that OPRT is involved in the invasion and metastasis of CRC.

A 31-year-old man with neurofibromatosis 1 (NF1) was admitted for the treatment of solitary lung tumor. Nine months earlier he had undergone a large resection for malignant peripheral nerve sheath tumors (MPNSTs) in his back. Surgical resection of the right lower lobe was performed, and the tumor was pathologically diagnosed as a metastasis of MPNST. The survival of patients with pulmonary metastasis of MPNST is extremely poor, especially of those with NF1, but this patient has survived 5 years without recurrence. Based on our knowledge of the literature, a 5-year survival is extremely rare, and select patients have benefited from a resection of pulmonary metastasis.

Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyltransferase (OPRT) are fluoropyrimidine metabolic enzymes which play important roles in the response of cancer patients to chemotherapy. In esophageal cancer, little is known about the relationship between the expression of these enzymes and corresponding clinicopathological features. In the present study, TS, DPD and OPRT expression levels were evaluated in 72 resected esophageal cancer specimens using immunohistochemistry. The relationship between enzyme expression and clinicopathological features was assessed using Fisher's exact test or the χ2 test (categorical variables), or the Mann-Whitney rank-sum test (continuous variables). Survival curves were calculated using the Kaplan-Meier method, and differences evaluated using the log-rank test. The Cox proportional hazards model was also used. High DPD expression was associated with depth of invasion, nodal status, tumor stage, lymphatic invasion and venous invasion (P<0.001, P=0.004, P<0.001, P=0.006, P=0.038, respectively), as well as with decreased patient survival (P=0.007). In patients receiving adjuvant chemotherapy, low DPD expression did not significantly improve recurrence-free survival. OPRT was particularly expressed in esophageal cancer cells as compared to normal squamous cells. High OPRT expression was associated with depth of invasion and venous invasion (P=0.006, P=0.003, respectively). To conclude, in esophageal cancer DPD expression was associated with tumor progression and prognosis, and OPRT expression was correlated with carcinogenesis and tumor progression.

Unlabelled: This phase I study was designed to determine the maximum-tolerated dose (MTD) of docetaxel (TXT) and toxicities of combining weekly administration of TXT and continuous infusion of 5-fluorouracil (5-FU) with concomitant radiotherapy for advanced esophageal cancer., Patients and Methods: Patients received TXT by i.v. infusion over 1 h on days 1, 8, 22 and 29. They were also given 5-FU 250 mg/m2/day by continuous infusion for 24 h on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40 and 43-45. Fractionated radiotherapy was performed on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40 and 43-45, and a total dose of 60 to 66 Gy was delivered. The starting dose level (Level 1) of TXT was set at 7.5 mg/m2. Dose escalation was conducted in increments of 25 mg/m2, until the dose reached Level 4 (15 mg/m2). At least three patients were enrolled at each level., Results: Seven patients (median age, 64 years) were enrolled. Six patients had stage III (T4NIMO) and one had stage IVb (T4N1M1b) esophageal cancer; six had squamous cell carcinoma and one had carcinosarcoma. No patient had received prior chemotherapy or radiotherapy, and two patients had undergone esophageal bypass surgery using a whole stomach tube without resection of primary or metastatic lesions. In the 7patients, the regimen was well-tolerated, with esophagitis as the most common toxicity (grade 3: n=1; grade 4: n=3). In general, hematological toxicity was mild. Dose-limiting toxicity (DLT) was observed at Level 2 (TXT 10 mg/m2) when three patients developed grade 4 esophagitis and this dose was deemed the MTD for this regimen. In the 7 assessable patients, the overall clinical response rate was 85.7%., Conclusion: The MTD of TXT in this regimen was 10 mg/m2 and the recommended dose of TXT was 7.5 mg/m2. Although esophagitis was the dose-limiting and the most frequent toxicity, the regimen was safe and well-tolerated, and demonstrated the possibility of good efficacy in patients with advanced esophageal cancer.

Rapid regrowth or recurrent growth of occult cancer cells are often observed after esophagectomy or postoperative complications. In order to clarify the mechanism of such oncological circumstances, we focused on neutrophil elastase (NE), which degrades a broad spectrum of extracellular matrix and cell surface proteins. In the present study, we demonstrated that NE stimulated the growth of all of the five esophageal cell lines (TE-1, -7, -8, -12 and -13) by MTT assay and promoted cell invasion by cell migration assay. Pro-transforming growth factor-alpha (pro-TGF-alpha) from the cell membrane was released to the culture medium as a mature form after treatment with 5 microg/ml NE, and it reached the maximum level of 153% compared to the control values at 15 min of treatment in TE-13 cells. The phosphorylation of epidermal growth factor receptor (EGFR) rapidly occurs after treatment with NE and triggered the extracellular signal-regulated kinases 1 and 2 (ERK) signaling pathway. Moreover, NE induced release of platelet-derived growth factor-AA (PDGF-AA), PDGF-BB and vascular endothelial growth factor (VEGF) to 141.9, 227.7, and 171.6% of the control values, respectively. A specific NE inhibitor, sivelestat, significantly inhibited the NE-induced cell proliferation, cell invasion and subsequently inhibited the signal transduction pathway. Furthermore, sivelestat significantly inhibited NE-induced release of TGF-alpha, PDGF-AA, PDGF-BB and VEGF in the medium in TE-13 esophageal carcinoma cells. These results strongly indicate that NE released from activated neutrophils stimulates the growth and progression of esophageal cancer cells by releasing the growth factors on the cell surface and that sivelestat, a specific NE inhibitor, blocks these processes. Furthermore, we postulate that postoperative administration of sivelestat might be useful as a new molecular-targeting cancer therapy as well as for the treatment of postoperative respiratory complications.

Neutrophil elastase is a neutral serine proteinase produced by polymorphonuclear leukocytes and monocytes/macrophages, especially under surgical stress. In the present study, we investigated whether NE promotes cell growth by activation of EGFR to elucidate whether surgical stress induces tumor proliferation and progression. Furthermore, we examined the antitumor effect of a specific NE inhibitor, sivelestat. Cell growth assays were carried out in vitro and in vivo using TMK-1 gastric cancer cells. TMK-1 cell growth was stimulated to 118% of that of the control cells after 48 h stimulation with 1 microg/mL NE according to an MTT assay. Sivelestat inhibited cell growth to 23.4 and 58.0% of control values at concentrations of 100 and 1,000 microg/mL, respectively. NE rapidly phosphorylated EGFR in only 5 min and triggered the ERK1/2-mitogenic signaling pathway in TMK-1. It was further demonstrated that NE-induced EGFR phosphorylation was transactivated through TGF-alpha, using ELISA. NE increased the cleavage of TGF-alpha from the cell surface 30-fold compared with the cells without treatment. Interestingly, sivelestat significantly reduced NE-induced EGFR phosphorylation and ERK1/2 activation and completely blocked the release of TGF-alpha from the TMK-1 cell surface. In a xenograft study, the addition of ventrotomy as a surgical stress promoted tumor growth. Sivelestat significantly suppressed the tumor growth induced by surgical stress. These results indicate that sivelestat suppresses the growth of gastric cancer cells by inhibiting the release of TGF-alpha stimulated by NE, which often occurs after surgical stresses.

We herein report a case of gastrointestinal bleeding induced by angiodysplasia of the cecum in a case of Bernard-Soulier syndrome with recurrent breast cancer. In spite of endoscopic hemostatic therapy and interventional embolization, she had repeated massive bleeding from the cecal lesion. In addition, she had chronic hepatitis C and progressive liver tumors metastasized from breast cancer, and she finally died of hepatic failure. There are four case reports in the literature describing Bernard-Soulier syndrome with gastrointestinal bleeding angiodysplasia. The reported cases benefited from hormonal, endoscopical hemostasis and surgical therapy. In our case, because of her terminal metastatic breast cancer, only conservative treatments were administered after the third bleed. Both the endoscopic hemostatic method and interventional embolization showed only a temporary effect. Surgical treatment should be considered if the general condition can tolerate a surgical procedure.

The clinical efficacy and safety of TS-1 therapy were studied retrospectively in patients with inoperable and recurrent gastric cancer. The subjects were 67 patients who were treated with TS-1 in our department between June 1999 and September 2004. The objective overall response rate was 41.0% (16/39; 95% confidence interval, CI, 25.3-56.7). By location, the response rate of peritoneal dissemination was high (57.1%), as were those of primary lesion (53.3%) and lymph nodes (42.9%). The prevalence of adverse reactions with a grade of 3 or 4 was 12.8%. The median survival rate (MST) was 276 days with 1-year and 2-year survival rates of 48.9% and 27.8%, respectively. This resulted in 6 long-term survival cases (over 2.5 years) after TS-1 therapy, and the longest survival time was 3y 5m after TS-1 therapy. PRs or long-term NCs after TS-1 therapy were likely to be important factors for long-term survival. In conclusion, TS-1 is safe and effective for patients with inoperable and recurrent gastric cancer, and is promising as a first-line treatment.