北山 丈二

Mouse studies have reported anti-stress effects of Lactiplantibacillus plantarum SNK12 (SNK). Specifically, oral SNK administration increased mRNA levels of hippocampal neurotrophic factor and gamma-aminobutyric acid receptor in mice with sub-chronic mild stress-induced social defeat; moreover, it improved depressive behavior. We aimed to evaluate the efficacy of SNK ingestion against stress in healthy adults. We used the Uchida–Kraepelin test for the stress load, with a low-dose (50 mg/day), high-dose (150 mg/day), and placebo groups (dextrin). The primary outcome was the psychological evaluation as measured by the Profile of Mood States 2nd Edition (POMS2) using total mood disturbance (TMD) scores. The secondary outcomes were the score of each POMS2 item, salivary cortisol as a stress marker, and autonomic balance with the low frequency (LF)/ high frequency (HF) ratio. Compared with the placebo group, the SNK ingestion group showed significantly lower TMD scores. Additionally, compared with the placebo group, the high-dose group showed significantly lower scores for Tension-Anxiety and Confusion-Bewilderment, while the low-dose group showed significantly lower Anger-Hostility scores, salivary cortisol levels, and LF/HF scores. Our findings suggest that SNK ingestion could relieve stress (negative feelings, anxiety, tension, embarrassment, confusion, anger, and hostility) resulting from the temporary load caused by work and study.

PURPOSE: Although neutrophil extracellular traps (NETs) are present in various tumors, their roles in tumor biology have not been clarified yet. In this study, we examined how NETs affect the pharmacokinetics and effects of doxorubicin (DOX). METHODS: NETs were generated by neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide (LPS). DOX was added to NETs and their distribution was observed under fluorescein microscopy, and the diffusion of DOX through 3 μM pores from lower to upper chambers was evaluated with a fluorescence-based assay. Ovarian cancer cells, KOC-2S and SKOV3, were embedded in collagen gel droplets and cultured in 3D way and their apoptosis was examined with flow cytometry. RESULTS: DOX was mostly co-localized with NETs. The transfer of DOX to upper chambers increased over time, which was significantly decreased by the presence of neutrophils stimulated with PMA or LPS in the lower chamber. DOX outside of the gel increased the rates of annexin V (+) apoptotic cells, which were significantly reduced by the addition of LPS-stimulated neutrophils in media both in KOC-2S and SKOV3. The reduced diffusion and apoptosis were mostly restored by the destruction of the NETs structure with 1000 u/ml DNAse I. CONCLUSION: NETs efficiently trap and inhibit the diffusion of DOX which may attenuate its ability to induce apoptosis of ovarian cancer cells. Degradation of NETs with DNAse I may augment the response of ovarian cancer to DOX.

BACKGROUND: Osteopenia is defined as low bone mineral density (BMD) and has been shown to be associated with outcomes of patients with various cancers. The association between osteopenia and perihilar cholangiocarcinoma is unknown. The aim of this study was to evaluate osteopenia as a prognostic factor in patients with perihilar cholangiocarcinoma. METHODS: A total of 58 patients who underwent surgery for perihilar cholangiocarcinoma were retrospectively analyzed. The BMD at the 11th thoracic vertebra was measured using computed tomography scan within one month of surgery. Patients with a BMD < 160 HU were considered to have osteopenia and b BMD ≥ 160 did not have osteopenia. The log-rank test was performed for survival using the Kaplan-Meier method. After adjusting for confounding factors, overall survival was assessed by Cox's proportional-hazards model. RESULTS: The osteopenia group had 27 (47%) more females than the non-osteopenia group (p = 0.036). Median survival in the osteopenia group was 37 months and in the non-osteopenia group was 61 months (p = 0.034). In multivariable analysis, osteopenia was a significant independent risk factor associated with overall survival in patients with perihilar cholangiocarcinoma (hazard ratio 3.54, 95% confidence interval 1.09-11.54, p = 0.036), along with primary tumor stage. CONCLUSIONS: Osteopenia is associated with significantly shorter survival in patients with perihilar cholangiocarcinoma.

【目的】高度肥満症患者に対する減量・代謝改善手術症例の治療効果を検討する。【方法】2010年7月から2021年3月までに当院で行った107回(103症例)の減量・代謝改善手術を対象とした。主に体重変化と糖尿病治療効果を後ろ向きに評価した。【結果】99症例がデータ解析可能であった。術後総体重減少率は、術後1年目で28.4%、2年目で28.3%、5年目で27.3%であり、約30%の体重減少効果を認めた。糖尿病患者は47例であり、HbA1cの推移は術前の6.8%±1.4から術後6ヵ月で5.9%(±0.8)、術後1年で5.8%(±0.93)と改善を認めた。糖尿病寛解率は、術後6ヵ月で65.9%、術後1年で76.5%、術後4年で50.0%であり、糖尿病患者の半数で寛解を認めた。術前インスリン非使用群でインスリン使用群より糖尿病寛解率が良好な傾向が認められた。また、術前mABCDスコアが高い症例ほど術後寛解度が高かった。【結語】当院での減量・代謝改善手術症例において比較的良好な減量効果・糖尿病治療効果が得られた。(著者抄録)

The prognosis of pancreatic ductal carcinoma (PDAC) with peritoneal metastasis remains dismal. Systemic chemotherapy alone may not be effective, and the combination of intraperitoneal chemotherapy with systemic chemotherapy is expected to prolong the overall survival in patients with peritoneal metastasis. We have designed a randomized phase III trial to confirm the superiority of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel (PTX) with S-1 relative to gemcitabine plus nab-PTX (GnP), which is the current standard therapy for patients with metastatic PDAC. A total of 180 patients will be accrued from 30 institutions within 3 years. Patients will be randomly assigned in a 1:1 ratio to receive either i.v. and i.p. PTX with S-1 or GnP (target of 90 patients per group). The primary endpoint is overall survival; secondary endpoints are progression-free survival, response rate, proportion with negative peritoneal washing cytology during chemotherapy, proportion requiring conversion surgery, and adverse event profiles. Japan Registry of Clinical Trials jRCTs051180199 ( https://jrct.niph.go.jp/ ).

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.

Patients with peritoneal dissemination (PD) caused by abdominal malignancies are often associated with massive ascites, which shows extremely dismal prognosis because of the discontinuation of systemic chemotherapy mostly due to poor performance status. Many treatment methods, such as simple drainage, peritoneovenous shunting (PVS) and cell-free and concentrated reinfusion therapy (CART), have been used for symptom relief. However, the clinical efficacies of these methods have not been fully investigated yet. Recently, we developed the Clinical Practice Guideline for PD caused by various malignancies according to "Minds Clinical Practice Guideline Development Guide 2017". In this guideline, we systematically reviewed information on clinical diagnosis and treatments for PD using PubMed databases (2000 - 2020), and clarified the degree of recommendation for clinical questions (CQ). The evidence level was divided into groups by study design and quality. The literature level and a body of evidence were evaluated in reference to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Based on the results of systematic review, the strength of the recommendations was evaluated at a consensus meeting of the Guideline Committee. This is the English synopsis of the part of treatment of malignant ascites in Clinical Practice Guideline for PD, 2021 in Japanese. The guidelines summarize the general aspect of the treatment of malignant ascites and statements with recommendation strengths, evidence levels, agreement rates and future perspective for four raised clinical questions.

Patients with pancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination have a dismal prognosis because discontinuation of systemic chemotherapy is required for massive ascites or poor performance status. The natural history, diagnosis and treatment of PDAC with peritoneal dissemination have not been fully investigated. We systematically reviewed published information on the clinical diagnosis and treatment of PDAC with peritoneal dissemination using the PubMed database (2000-2020) and provided recommendations in response to clinical questions. This guideline was created according to the "Minds Clinical Practice Guideline Development Guide 2017". The literature quality and body of evidence were evaluated with the GRADE System and classified into four levels ("strong", "medium", "weak", "very weak"). The strength of each final recommendation was decided by a vote of committee members based on the GRADE Grid method. These guidelines address three subjects: diagnostic, chemotherapeutic, and surgical approaches. They include nine clinical questions and statements with recommendation strengths, evidence levels, and agreement rates, in addition to one "column". This is the English synopsis of the 2021 Japanese clinical practice guideline for PDAC with peritoneal dissemination. It summarizes the clinical evidence for the diagnosis and treatment of PDAC with peritoneal dissemination and provides future perspectives.

膵全摘では周術期血糖・栄養管理が重要である.12年間の膵全摘32例の周術期血糖・栄養状態を検討した.一期的・二期的膵全摘は各々16例で計48病変の約80%を膵管内乳頭粘液性腫瘍と浸潤性膵管癌が占めた.5年生存率は60.2%,一期的・二期的膵全摘で差はなかった.HbA1cは術前6.7%,術後1年は7.7%と上昇,prognostic nutritional index(PNI)は術前47.8,術後1年は43.0と低下した.予後因子を単変量解析すると術後1年neutrophil-lymphocyte ratio,術前platelet-lymphocyte ratio,術後1年PNIが抽出され,多変量解析では術後1年PNIが有意な因子であった.術後1年PNI 40.5未満は予後不良で,高力価パンクレアチン製剤投与群は予後良好であった.膵全摘後は正しい病態把握のもとに内外分泌治療を行うことが重要である.(著者抄録)

The prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combined chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled.

Polyamines are important to the survival and activation of organs and tissues via a homeostatic cell-metabolic process, and the polyamine content in cytoplasm decreases with aging. Decreases in cellular polyamine have been known to augment mutagenesis and cell death. Thus, supplementary polyamine in food is important to the prevention of aging. Here we show the anti-aging effects of oral intake of polyamine using luciferase-transgenic rats. Healthy rats, 10-12 weeks old, were given foods containing 0.01% and 0.1% (w/w) of polyamine, as compared a control food without polyamine, for 4 weeks. Using a bioimaging system, the photon intensities seen in the whole bodies and livers of rats consuming 0.1% of polyamine in food were stronger than those in rats consuming 0.01% and 0% of polyamine. However, there were no differences between groups in other characteristics, such as liver damage and body weight. In conclusion, we found that polyamine intake can activate cells throughout the whole body, providing an anti-aging effect.

BACKGROUND/AIMS: Recent studies have demonstrated that the populations of several microbes are significantly increased in fecal samples from patients with colorectal cancer (CRC), suggesting their involvement in the development of CRC. The aim of this study was to identify microbes which are increased in distal CRCs and to identify the specific location of microbes increased in mucosal tissue around the tumor. METHODS: Tissue specimens were collected from surgical resections of 28 distal CRCs. Five samples were collected from each specimen (location A: tumor, B: adjacent normal mucosa, C: normal mucosa 1 cm proximal to the tumor, D: normal mucosa 3 cm proximally, and E: normal mucosa 6 cm proximally). The microbiota in the sample were analyzed using 16S rRNA gene amplicon sequencing and the relative abundance (RA) of microbiota compared among the 5 locations. RESULTS: At the genus level, the RA of Fusobacterium and Streptococcus at location A was the highest among the 5 locations, significantly different from that in location E. The dominant species of each genus was Fusobacterium nucleatum and Streptococcus anginosus. The RAs of these species gradually decreased from locations B to E with a statistically significant difference in F. nucleatum. The genus Peptostreptococcus also showed a similar trend, and the RA of Peptostreptococcus stomatis in location A was significantly associated with depth of tumor invasion and tumor size. CONCLUSION: Although the clinical relevance is not clear yet, these results suggest that F. nucleatum, S. anginosus, and P. stomatis can spread to the adjacent normal tissues and may change the surrounding microenvironment to support the progression of CRC.