齋藤 心

Introduction: Peritoneal metastasis (PM) is the most common site of recurrence following curative resection for advanced gastric cancer (GC). Along with disease progression, it can lead to complications such as intestinal obstruction, hydronephrosis, obstructive jaundice, and ascites, significantly impairing the patient's quality of life. Therefore, peritoneal metastasis is considered a critical target for treatment. In general, these patients are treated with systemic chemotherapy; however, the therapeutic effect is often limited due to the anticancer agents' poor penetration into the peritoneal cavity. We aim to identify factors associated with the best overall survival (OS) in GC patients with peritoneal metastasis. Methods: Patients with advanced GC who were diagnosed as having macroscopic PM or positive peritoneal cytology by staging laparoscopy were enrolled. We introduced intraperitoneal Paclitaxel (IP-PTX) combined with S-1 plus oxaliplatin (SOX). Gastrectomy with lymph node dissection was performed as conversion surgery when the PM showed an excellent response. Results: Ninety-six patients received IP-PTX + SOX, with a median of 16 courses. The 1- and 5-year OS rates were 70.2% and 24.5%, respectively, with a mean survival time (MST) of 20.0 months. No chemotherapy-related mortality was observed. Conversion surgery was performed in 44 patients (45.8%), with a 1-year OS rate of 100%. Conclusions: Combination chemotherapy using the IP-PTX + SOX regimen is highly effective and is recommended as induction chemotherapy for patients with PM from GC. Conversion gastrectomy should be considered following an excellent response, particularly in patients with peritoneal cancer index (PCI) scores below 20.

BACKGROUND: Patients with advanced gastric cancer (GC) with peritoneal involvement have a dismal prognosis. Recent clinical trials have shown that anti-Claudin18.2 (CLDN18.2) antibody (zolbetuximab) enhances survival in patients with GC expressing high levels of CLDN18.2. However, the effectiveness of the zolbetuximab in patients with peritoneal metastases (PMs) remains unclear. In this study, we aimed to evaluate the expression of CLDN18.2 in disseminated lesions to assess the clinical utility of zolbetuximab in the treatment of GC with PM. METHODS: In 42 patients diagnosed with stage IV GC with PM, biopsy samples from the primary tumors and peritoneal metastatic nodules were collected and immunostained using the specific antibody (43-14A, Ventana). The expression of CLDN18.2 was comparatively evaluated based on staining intensity and the proportion of positive cells. RESULTS: Positive immunoreactivity of CLDN18.2 was observed in 37 (88%) of the primary tumors. Specifically, CLDN18.2 positivity was identified in 26 (62%) or 12 (29%) patients based on moderate to strong membrane staining in at least 40% or 75% of tumor cells, respectively. In comparison, the staining intensity in tumor cells was consistently reduced in PM across all patients. CLDN18.2 expression was absent in PM of 29 (69%) patients, while 3 (7.1%) cases were determined to be CLDN18.2-positive based on a cutoff value of 40% for high staining. This trend was particularly pronounced in cases with undifferentiated type and human epidermal growth factor receptor 2 (HER-2) negative primary tumors. CONCLUSIONS: Although CLDN18.2 expression in PM mirrored that in primary lesions, the levels were generally reduced. When zolbetuximab is used for GC patients with peritoneal involvement, it is preferable to assess the expression of CLDN18.2 in the disseminated lesions.

PURPOSE: Bariatric/metabolic surgery has been reported to reduce the incidence of severe coronavirus disease 2019 (COVID-19); however, its ability to reduce risk is controversial. Therefore, this study aimed to elucidate the incidence and severity of COVID-19 in bariatric patients in Japan. METHODS: The first survey of patients infected with COVID-19 after bariatric/metabolic surgery until June 30, 2022, was sent to 83 Japanese institutions. A second survey was conducted in institutions that reported on COVID-19 patients. The severity of COVID-19 was compared between the general population and bariatric patients, and risk factors correlated with severity were also evaluated. RESULTS: Twenty-six institutions (31.3%) reported 119 patients with COVID-19 after laparoscopic bariatric/metabolic surgery. There were no severe cases or deaths; however, moderate COVID-19 (pneumonia) was significantly more common in bariatric patients than in the general population (11.4% vs. 1.3%). The risk factors for moderate COVID-19 in bariatric patients included incurable dyslipidemia and infection before the 6th wave of the pandemic. CONCLUSION: In Japan, the number of moderate COVID-19 cases may be higher in bariatric patients than in the general population. This study did not show that bariatric/metabolic surgery reduces the risk of COVID-19 complications.

This study explores a novel therapeutic approach for peritoneal metastasis (PM) using AAV-mediated delivery of tumor suppressor microRNA-29b (miR-29b) to peritoneal mesothelial cells (PMC). AAV serotypes 2 and DJ demonstrate high transduction efficiency for human and murine PMC, respectively. In vitro analysis indicates that AAV vectors encoding miR-29b precursor successfully elevate miR-29b expression in PMC and their secreted small extracellular vesicle (sEV), thereby inhibiting mesothelial mesenchymal transition and reducing subsequent attachment of tumor cells. A single intraperitoneal (IP) administration of AAV-DJ-miR-29b demonstrates robust and sustained transgene expression, suppressing peritoneal fibrosis and inhibiting the development of PM from gastric and pancreatic cancers. Additionally, AAV-DJ-miR-29b enhances the efficacy of IP chemotherapy using paclitaxel, restraining the growth of established PM. While conventional gene therapy for cancer encounters challenges targeting tumor cells directly but delivering miRNA to the tumor stroma offers a straightforward and efficient means of altering the microenvironment, leading to substantial inhibition of tumor growth. AAV-mediated miR-29b delivery to peritoneum via IP route presents a simple, minimally invasive, and promising therapeutic strategy for refractory PM.

Abstract Background Osteopenia reflects frailty and has been shown to be associated with outcomes in cancer patients. This study was undertaken to examine whether osteopenia is an independent prognostic factor in patients with esophageal cancer after resection. Methods A total of 214 patients who underwent surgery for esophageal cancer were analyzed retrospectively. Bone mineral density (BMD) of the 11th thoracic vertebra was measured by computed tomography scan, and patients classified into osteopenia and normal BMD groups with BMD <160 Hounsfield units as the cutoff. Clinicopathological data and prognosis were analyzed. Results The 5‐year survival rate was 55.4% for the osteopenia group and 74.7% for the normal BMD group with a significantly worse prognosis in the osteopenia group (p = 0.0080). In multivariable analysis, osteopenia was a significant independent risk factor associated with overall survival (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.27–3.34, and p = 0.0151) along with R1/2 resection (HR 3.02, 95% CI 1.71–5.18, and p = 0.0002). Conclusion In patients with esophageal cancer undergoing resection, osteopenia may be a surrogate marker for frailty and an independent predictor of prognosis.

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.

＜文献概要＞胃癌治療において腹膜播種は重要な予後規定因子であるが,標準治療である全身化学療法では腹膜への薬剤移行性がわるい.タキサン製剤の腹腔内散布は,脂溶性という薬剤特性から高い腹腔内薬物濃度が維持され,強い抗腫瘍効果を発揮することが期待される.S-1+paclitaxel経静脈投与に加えてpaclitaxel腹腔内投与を併用するPHOENIX-GC試験では,主解析ではS-1+cisplatin併用療法と比較して優越性は示せなかったが,per protocol set analysisでは有意差を認めた.腹膜播種陽性(P1)または腹水細胞診陽性(CY1)と診断された非切除進行胃癌症例に対してpaclitaxel腹腔内投与+SOX療法を導入する当科の臨床研究でも,生存期間中央値(MST)19.0ヵ月,1年全生存率(OS)74.8%,2年OS 47.2%,5年OS 27.8%と良好な成績を示した.さらに播種消失や細胞診陰転化がみられた39例(46%)にconversion surgeryとして胃切除を施行し,手術症例のMSTは39ヵ月,1年・2年・5年OSはそれぞれ100%,71.3%,43.8%と非切除群と比べてOSが有意に延長した.胃癌腹膜播種に対する腹腔内化学療法,奏効例に対するconversion surgeryは予後の改善が期待できる.今後は患者の生命予後改善に寄与する新規バイオマーカーの発見が望まれる.

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.

＜文献概要＞ポイント ◆腹膜播種陽性胃癌に対するIp-PTX+SOX療法は,安全で有効な治療である.◆腹膜播種奏効例に対するconversion surgeryは,予後改善に貢献できる可能性がある.◆高度腹水を伴う胃癌腹膜播種症例でも,CART併用Ip-PTX+SOX療法により腹水コントロールが期待できる.

INTRODUCTION AND IMPORTANCE: Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. Surgical treatment of unilateral PA usually resolves excessive aldosterone secretion. Obesity is an independent factor for postoperative persistent hypertension for patients with unilateral PA. Laparoscopic sleeve gastrectomy has become popular due to its efficacy in resolving obesity. A specific strategy might to be needed for patients with unilateral PA and obesity. CASE PRESENTATION: Two males with PA and obesity (Body Mass Index: BMIs of 35.9 and 39.0, respectively) were referred for evaluation. Both patients had hypertension caused by PA and obesity. We performed laparoscopic sleeve gastrectomy (LSG) prior to adrenalectomy to avoid persistent postoperative hypertension and perioperative obesity related comorbidities. LSG could lead to decreasing of BMIs to 27.7 and 32.1. Comorbidities associated with obesity were also resolved in both patients. Laparoscopic adrenalectomy was then safely performed in these two patients with PA. CLINICAL DISCUSSIONS: Patients with PA developing resistant hypertension were estimated to be 20 % of those who underwent adrenalectomy. Decreased BMI can be an independent preoperative determinant for successful outcome after adrenalectomy regarding hypertension. We need to review with special care the preoperative BMI and the nature of hypertension before performing surgery on patients with unilateral PA. CONCLUSIONS: A successful strategy was used to treat two obese patients with unilateral PA who underwent laparoscopic adrenalectomy after LSG to minimize complications associated with obesity-related comorbidities.

Small extracellular vesicles (sEV) contain various microRNAs (miRNAs) and play crucial roles in the tumor metastatic process. Although miR-29b levels in peritoneal exosomes were markedly reduced in patients with peritoneal metastases (PM), their role has not been fully clarified. In this study, we asked whether the replacement of miR-29b can affect the development of PM in a murine model. UE6E7T-12, human bone marrow-derived mesenchymal stem cells (BMSCs), were transfected with miR-29b-integrating recombinant lentiviral vector and sEV were isolated from culture supernatants using ultracentrifugation. The sEV contained markedly increased amounts of miR-29b compared with negative controls. Treatment with transforming growth factor-β1 decreased the expression of E-cadherin and calretinin with increased expression of vimentin and fibronectin on human omental tissue-derived mesothelial cells (HPMCs). However, the effects were totally abrogated by adding miR-29b-rich sEV. The sEV inhibited proliferation and migration of HPMCs by 15% (p < 0.005, n = 6) and 70% (p < 0.005, n = 6), respectively, and inhibited adhesion of NUGC-4 and MKN45 to HPMCs by 90% (p < 0.0001, n = 5) and 77% (p < 0.0001, n = 5), respectively. MicroRNA-29b-rich murine sEV were similarly obtained using mouse BMSCs and examined for in vivo effects with a syngeneic murine model using YTN16P, a highly metastatic clone of gastric cancer cell. Intraperitoneal (IP) transfer of the sEV every 3 days markedly reduced the number of PM from YTN16P in the mesentery (p < 0.05, n = 6) and the omentum (p < 0.05, n = 6). Bone marrow mesenchymal stem cell-derived sEV are a useful carrier for IP administration of miR-29b, which can suppress the development of PM of gastric cancer.

UNLABELLED: This study was undertaken to compare performance using a surgical robot after training with one of three simulators of varying fidelity. METHODS: Eight novice operators and eight expert surgeons were randomly assigned to one of three simulators. Each participant performed two exercises using a simulator and then using a surgical robot. The primary outcome of this study is performance assessed by time and GEARS score. RESULTS: Participants were randomly assigned to one of three simulators. Time to perform the suturing exercise (novices vs. experts) was significantly different for all 3 simulators. Using the da Vinci robot, peg transfer showed no significant difference between novices and experts and all participants combined (mean time novice 2.00, expert 2.21, p = 0.920). The suture exercise had significant differences in each group and all participants combined (novice 3.54, expert 1.90, p = 0.001). ANOVA showed p-Values for suturing (novice 0.523, expert 0.123) and peg transfer (novice 0.742, expert 0.131) are not significantly different. GEARS scores were different (p < 0.05) for novices and experts. CONCLUSION: Training with simulators of varying fidelity result in similar performance using the da Vinci robot. A dry box simulator may be as effective as a virtual reality simulator for training. Further studies are needed to validate these results.

Peritoneal dissemination is a major metastatic pathway for gastrointestinal and ovarian malignancies. The miR-29b family is downregulated in peritoneal fluids in patients with peritoneal metastases (PM). We examined the effect of miR-29b on mesothelial cells (MC) which play critical a role in the development of PM through mesothelial-mesenchymal transition (MMT). Human peritoneal mesothelial cells (HPMCs) were isolated from surgically resected omental tissue and MMT induced by stimulation with 10 ng/ml TGF-β1. MiR-29b mimics and negative control miR were transfected by lipofection using RNAiMAX and the effects on the MMT evaluated in vitro. HPMC produced substantial amounts of miR-29b which was markedly inhibited by TGF-β1. TGF-β1 stimulation of HPMC induced morphological changes with decreased expression of E-cadherin and calretinin, and increased expression of vimentin and fibronectin. TGF-β1 also enhanced proliferation and migration of HPMC as well as adhesion of tumor cells in a fibronectin dependent manner. However, all events were strongly abrogated by simultaneous transfection of miR-29b. MiR-29b inhibits TGF-β1 induced MMT and replacement of miR-29b in the peritoneal cavity might be effective to prevent development of PM partly through the effects on MC.

Background: The peritoneal cavity contains many site-specific immune cells which constitute a unique immune microenvironment. However, it is unclear how the local immune signature is altered in patients with peritoneal metastases (PM). Methods: Peritoneal lavage fluid or ascites were obtained from 122 patients with various stages of gastric cancer (GC). Cells recovered from peritoneal fluids were immunostained with mAbs for lymphocyte-, macrophage- and tumor cell-specific antigens and the frequencies of leukocyte subsets and antigen expression levels were evaluated with multi-color flowcytometry. Results: The proportions of CD8(+) T cells, CD3(+)CD56(+) NKT-like cells, and CD3(-)CD56(+) NK cells to CD45(+) leukocytes were significantly reduced in patients with PM compared to those without PM. In patients with PM, the rates of CD8 (+) T cells and NKT-like cells correlated inversely with the tumor leukocyte ratio (TLR), the relative frequency of CD326(+) tumor cells to CD45(+) leukocytes. In contrast, the proportion of CD19(+) B cells was significantly increased in patients with PM, and their proportion correlated positively with the TLR and peritoneal carcinomatosis index (PCI) score. In patients with PM, CD14(+) macrophages tended to be increased with enhanced expression of CD14, CD16 and a M2-macrophage marker, CD163. In particular, macrophages in patients with high TLR contained many granules with high side scatter and CD14 expression in their flow profile compared to those without PM. Conclusion: PM are accompanied by a drastic change in phenotypes of lymphocyte and macrophage in the peritoneal cavity, which might be involved in the development and progression of intraperitoneal tumor growth.

BACKGROUND: Leiomyosarcoma is a rare tumor that could originate from the gastrointestinal tract, uterus, kidney, retroperitoneum, and the soft tissues of the extremities. It accounts for only 1% of all gastrointestinal mesenchymal tumors and primary leiomyosarcoma of the stomach is extremely rare. Most cases reported as leiomyosarcoma of the stomach before the development of KIT immunohistochemistry might be gastrointestinal stromal tumors (GISTs) of the stomach and only 18 cases of leiomyosarcoma of the stomach have been reported since early 2000s. We report here a patient with leiomyosarcoma of the stomach treated by laparoscopic and endoscopic cooperative surgery (LECS). CASE PRESENTATION: A 59-year-old man was referred to our hospital for an early gastric cancer, which was initially treated by endoscopic submucosal dissection. Six months after his initial treatment, a follow-up esophagogastroduodenoscopy revealed a small polypoid lesion at the lesser curvature of the proximal stomach, which appeared to be a hyperplastic polyp. However, one and a half years later, the lesion grew and showed more irregular surface. Biopsy at the time revealed smooth muscle cell proliferation suggestive of leiomyoma. Three years later, the lesion grew even larger and biopsy showed pleomorphic spindle cells. Immunohistochemical study showed positive staining for alpha-smooth muscle actin and desmin, but negative for c-kit and CD34. Ki-67 labeling index was nearly 60%. Based on these findings, the diagnosis of leiomyosarcoma was established. The patient subsequently underwent a partial gastrectomy by LECS. The patient is currently in good condition without recurrence or metastasis at 12 months after surgery. CONCLUSIONS: Leiomyosarcoma of the stomach is extremely rare. This is the first report of leiomyosarcoma of the stomach treated by LECS. We could also follow its appearance change through endoscopic examination for 3 years.

BACKGROUND: The frequency of tumor cell dissemination in the peritoneal cavity is critically related to the progression of peritoneal metastases (PM). Recently, flow cytometry (FCM) has been successfully used to detect tumor cells in malignant effusions. METHODS: A total of 143 single cell suspensions derived from ascites or peritoneal lavages from patients with advanced gastric cancer (GC) were stained with monoclonal antibodies to CD45 and to CD326 as well as 4,6-diamidino-2-phenylindole (DAPI) and FVS780. Using FCM, tumor-leukocyte ratio (TLR) were calculated from CD45(-)CD326(+) tumor cell counts/ CD45(+)CD326(+) leukocyte counts in DAPI (+) FVS780(-) gated area. In 54 patients, the ratios of CD11b(+), CD4(+) and CD8(+) cells in CD45(+) leukocytes were evaluated in parallel. RESULTS: TLR of 69 patients with PM were significantly higher than those of 74 without PM (p < .001) and log(TLR) showed strong correlation with peritoneal cancer index scores in 51 PM (+) patients (r = 0.439). TLR in PM (+) patients also correlated with the ratio of CD11b (+) myeloid cells (r = 0.547), and correlated inversely with those of CD4(+) (r = -0.490) and CD8(+) T cells (r = -0.648). In PM (-) patients who underwent gastrectomy, TLR never exceeded 0.1% in patients with primary GC without serosal involvement (<T4). However, TLR in patients with T4 GC were significantly higher (p < .05) and peritoneal recurrence occurred in 6/8 patients whose TLR exceeded 0.1%. CONCLUSION: TLR in peritoneal fluid reflects tumor burden and the immune environment in peritoneal cavity. Multicolor FCM may provide additional information which can be used for the treatment of the patients with PM.