北山 丈二

Abstract Intestinal adaptation does not necessarily recover absorptive capacity in short bowel syndrome (SBS), sometimes resulting in intestinal failure-associated liver disease (IFALD). Additionally, its therapeutic options remain limited. Polyamines (spermidine and spermine) are known as one of the autophagy inducers and play important roles in promoting the weaning process; however, their impact on intestinal adaptation is unknown. The aim of this study was to investigate the impact of polyamines ingestion on adaptation and hepatic lipid metabolism in SBS. We performed resection of two-thirds of the small intestine in male Lewis rats as an SBS model. They were allocated into three groups and fed different polyamine content diets (0%, 0.01%, 0.1%) for 30 days. Polyamines were confirmed to distribute to remnant intestine, whole blood, and liver. Villous height and number of Ki-67-positive cells in the crypt area increased with the high polyamine diet. Polyamines increased secretory IgA and mucin content in feces, and enhanced tissue Claudin-3 expression. In contrast, polyamines augmented albumin synthesis, mitochondrial DNA copy number, and ATP storage in the liver. Moreover, polyamines promoted autophagy flux and activated AMP-activated protein kinase with suppression of lipogenic gene expression. Polyamines ingestion may provide a new therapeutic option for SBS with IFALD.

Abstract The spleen is a key source of circulating and tumor-infiltrating immune cells. However, the effect of splenectomy on tumor growth remains unclear. At 3 weeks after splenectomy, we subcutaneously injected LuM1 cells into BALB/c mice and evaluated the growth of primary tumors and lung metastases at 4 weeks after tumor inoculation. In addition, we examined the phenotypes of immune cells in peripheral blood by using flow cytometry and in tumor tissue by using multiplex immunohistochemistry. The growth of primary tumors was reduced in splenectomized mice compared with the sham-operated group. Conversely, splenectomized mice had more lung metastases. Splenectomized mice had fewer CD11b⁺cells, especially monocytic MDSCs (CD11b⁺Gr-1^neg-lowLy6c^high), and NK cells (CD49b⁺CD335⁺). The proportion of NK cells was inversely correlated with the number of lung metastases. In splenectomized mice, the density of CD3⁺ and granzyme B⁺ CD8⁺ T cells was increased, with fewer M2-type macrophages in primary tumors, but NK cells were decreased markedly in lung. Splenectomy concurrently enhances T cell-mediated acquired immunity by reducing the number of monocytic MDSCs and suppresses innate immunity by decreasing the number of NK cells. Splenectomy has opposite effects on primary and metastatic lesions through differential regulation on these two immune systems.

BACKGROUND: Intraperitoneal chemotherapy is promising for gastric cancer with peritoneal metastasis. Although a phase III study failed to show a statistically significant superiority of intraperitoneal paclitaxel combined with S-1 and intravenous paclitaxel, the sensitivity analysis suggested clinical efficacy. Thus, attempts to combine intraperitoneal paclitaxel with other systemic therapies with higher efficacy have been warranted. We sought to explore the efficacy of intraperitoneal paclitaxel with S-1 and cisplatin. PATIENTS AND METHODS: Gastric cancer patients with peritoneal metastasis were enrolled in the phase II trial. In addition to the established S-1 and cisplatin regimen every 5 weeks, intraperitoneal paclitaxel was administered on days 1, 8, and 22 at a dose of 20 mg/m2. The primary endpoint was overall survival rate at 1 year after treatment initiation. Secondary endpoints were progression-free survival and toxicity. RESULTS: Fifty-three patients were enrolled and fully evaluated for efficacy and toxicity. The 1-year overall survival rate was 73.6% (95% confidence interval 59.5-83.4%), and the primary endpoint was met. The median survival time was 19.4 months (95% confidence interval, 16.1-24.6 months). The 1-year progression-free survival rate was 49.6% (95% confidence interval, 34.6-62.9%). The incidences of grade 3/4 hematological and non-hematological toxicities were 43% and 47%, respectively. The frequent grade 3/4 toxicities included neutropenia (25%), anemia (30%), diarrhea (13%), and anorexia (17%). Intraperitoneal catheter and implanted port-related complications were observed in four patients. There was one treatment-related death. CONCLUSIONS: Intraperitoneal paclitaxel combined with S-1 and cisplatin is well tolerated and active in gastric cancer patients with peritoneal metastasis.

BACKGROUND: Adjuvant nivolumab therapy has become the standard therapy for patients with localized advanced esophageal cancer with non-pathological complete response after neoadjuvant chemoradiotherapy followed by curative surgery. However, the necessity of this therapy for patients after neoadjuvant chemotherapy (NAC) with docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen followed by surgery is unclear, and the prognosis of grouping based on the presence or absence of pathological tumor and lymph node findings has not been analyzed. Therefore, our study aimed to address these questions. METHODS: This retrospective cohort study included patients with cT1N1-3M0 and cT2-3N0-3M0 esophageal cancer according to the Japanese Classification of Esophageal Cancer, 11th edition, who received NAC with DCF followed by curative surgery between 2008 and 2020 at Jichi Medical University Hospital. We divided patients with ypT0-3N0-3M0 into four histological groups, namely ypT0N0, ypT+N0, ypT0N+, and ypT+N+, and we evaluated overall survival as the primary outcome and the prognostic relationship of lymph node metastasis as the secondary outcome. RESULTS: A total of 101 patients were included in this study. Kaplan-Meier analysis showed that the curves of the ypT0N0 and ypT+N0 groups were almost identical, while they differed from the other two groups. The hazard ratio of ypN+ was 4.44 (95% confidence interval: 2.03-9.71; P<0.001). CONCLUSIONS: The prognosis of the ypT+N0 group after NAC with DCF followed by surgery was similar to that of pathological complete remission. Grouping patients according to pathological lymph node status is a reasonable predictor of prognosis.

Lateral lymph node (LLN) metastasis in T1 rectal cancer has an incidence of less than 1%. However, its clinical features are largely uncharted. We report a case of LLN metastasis in T1 rectal cancer and review the relevant literature. A 56-year-old female underwent rectal resection for lower rectal cancer 2 years previously (pT1bN0M0). During follow-up, an elevated tumor marker CA19-9 was documented. Enhanced CT and MRI showed a round shape nodule 2 cm in size on the left side of pelvic wall. PET-CT showed high accumulation of FDG in the same lesion, leading to a diagnosis of isolated LLN recurrence. Because no other site of recurrence was detected, surgical resection of the LLN was performed. Microscopic findings were consistent with metastatic lymph node originating from the recent rectal cancer. Adjuvant chemotherapy for six months was given, and patient remains free of recurrent disease seven months after LLN resection. Although LLN recurrence after surgery for T1 rectal cancer is rare, post-surgical follow-up should not be omitted. When LLN metastasis is suspected on CT, MRI and/or PET-CT will be recommended. Surgical resection of LLN metastasis in patients with T1 rectal cancer may lead to favorable outcomes, when recurrence in other areas is not observed.

OBJECTIVES: The aim of this study was to identify the microbiota whose decrease in tumor area was associated with the metastatic process of distal colorectal cancer (CRC). METHODS: Twenty-eight consecutive patients with distal CRC undergoing surgical resection in our hospital were enrolled. Microbiota in 28 specimens from surgically resected colorectal cancers were analyzed using 16S ribosomal ribonucleic acid gene amplicon sequencing and the relative abundance (RA) of microbiota was evaluated. The densities of tumor-infiltrating lymphocytes (TIL) and tumor associated macrophages (TAM) in the colorectal cancers were immunohistochemically evaluated. RESULTS: Phocaeicola was the most abundant microbiota in normal mucosa. The RA of Phocaeicola in tumor tissues tended to be lower than that in normal mucosa although the difference was not significant (p=0.0732). The RA of Phocaeicola at tumor sites did not correlate either with depth of tumor invasion (pT-stage) or tumor size, however they were significantly reduced in patients with nodal metastases (p<0.05) and those with distant metastases (p<0.001). The RA of Phocaeicola at tumor sites showed positive correlation with the densities of CD3(+) or CD8(+) TIL. Since P. vulgatus was the most dominant species (47%) of the Phocaeicola, the RA of P. vulgatus and CRC metastasis and its association with TIL and TAM were also investigated. P. vulgatus showed a similar trend to genus Phocaeicola but was not statistically significant. CONCLUSIONS: A relative reduction of Phocaeicola attenuates the local anti-tumor immune response in distal CRC, which may facilitate metastatic spread.

Segmental grafts from living donors have advantages over grafts from deceased donors when used for small intestine transplantation. However, storage time for small intestine grafts can be extremely short and optimal graft preservation conditions for short-term storage remain undetermined. Secreted factors from mesenchymal stem cells (MSCs) that allow direct activation of preserved small intestine grafts. Freshly excised Luc-Tg LEW rat tissues were incubated in preservation solutions containing MSC-conditioned medium (MSC-CM). Preserved Luc-Tg rat-derived grafts were then transplanted to wild-type recipients, after which survival, injury score, and tight junction protein expression were examined. Luminance for each graft was determined using in vivo imaging. The findings indicated that 30-100 and 3-10 kDa fractions of MSC-CM have superior activating effects for small intestine preservation. Expression of the tight-junction proteins claudin-3, and zonula occludens-1 preserved for 24 h in University of Wisconsin (UW) solution containing MSC-CM with 50-100 kDa, as shown by immunostaining, also indicated effectiveness. Reflecting the improved graft preservation, MSC-CM preloading of grafts increased survival rate from 0% to 87%. This is the first report of successful transplantation of small intestine grafts preserved for more than 24 h using a rodent model to evaluate graft preservation conditions that mimic clinical conditions.

The prognosis of patients with peritoneal metastases from pancreatic cancer is poor, largely due to massive ascites, which precludes systemic treatment. Two patients with a poor performance status and malignant ascites were treated with cell-free and concentrated ascites reinfusion therapy followed by combined chemotherapy with intraperitoneal paclitaxel, intravenous gemcitabine, and nab-paclitaxel. These patients achieved a survival of 19 and 36 weeks with a relatively good quality of life. Combined intraperitoneal paclitaxel and systemic chemotherapy may provide effective palliative management for some patients with peritoneal metastases from pancreatic cancer.

Although miR-29b levels in peritoneal exosomes was markedly reduced in patients with peritoneal metastases(PM), their role has not been fully clarified. Bone marrow derived mesenchymal stem cells(BMSC)were transfected with miR-29b- integrating lentivirus and exosomes isolated from culture supernatants using ultracentrifugation. The effects of the exosomes on human peritoneal mesothelial cells(HPMC)were examined in vitro. The in vivo effect of murine BMSC-derived exosomes was examined with a syngeneic PM model. Culture of HPMC with TGF-β1 decreased expression of E-cadherin and calretinin with increased expression of vimentin, totally restored by adding miR-29b-rich exosomes. The exosomes inhibited proliferation and migration of HPMC, and inhibited adhesion of gastric cancer cells to HPMC. Intraperitoneal(IP)transfer of miR- 29b-rich exosomes every 3 days markedly reduced the number of PM of a murine gastric cancer cell, YTN16P, on the mesentery of C57/BL6 mice. IP administration of miR-29b-containing exosome suppresses the development of PM of gastric cancer.

Abstract It is important to assess the prognosis and intervene before and after surgery in patients with hepatocellular carcinoma. This study aims to elucidate the association of outcomes and residual liver function after hepatectomy. A total of 176 patients who underwent the initial resection for hepatocellular carcinoma between January 2011 and March 2021 at Jichi Medical University were included. Hepatic clearance of the remnant liver was measured using 99mTc-galactosyl serum albumin scintigraphy. The log-rank test was used to analyze survival using the Kaplan–Meier method. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival were calculated using Cox’s proportional hazard model. In multivariate analysis, microvascular invasion, intraoperative blood loss, and hepatic clearance of the remnant liver were independently associated with overall survival. Hepatic clearance of the remnant liver was independently associated with recurrence free survival. This is the first report to show that lower residual liver function is associated with shorter survival in patients with hepatocellular carcinoma undergoing hepatectomy. Preoperative determination of remnant liver function may allow assessment of prognosis in patients planned to undergo resection of hepatocellular carcinoma. Preservation of liver functional reserve may be crucial for improved long-term outcomes after hepatectomy.

BACKGROUND: The safety of intraperitoneally administrated paclitaxel (op PTX) was demonstrated in the phase I trial of ip PTX combined with conventional systemic chemotherapy for colorectal cancer with peritoneal carcinomatosis. Moreover, the median survival time was 29.3 months, which was longer than that observed in previous studies. Here, we planned the phase II trial of ip PTX: the iPac-02 trial. METHODS: This multicenter, open-label, single assignment interventional clinical study includes patients with colorectal cancer with unresectable peritoneal carcinomatosis. FOLFOX-bevacizumab or CAPOX-bevacizumab is administered concomitantly as systemic chemotherapy. PTX 20 mg/m2 is administered weekly through the peritoneal access port in addition to these conventional systemic chemotherapies. The response rate is the primary endpoint. Progression-free survival, overall survival, peritoneal cancer index improvement rate, rate of negative peritoneal lavage cytology, safety, and response rate to peritoneal metastases are the secondary endpoints. A total of 38 patients are included in the study. In the interim analysis, the study will continue to the second stage if at least 4 of the first 14 patients respond to the study treatment. The study has been registered at the Japan Registry of Clinical Trials (jRCT2031220110). RESULTS: We previously conducted phase I trial of ip PTX combined with conventional systemic chemotherapy for colorectal cancer with peritoneal carcinomatosis [1]. In the study, three patients underwent mFOLFOX, bevacizumab, and weekly ip PTX, and the other three patients underwent CAPOX, bevacizumab, and weekly ip PTX treatment. The dose of PTX was 20 mg/m [2]. The primary endpoint was the safety of the chemotherapy, and secondary endpoints were response rate, peritoneal cancer index improvement rate, rate of negative peritoneal lavage cytology, progression-free survival, and overall survival. Dose limiting toxicity was not observed, and the adverse events of ip PTX combined with oxaliplatin-based systemic chemotherapy were similar to those described in previous studies using systemic chemotherapy alone [3, 4]. The response rate was 25%, peritoneal cancer index improvement rate was 50%, and cytology in peritoneal lavage turned negative in all the cases. The progression-free survival was 8.8 months (range, 6.8-12 months), and median survival time was 29.3 months [5], which was longer than that observed in previous studies. CONCLUSION: Here, we planned the phase II trial of ip paclitaxel combined with conventional chemotherapy for colorectal cancer with peritoneal carcinomatosis: the iPac-02 trial.