Role of mast cell in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

The pro-tumor effects of mast cell (MC) in the tumor microenvironment (TME) are becoming increasingly clear. Recently, MC were shown to contribute to tumor malignancy by supporting the migration of tumor-associated macrophages (TAMs), suggesting a relationship with tumor immunity. In the current study, we aimed to examine the correlation between MC infiltration and neoadjuvant chemoradiotherapy (nCRT) response for locally advanced rectal cancer (LARC). Ninety-five LARC patients who recieved nCRT were enrolled in this study. Protein levels of the MC marker tryptase and TAM marker CD206 were evaluated with immunohistochemistry (IHC). The correlation between MC infiltration and prognostic factors was evaluated. The effects of MCs on the malignant potential were examined using in vitro proliferation and invasion assays with a colorectal cancer (CRC) cell line (HCT-116). Following nCRT, 31.6% of resected LARC patient specimens were positive for MC infiltration by tryptase IHC analysis. MC infiltration was significantly correlated with nCRT response. The 5-year disease-free survival (DFS) rate was significantly lower in the MC-positive group compared with the MC-negative group (52.3% vs. 76.8%). Univariate and multivariate analyses revealed that MC infiltration was the independent prognostic indicator for DFS. MC infiltration was significantly correlated with CD206 expression, and therefore TAMs. In vitro experiments suggested that tumor activated mast cells could promote CRC cell malignant behavior via production of macrophage inhibitory factor. MC infiltration in LARC patients was positively correlated with TAM infiltration and resistance to nCRT, and was also an independent poor prognostic indicator.


Reply: Circulating Exosomal MicroRNA Signature Predicts Peritoneal Metastasis in Patients with Advanced Gastric Cancer.


The introduction of surgical telementoring systems in rural hospitals.

The shortage of surgeons in rural hospitals is a serious problem in Japan. In this study, we investigated the potential contribution of surgical telementoring systems to improving surgical skills and resolving the shortage of surgeons in rural hospitals. The conference room at Tokushima University was connected to the operating room at Miyoshi Hospital, a rural hospital approximately 75 km away, via a virtual private network. Telementoring was conducted for surgeries performed at Miyoshi Hospital from Tokushima University using ADMENIC ANNOTATOR (Carina Corporation). A questionnaire using the NASA Task Load Index was completed by two surgeons who received remote instruction. The surgeries when using the surgical telementoring system had significantly better "mental", "performance", and "frustration" scores compared with those performed without using the system. In a questionnaire about the surgical telementoring system, both surgeons did not notice a communication delay and indicated that annotation and voice instruction was easier to understand than voice only. In addition, fifty fifth-year medical students completed a questionnaire. After experiencing the surgical telementoring system, the number of students who responded favorably to working in a rural hospital increased from 22 (44%) to 31 (62%) (p < 0.01). Surprisingly, 10 of the 27 students who were not interested in becoming a surgeon indicated that they were now interested in becoming a surgeon (p < 0.01). This study suggests that the introduction of a surgical telementoring system in rural hospitals may help improve the skills of rural surgeons and contribute to eliminating the maldistribution and shortage of surgeons in the future.


Alteration of Apparent Diffusion Coefficient Measurements Predict Survival Outcomes During Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Neoadjuvant chemoradiation therapy (nCRT) followed by surgery is recommended for patients with locally advanced rectal cancer (LARC). However, because 30%-40% of patients with LARC do not respond to nCRT, better prediction of treatment responses and survival outcomes is required. Therefore, this study aimed to identify apparent diffusion coefficient (ADC) values that predict survival outcomes after nCRT in patients with LARC. We analyzed data from 66 patients with LARC who underwent nCRT and evaluated the ADC values pre- and post-nCRT. Cox proportional hazard regression analyses were conducted to assess survival outcomes. There were no significant differences in disease-free survival (DFS) and overall survival (OS) between low and high ADC values pre-nCRT. However, patients classified as low ADC in post-nCRT had a significantly worse prognosis in OS and DFS (OS: =0.01; DFS: <0.01) than patients classified as high ADC. Moreover, an alteration in ADC values between pre- and post-nCRT was associated with poor OS [univariate, <0.01; multivariate: =0.01]. Finally, we identified ADC values that were significantly superior in predicting tumor regression grade, demonstrating remarkable diagnostic accuracy [post-nCRT: area under the curve (AUC)=0.79; alteration-nCRT: AUC=0.85]. We identified the clinical importance of changes in ADC values as a predictor of survival outcomes in patients with LARC. These results highlight the clinical importance of ADC values on improving the treatment strategies of patients.


Impact of pure desmoplastic histological growth patterns in colorectal liver metastasis.

Colorectal cancer (CRC) has increasingly come into worldwide cancer and almost half of patients have liver metastasis (CRLM) during the progression. Therefore, treatment of colorectal cancer liver metastasis (CRLM) is important to improve the prognosis of CRC patients. Histopathological growth patterns (HGPs) of CRLM have emerged as a reliable prognostic marker. In this study, we investigated the role of prognostic impact of pure desmoplastic HGPs (dHGPs), 100% desmoplastic, in CRLM. The present study evaluated the HGPs in 71 patients with CRLM who underwent surgery (R0) between 1995 and 2012. HGPs were classified by international consensus guidelines with H&E stained slides. The pure dHGPs was defined as a complete peripheral fibrotic rim around the tumor. The dHGP was present in 36.6% (n = 26) and the pure-dHGPs was present in 73% (n = 19) among dHGPs patients. Pure-dHGPs were significantly associated with sex (male), metachronous metastatic period, normal CEA level, shallow tumor invasion and less lymph node metastasis. Patients with dHGPs had longer overall survival (OS) compared to other HGPs (p < 0.05). Furthermore, pure dHGPs patients had longer OS than non-pure dHGPs (90.9% vs. 51.4%, p < 0.05). Multivariate analysis identified pure dHGPs (p = 0.04) and better primary tumor differentiation (p < 0.001) were identified as independent prognostic indicators for OS. Patients with pure dHGPs also had longer disease-free survival (DFS) compared to other HGPs (p < 0.05). Pure-dHGPs patients had longer DFS than non-pure dHGPs (63.4% vs. 28.8%, p < 0.05). Multivariate analysis identified pure dHGPs (p = 0.04) and better primary tumor differentiation (p = 0.03) as independent prognostic indicators. Pure desmoplastic HGP might be a good prognostic marker in CRLM.


Feasibility of robot-assisted surgery for defining circumferential resection margins for rectal cancer: a retrospective study.

Local recurrence is a major problem after surgery for rectal cancer. Precision of the circumferential resection margin (CRM) has been shown to be an independent predictor of local recurrence. The purpose of this study is to evaluate the usefulness of robotic surgery for defining the CRM. A retrospective cohort study of patients with rectal cancer who underwent radical surgery at Tokushima University Hospital from January 2012 to April 2023 was included in this study to evaluate risk factors for CRM involvement. Short-term outcomes, including CRM rates, as well as long-term outcomes, were compared between patients who had undergone robot-assisted versus laparoscopic surgery following propensity score analysis. A total of 223 patients were analyzed in this study. Multivariate analysis demonstrated that lymph node metastasis was the most significant predictive factor for CRM involvement (p = 0.030), and that robot-assisted surgery tended to lead to less CRM involvement (p = 0.085). The CRM involvement rate for robotic and laparoscopic surgery before propensity score matching was 4.7% and 11.7%, respectively. Following propensity score matching, the CRM involvement rate for robotic surgery was 4.5% versus 11.4% for laparoscopic surgery. Disease-free survival (DFS) and overall survival (OS) rates for patients who had undergone robot-assisted and laparoscopic surgery were not significantly different before or after matching (DFS before matching: p = 0.876, DFS after matching: p = 0.805, OS before matching: p = 0.511, OS after matching: p = 0.458). Robot-assisted surgery may be useful in defining the CRM for rectal cancer.


Impact of robotic gastrectomy in patients with primary T3 or more advanced gastric cancer.

The use of robotic surgery (RS) for gastric cancer (GC) has been rapidly increasing. However, the utility of RS for advanced GC (AGC), especially T3 or more AGC, is unclear. Ninety patients who underwent curative upfront minimally invasive surgery (MIS) (D2 lymph node dissection) for fStage II or III GC were enrolled in this study. Among these patients, 68 underwent MIS for T3 or more AGC. Thirty-six patients underwent RS, and 32 patients underwent laparoscopic surgery (LS). The short-term and long-term surgical outcomes were compared between the two groups. In the T3 or more AGC cohort, there were no significant intergroup differences in the operative time or blood loss volume. The number of retrieved lymph nodes tended to be higher in the RS than LS group (38.5 vs. 33.0, p = .11). The drain amylase content on postoperative day 1 was significantly lower in the RS than LS group (243.5 vs. 521.0 IU/L, p < .01). The morbidity rate (Clavien-Dindo grade ≥2) was similar between the groups. There were no significant differences between the LS and RS groups in the 3-year overall survival rate (80.7% vs. 74.5%, respectively; p = .95) or 3-year disease-free survival rate (75.0% vs. 69.7%, respectively; p = .95). RS for primary T3 or more AGC was safe and contributed to similar short-term and long-term outcomes compared with LS.


Evaluation of malignancy in gallbladder tumors using the apparent diffusion coefficient obtained by diffusion-weighted MRI.

The utility of the apparent diffusion coefficient (ADC) of diffusion-weighted image (DWI) magnetic resonance imaging was examined for evaluating malignancy and prognosis in gallbladder tumors. A total of 63 patients (benign tumors, n=33; cancer, n=30) were included after surgical resection for gallbladder tumors, and their mean ADC values by DWI were obtained. Cases of advanced gallbladder cancer (n=25) were divided into ADC and ADC groups, and clinicopathological factors were compared. In 63 cases, ADC values in advanced gallbladder cancer were significantly lower compared with benign tumors and non-advanced gallbladder cancer (P<0.05), and ADC values in early gallbladder cancer were also significantly lower compared with benign tumors (P<0.05). In 25 advanced gallbladder cancer cases, the ADC group tended to have a higher rate of advanced stage disease (P=0.09). Disease-free survival and overall survival (OS) of the ADC group were worse compared with the ADC group (P<0.01). In the multivariate analysis of OS, poor differentiation and low ADC value were independent prognostic factors. ADC values may be useful for evaluating tumor malignancies in gallbladder tumors.


【必携小児外科レジデントマニュアル2】倫理規定

【必携小児外科レジデントマニュアル2】倫理規定

<文献概要>はじめに 法は国家権力などによって強制される他律的な規範であり,守るべき最低限のルールである．一方,倫理は自主的な遵守が期待される自律的な規範である．これら2つは相反するものではなく互いに補完し合うべきもので,これまで「ヒポクラテスの誓い」に始まるさまざまな医の倫理が発展してきた．すなわち,医療を行うにあたり合理性をもって判断するために守るべき規範が医療倫理である．


膵液瘻高リスク患者における膵頭十二指腸切除術後の早期経口摂取と膵液瘻発生との関連

【諸言】膵頭十二指腸切除術後の膵液瘻高リスク患者において，術後の経口摂取開始時期および経口摂取栄養量と膵液瘻発生等との関連について検討した．【方法】術後経口摂取開始時期がPOD5以降のNot early群，POD4以前のEarly群で主要アウトカム(膵液瘻発生)と副次アウトカム(術後在院日数，POD7までの蓄積経口摂取エネルギー量)を比較した．また，術後経口摂取エネルギー量・脂肪量で層別化し，膵液瘻オッズ比を算出した．【結果】BMI，膵液瘻リスク因子で調整した多変量解析の結果，Early群は膵液瘻発生のリスク因子ではなかった．Early群とNot Early群で術後在院日数に有意差はなく，蓄積経口摂取量はEarly群で有意に多かった．さらに，術後経口摂取エネルギー量・脂肪量の増加は膵液瘻発生と関連がなかった．【結論】膵頭十二指腸切除後の栄養管理として，膵液瘻高リスク患者においても，早期経口摂取および術後経口摂取エネルギー量・脂肪量の増加は膵液瘻発生と関連がなかった．(著者抄録)

The Journal of Metabolism and Clinical Nutrition


Circulating Exosomal MicroRNA Signature Predicts Peritoneal Metastasis in Patients with Advanced Gastric Cancer.

Despite a radical operation, about half of gastric cancer (GC) patients with advanced GC experience peritoneal metastasis (PM), and the patients with PM have a poor prognosis. However, because staging laparoscopy was a highly invasive procedure for patients, identification of PM using a liquid biopsy can be useful for patients with GC. This study analyzed two genome-wide miRNA expression profiling datasets (GSE164174 and TCGA). The study prioritized biomarkers in pretreatment plasma specimens from clinical training and validation cohorts of patients with GC. The authors developed an integrated exosomal miRNA panel and established a risk-stratification model, which was combined with the miRNA panel and currently used tumor markers (CEA, CA19-9, CA125, and CA72-4 levels). The comprehensive discovery effort identified a four-miRNA panel that robustly predicted the metastasis with excellent accuracy in the TCGA dataset (area under the curve [AUC] 0.86). A circulating exosomal miRNA panel was established successfully with remarkable diagnostic accuracy in the clinical training (AUC 0.85) and validation (AUC 0.86) cohorts. Moreover, the predictive accuracy of the panel was significantly superior to that of conventional clinical factors (P < 0.01), and the risk-stratification model was dramatically superior to the panel and currently used clinical factors for predicting PM (AUC 0.94; univariate: odds ratio [OR] 77.00 [P < 0.01]; multivariate OR 57.71 [P = 0.01]). The novel risk-stratification model for predicting PM has potential for clinical translation as a liquid biopsy assay for patients with GC. The study findings highlight the potential clinical impact of the model for improved selection and management of patients with GC.


Prognostic impact of the combination of p16, p21 and Immunoscore in rectal cancer.

The association between p16 and p21, a marker of cellular senescence, and the Immunoscore, an immunological prognostic indicator, in rectal cancer patients undergoing curative surgery were investigated. A total of 82 patients who underwent curative surgery for rectal cancer were evaluated. The resected specimens were analyzed for p16, p21, CD3 and CD8 expression by immunohistochemistry. Immunoscore was calculated on the basis of CD3 and CD8 expressions. The clinicopathological characteristics and long-term outcomes were evaluated. Among the 82 patients, 24 (29.3%) were p16-positive and 11 (13.4%) were p21-positive. The patients were classified into the following five Immunoscore groups (IS0-5). IS0, IS1 and IS2 were classified as the low Immunoscore group (45 patients, 54.9%) and IS3 and IS4 as the high Immunoscore group (37 patients, 45.1%). There was no significant difference in age, sex, body mass index, American Society of Anesthesiologists physical status, depth of invasion of the tumor, lymph node metastasis and histological classification of the tumor with p16 or p21 expression or Immunoscore. p16-positive expression and low Immunoscore each showed a tendency to indicate poor prognosis of disease-free survival (DFS). Patients with the combination of p16 and p21 positivity and with p16 positivity and low Immunoscore showed significantly poor prognosis of DFS. Patients with p21 positive positivity and low Immunoscore tended to have worse DFS. p16, p21 and Immunoscore may be prognostic indicators of rectal cancer. The combination of them may provide more accurate prognostic prediction than either factor alone.

International Journal of Clinical Oncology


【教科書にない小児外科疾患の最新情報-国内外の文献・ガイドラインから-】鼠径ヘルニア


Blue light irradiation inhibits the M2 polarization of the cancer-associated macrophages in colon cancer.

Recent studies have shown that blue light-emitting diode (LED) light has anti-tumor effects, suggesting the possibility of using visible light in cancer therapy. However, the effects of blue light irradiation on cells in the tumor microenvironment, including tumor-associated macrophages (TAMs), are unknown. Here, THP-1 cells were cultured in the conditioned medium (CM) of HCT-116 cells to prepare TAMs. TAMs were divided into LED-irradiated and control groups. Then, the effects of blue LED irradiation on TAM activation were examined. Expression levels of M2 macrophage markers CD163 and CD206 expression were significantly decreased in LED-irradiated TAMs compared with the control group. While control TAM-CM could induce HCT-116 cell migration, these effects were not observed in cells cultured in TAM-CM with LED irradiation. Vascular endothelial growth factor (VEGF) secretion was significantly suppressed in LED-exposed TAMs. PD-L1 expression was upregulated in HCT-116 cells cultured with TAM-CM but attenuated in cells cultured with LED-irradiated TAM-CM. In an in vivo model, protein expression levels of F4/80 and CD163, which are TAM markers, were reduced in the LED-exposed group. These results indicate that blue LED light may have an inhibitory effect on TAMs, as well as anti-tumor effects on colon cancer cells.


Lenvatinib-resistant hepatocellular carcinoma promotes malignant potential of tumor-associated macrophages via exosomal miR-301a-3p.

The interactions between cancer cells and tumor-associated macrophages (TAMs) via microRNAs (miRNAs) play crucial roles in malignant potential and drug resistance. However, it remains unclear how lenvatinib-resistant hepatocellular carcinoma (LR HCC) promotes TAM tumor biology. Here we investigated the crosstalk between LR HCC cells and TAMs for cancer progression and lenvatinib resistance, focusing on an exosomal miRNA. We used two bioinformatics software programs to identify miRNAs that target PTEN in gastrointestinal cancers, then investigated exosomal miRNA expression in LR HCC conditioned medium (CM). After modifying TAMs with LR HCC CM (LR TAM), macrophage phenotype and PTEN-Nrf2 signaling pathway component expression were analyzed in LR TAMs. The malignant potential and drug resistance were investigated in naïve HCC cells cultured with LR TAM CM. LR HCC cells highly induced M2-like properties in macrophages compared with naïve HCC cells. Exosomal miR-301a-3p expression was increased in LR HCC CM, with higher activation of the PTEN/PI3K/GSK3β/Nrf2 signaling pathway in LR TAMs. Naïve HCC cells were educated with LR TAM CM to promote malignant potential and lenvatinib resistance. Inhibition of exosomal miR-301a-3p prevented the malignant potential of LR TAMs. Activation of Nrf2 signaling by LR HCC cell-derived exosomal miR-301a-3p skewed the transformation of macrophages to the M2 phenotype. Our study provides new findings on the role of miR-301a-3p, suggesting it is a promising therapeutic target to improve HCC lenvatinib resistance.


Number of Healthy Teeth Can Predict the Response of Rectal Cancer to Chemoradiotherapy: A Retrospective Study.

It has been reported that the oral and gut microbiomes are associated with the prognosis in patients who undergo surgery, chemotherapy, and radiation for colorectal cancer. This study is the first to identify a correlation between the number of healthy teeth, which is an oral health indicator, and the efficacy of preoperative chemotherapy for rectal cancer. This retrospective single-center study included 30 patients who underwent radical surgery after preoperative chemoradiotherapy (CRT) between December 2013 and June 2021. The relationship between number of teeth before CRT and the efficacy of CRT, CRT-related adverse events, postoperative complications, and long-term postoperative outcomes was examined. The number of healthy teeth was significantly greater in patients with downstaging of their disease than in those without downstaging ( = .027) and in patients with a complete response according to the Response Evaluation Criteria in Solid Tumors than in those who did not have a complete response ( = .014). Patients were divided into two groups according to whether they had ≥15 teeth or ≤14 teeth. There was no significant between-group difference in CRT-related adverse events. The incidence of all postoperative complications and grade II postoperative complications tended to be higher in patients with ≥15 teeth ( = .071 and = .092, respectively), as did the 5-year overall survival rate ( = .083) and the 5-year disease-free rate ( = .007). The number of healthy teeth predicted the response to preoperative CRT, postoperative complications, and the outcome of subsequent surgery in patients with rectal cancer.


Generation of Highly Functional Hepatocyte-like Organoids from Human Adipose-Derived Mesenchymal Stem Cells Cultured with Endothelial Cells.

Previously, we successfully established a highly functional, three-dimensional hepatocyte-like cell (3D-HLC) model from adipose-derived mesenchymal stem cells (ADSCs) via a three-step differentiation protocol. The aim of the present study was to investigate whether generating hepatocyte-like organoids (H-organoids) by adding endothelial cells further improved the liver-like functionality of 3D-HLCs and to assess H-organoids' immunogenicity properties. Genes representing liver maturation and function were detected by quantitative reverse transcription-PCR analysis. The expression of hepatic maturation proteins was measured using immunofluorescence staining. Cytochrome P (CYP)450 metabolism activity and ammonia metabolism tests were used to assess liver function. H-organoids were successfully established by adding human umbilical vein endothelial cells at the beginning of the definitive endoderm stage in our 3D differentiation protocol. The gene expression of alpha-1 antitrypsin, carbamoyl-phosphate synthase 1, and apolipoprotein E, which represent liver maturation state and function, was higher in H-organoids than non-organoid 3D-HLCs. H-organoids possessed higher CYP3A4 metabolism activity and comparable ammonia metabolism capacity than 3D-HLCs. Moreover, although H-organoids expressed human leukocyte antigen class I, they expressed little human leukocyte antigen class II, cluster of differentiation (CD)40, CD80, CD86, and programmed cell death ligand 1, suggesting their immunogenicity properties were not significantly upregulated during differentiation from ADSCs. In conclusion, we successfully established an H-organoid model with higher liver-like functionality than previously established 3D-HLCs and comparable immunogenicity to ADSCs.


Comparison of the short-term surgical outcomes of lateral lymph node dissection for low rectal cancer using a robotic-assisted transabdominal approach alone or supported by a transanal approach.

Lateral lymph node metastases are a major cause of local recurrence after surgery for advanced low rectal cancer. Lateral lymph node dissection (LLND) may reduce the risk of local recurrence in patients with suspected lateral lymph node metastasis. Recent reports have shown that robotic-assisted LLND can help to reduce the postoperative complication rate, such as urinary disturbance. Furthermore, with the advent of transanal total mesorectal excision, a novel LLND procedure that combines a transabdominal approach with a transanal approach has been reported. This study aimed to clarify the safety and feasibility of robotic-assisted LLND supported by a transanal approach for advanced low rectal cancer. Thirty-nine patients diagnosed to have low rectal cancer between June 2019 and May 2023 were retrospectively enrolled and divided according to whether they underwent LLND via a robotic-assisted transabdominal approach alone (transabdominal group, n = 19) or in combination with a transanal approach (2team group, n = 20). The patient characteristics and short-term surgical outcomes were compared between the two groups. The total operation time was significantly shorter in the 2team group than in the transabdominal group (366 min vs. 513 min, P < 0.001), as was the time taken to perform unilateral LLND (64 min vs. 114 min, P < 0.001). Furthermore, there was significantly less intraoperative bleeding in the 2team group (30 mL vs. 80 mL, P = 0.004). There was no significant between-group difference in postoperative complications. The incidence of postoperative urinary disturbance was satisfactory at 5% in both groups. The operation time for LLND performed by a robotic-assisted transabdominal approach was shortened when supported by a transanal approach. The frequency of postoperative urinary disturbance was low in both groups. Therefore, robotic-assisted abdominal LLND supported by a transanal approach can be considered a promising treatment option for advanced low rectal cancer.


医療DXの可能性が広がる!XR(VR・AR・MR)とメタバースの最前線(第16回) XRを活用した骨盤手術 直腸がんに対する経肛門アプローチ


Preoperative evaluation to determine the difficulty of No. 6 lymphadenectomy in laparoscopic gastrectomy.

Laparoscopic gastrectomy (LG) requires a long learning curve because of the complicated surgical procedures. Infrapyloric (No. 6) lymph node dissection (LND) is one of the difficult procedures in LG, especially for trainees. This study investigated the impact of the prediction of the difficulty of No. 6 LND. We retrospectively reviewed the preoperative computed tomography (CT) images and individual operative video records of 57 patients who underwent LG with No. 6 LND to define and predict the No. 6 LND difficulty. To evaluate whether prediction of the difficulty of No. 6 LND could improve surgical outcomes, 48 patients who underwent laparoscopic distal gastrectomy were assessed (30 patients without prediction by a qualified surgeon and 18 patients with prediction by a trainee). The anatomical characteristic that LND required > 2 cm of dissection along the right gastroepiploic vein was defined as difficulty of No. 6 LND. Of the 57 LG patients, difficulty was identified intraoperatively in 21 patients (36.8%). Among the several evaluated anatomical parameters, the length between the right gastroepiploic vein and the right gastroepiploic artery in the maximum intensity projection in contrast-enhanced CT images was significantly correlated with the intraoperative difficulty of No. 6 LND (p < 0.0001). Surgical outcomes, namely intraoperative minor bleeding, postoperative pancreatic fistula, and drain amylase concentration were not significantly different between LG performed by a trainee with prediction compared with that by a specialist without prediction. Preoperative evaluation of the difficulty of No. 6 LND is useful for trainees, to improve surgical outcomes.


Role of stromal PD-L1 expression in colorectal liver metastasis.

The outcomes of immune checkpoint blockade for colorectal cancer (CRC) treatment are unsatisfactory. Furthermore, the efficacy of immune checkpoint blockade for liver metastasis of various cancer is poor. Here, we investigated the relationship between stromal programmed death-ligand 1 (PD-L1) expression and the prognosis of patients with colorectal cancer liver metastasis (CRLM). The present study enrolled 84 CRLM patients who underwent surgery (R0) for CRC. Immunohistochemistry was performed to analyze stromal PD-L1 expression in CRLM. Stromal PD-L1 was expressed in 52.3% of CRLM samples, which was associated with fewer not optimally resectable metastases (p = 0.04). Stromal PD-L1 also tended to associate with a lower tumor grade (p = 0.08). Stromal PD-L1-positive patients had longer overall survival (p = 0.003). Multivariate analysis identified stromal PD-L1 expression (p = 0.008) and poorer differentiation (p < 0.001) as independent prognostic indicators. Furthermore, stromal PD-L1 expression was correlated to a high number of tumor-infiltrating lymphocytes (TILs). Stromal PD-L1- and low TIL groups had shorter OS than stromal PD-L1 + and high TIL groups (46.6% vs. 81.8%, p = 0.05) Stromal PD-L1-positive patients had longer disease-free survival (DFS) (p = 0.03) and time to surgical failure (p = 0.001). Interestingly, stromal PD-L1 expression was positively related to the desmoplastic subtype (p = 0.0002) and inversely related to the replacement subtype of the histological growth pattern (p = 0.008). Stromal PD-L1 expression may be a significant prognostic marker for CRLM.


【腹腔鏡下噴門形成術-新技術認定制度に向けて】ラップ形成(Nissen-Rossetti法)


Impact of Daikenchuto (TU-100) on the early postoperative period in duodenal-jejunal bypass.

We investigated the effect of Daikenchuto (TU-100) on the early postoperative period in duodenal-jejunal bypass (DJB). Study 1:The effect of TU-100 on diabetic rats was investigated. Rats were sacrificed after receiving TU-100 for one week. Study 2:The effect of TU-100 on DJB was investigated. Rats in the DJB and TU-100 treated DJB groups were sacrificed 24 hours postoperation to evaluate blood glucose, cytokine expression, and gut microbiome. Study 1:TU-100 did not affect glucose or body weight. TU-100 suppressed intestinal inflammation and modified the gut microbiome. Specifically, Bifidobacterium and Blautia were increased, and Turicibacter were decreased in this group. Study 2:Both DJB and TU-100 treated DJB rats showed lower blood glucose at 24 hours postoperation than at preoperation. Cytokine expression in the liver and small intestine of the TU-100 treated DJB group was significantly lower than that of the DJB group. The gut microbiome composition in TU-100 treated DJB rats was altered. In particular, Bifidobacterium and Blautia were increased in this group. DJB suppressed blood glucose during the early postoperative period. TU-100 may enhance the anti-diabetic effect of metabolic surgery by changing the gut microbiome and suppressing inflammation in the early postoperative period. J. Med. Invest. 71 : 210-218, August, 2024.

The Journal of Medical Investigation : JMI


Feasibility of laparoscopic and endoscopic cooperative surgery for gastric gastrointestinal stromal tumor with tumor diameter of >5 cm.

Laparoscopic and endoscopic cooperative surgery (LECS) is an effective treatment for gastric gastrointestinal stromal tumors (GISTs). The utility of LECS for gastric GISTs of > 5 cm remains controversial. This study was performed to investigate the feasibility of LECS for gastric GISTs with a tumor diameter of >5 cm. We analyzed 43 patients with gastric GISTs who underwent LECS or laparoscopic partial gastrectomy (Lap-Partial Gx). We compared the surgical outcomes of LECS versus Lap-Partial Gx and of LECS for a tumor diameter of > 5 versus ≤ 5 cm. In the comparison of LECS versus Lap-Partial Gx, there were no significant intergroup differences in the operative time or blood loss volume. The morbidity rate was similar between the groups. No postoperative mortality occurred in either group. In the comparison of LECS for a tumor diameter of > 5 versus ≤ 5 cm, there were no significant intergroup differences in operative time, or blood loss volume. The morbidity rate was similar between the > 5-cm and ≤ 5-cm groups (0.0% vs. 4.5%, respectively ; p = 0.56). Additionally, no recurrence or death occurred during follow-up in either group. LECS is a feasible option for gastric GISTs with a tumor diameter of > 5 cm. J. Med. Invest. 71 : 148-153, February, 2024.


Pancreatoduodenectomy combined with intestinal de-rotation as a complete artery-first approach for inexperienced surgeons.

Recent technical advances have reduced the incidence of intraoperative complications associated with pancreatoduodenectomy (PD). We aimed to determine whether inexperienced surgeons (ISs) would be as successful as experienced surgeons (ESs) when performing the complete artery-first approach using the intestinal de-rotation method of PD. Seventy patients who underwent PD using the intestinal de-rotation method in Tokushima University Hospital were enrolled in the present study. Intra- and post-operative parameters were compared between patients operated on by ESs (n=20) or ISs (n=50). The surgical procedure lasted longer in the IS group (ES : 402 }68 min vs. IS : 483 }51 min, p<0.0001), but the volume of blood loss was similar (p=0.7304). There was no mortality in either group, and the incidences of postoperative complications with a Clavien-Dindo grade of>III did not differ between the groups. Grade B postoperative pancreatic fistulae developed in 20.0% of patients in the ES group and 22.0% in the IS group (p=0.9569). Finally, the postoperative hospital stay of the IS group (32 }33 days) was equivarent to that of the ES group (33 }16 days) (p=0.9256). ISs were able to perform similarly successful PDs using the intestinal de-rotation method to ESs. J. Med. Invest. 71 : 75-81, February, 2024.


Association between high expression of intratumoral fibroblast activation protein and survival in patients with intrahepatic cholangiocarcinoma.

Cancer-associated fibroblasts (CAFs) have been reported to exhibit protumorigenic effects. Among the well-known CAF markers such as smooth muscle actin (SMA) and fibroblast activation protein (FAP), high expression of SMA in the peritumoral stroma has been reported to be a prognostic factor in various cancers. However, the effect of high FAP expression in intrahepatic cholangiocarcinoma (IHCC) has not been fully clarified. We evaluated the expression of CAF markers, focusing on FAP expression in the peripheral and intratumoral regions, to clarify the association with survival in patients with IHCC. The study cohort comprised 37 patients who underwent curative resection for IHCC. The FAP expressions were evaluated in the peripheral and intratumoral regions of the resected tissues. Clinicopathological factors and survival outcomes were investigated between patients with high versus low FAP expression. Uni- and multivariate analyses were performed to identify the prognostic factors for overall survival and relapse-free survival. The median area percentages of FAP expression in the peripheral and intratumoral regions were 15.5% and 17.8%, respectively. High FAP expression in the intratumoral region was significantly associated with worse overall survival and disease-free survival than low FAP expression in the intratumoral region. Multivariate analysis identified high intratumoral FAP expression as a risk factor for worse overall survival (hazard ratio, 2.450; p = 0.049) and relapse-free survival (hazard ratio, 2.743; p = 0.034). High intratumoral FAP expression was associated with worse survival, suggesting that intratumoral FAP expression represents malignant progression in patients with IHCC.


Effects of green light-emitting diode irradiation on hepatic differentiation of hepatocyte-like cells generated from human adipose-derived mesenchymal cells.

Light-emitting diode (LED) irradiation has been used in the differentiation of mesenchymal stem cells into a variety of cell types. This study investigated the effect of green LED (GLED) irradiation on the differentiation of adipocyte-derived mesenchymal cells into hepatocyte-like cells (HLCs) and the mechanism of its action. HLCs in the hepatocyte maturation phase were irradiated with GLED (520 nm, 21 W/m, 5 min/day for 10 days). The cells were then assessed for expression of hepatocyte maturity genes and opsin 3 (OPN3), hepatocyte function, viability, apoptosis, and levels of reactive oxygen species (ROS), intracellular adenosine triphosphate (ATP) and calcium ions (Ca). GLED irradiation increased Alpha-1 antitrypsin and Ornithine transcarbamylase gene expression, promoted Cytochrome P450 3A4 activity and urea synthesis, and elevated intracellular ROS, ATP and Ca levels. OPN3 expression was significantly more upregulated in GLED-irradiated HLCs than in the non-irradiated HLCs. No significant difference in cell viability or apoptosis was observed between GLED-irradiated and non-irradiated HLCs. GLED irradiation can promote hepatocyte maturation and functions through OPN3. GLED irradiation also stimulated mitochondrial function via Ca/ATP/ROS activation. GLED irradiation has potential to support cell-based transplantation in patients.


Preoperative Weight Loss Program for Hepatocellular Carcinoma Patients with High Body Mass Index in Hepatectomy.

This study aimed to investigate the usefulness of a weight-loss program (WLP) in patients with a high body mass index (BMI) prior to liver resection (Hx) for hepatocellular carcinoma (HCC). Among 445 patients with HCC who underwent initial Hx between 2000 and 2020, 19 with a high BMI (≥25.0) were enrolled in our WLP since 2014. For calorie restriction, the amount of energy consumed was calculated as the standard body weight (SBW) kg × 20-25 kcal/day. Protein mass was calculated as SBW kg × 1.0-1.2 g/day to maintain skeletal muscle mass. Patients also performed both aerobic and resistance exercises. The before-and-after changes were compared, and the effect of WLP on the short- and long-term results was investigated. The average length of WLP was 21 days, and weight loss was successfully achieved in all patients. Body fat mass was reduced during the program, while skeletal muscle mass was maintained. WLP led to improvements in liver function and fibrotic markers, without tumor progression. There were no postoperative complications (≥Clavien-Dindo [CD] III). A retrospective comparison between with and without WLP using propensity score-matching analysis revealed that WLP group showed better NLR value, however, there were no significant differences in both short and long-term outcomes after Hx based on participation in the WLP. WLP with multidisciplinary intervention improved immune-nutrition status and liver function of obese patients. WLP had not affected both short and long-term outcomes after Hx.


患者は50代女性.検診の腹部超音波検査で肝S3に16×14mm大の腫瘤を指摘され精査加療目的に当科紹介となった.既往歴・生肉食歴なし.術前の血液検査で異常なく,末梢好酸球も正常.造影CTの動脈・門脈相では辺縁に造影効果を認めるが,平衡相では造影されず,MRI T1強調像で低信号,T2強調像で低∼等信号,拡散強調像でやや高信号であった.PET-CTで肝臓への集積は認めなった.悪性腫瘍の可能性を完全に否定できず,腹腔鏡下肝部分切除を施行した.病理組織学的には腫瘤全体に凝固壊死像が見られ,辺縁に線維増生を伴い,組織球が柵状に配列したpalisading granulomaであった.原因特定のために複数の染色を行ったが,病原体は同定できなかった.palisading granulomaは術前診断が困難であり,診断的治療として腹腔鏡下肝切除術は有用であると考えられた.(著者抄録)


Clinical impact of myosteatosis measured by magnetic resonance imaging on long-term outcomes of hepatocellular carcinoma after radical hepatectomy.

A variety of factors have been reported to affect long-term outcomes after radical resection of hepatocellular carcinoma (HCC). However, the indicators remain controversial. The purpose of this study was to evaluate the relationship between myosteatosis of the multifidus muscle and long-term outcomes after radical surgery for HCC. We retrospectively analyzed clinicopathological data for 187 patients with HCC who underwent radical surgery at Tokushima University between January 2009 and December 2020 and measured the density of fat in the multifidus muscle at L3 on their preoperative magnetic resonance images (MRI). Associations of myosteatosis and clinicopathological factors with long-term outcomes were evaluated. The patients were divided into a myosteatosis-negative group (n = 122) and a myosteatosis-positive group (n = 65). The cancer-specific survival rate after hepatectomy was significantly worse in the myosteatosis-positive group than in the myosteatosis-negative group (p = 0.03). Univariate analysis identified multiple tumors, stage III/IV disease, an alfa-fetoprotein level ≥ 10 ng/ml, PIVKA-II ≥ 400 AU/ml, vp(+) status, and myosteatosis to be prognostic factors for cancer-specific survival. Multivariate analysis revealed multiple tumors, an alfa-fetoprotein level ≥ 10 ng/ml, and myosteatosis to be independent prognostic factors. Myosteatosis measured by MRI is a simple and useful predictor of the long-term outcome after radical surgery for HCC.


Conversion surgery after successful response to chemotherapy (S-1 + oxaliplatin + nivolumab) in a patient with stage IV gastric cancer with peritoneal metastasis (P1, CY1): a case report.

We here present a case report of a patient with Stage IV gastric cancer with peritoneal metastasis (P1, CY1) who underwent conversion surgery after a successful response to chemotherapy (S-1 + oxaliplatin + nivolumab). The patient was a woman in her 60 s. Her chief complaint was epigastric pain. Upper gastrointestinal endoscopy showed Type 4 advanced carcinoma on the lesser curvature of the gastric body. Biopsy showed Group 5 (poorly differentiated adenocarcinoma) and HER2 was negative. Staging laparoscopy revealed seeding in the round ligament of the liver (P1) and adenocarcinoma cells in ascites (CY1). Ten courses of chemotherapy (S-1 + oxaliplatin + nivolumab) were administered, after which contrast-enhanced computed tomography showed that the primary tumor had shrunk and seeding was no longer detectable. Upper gastrointestinal endoscopy revealed scar-like changes. A second staging laparoscopy revealed that ascites cytology was negative and a biopsy of the round ligament of the liver showed no malignant cells (P0, CY0). Conversion surgery comprising laparoscopic total gastrectomy with D2 lymph node dissection and resection of the round ligament of the liver was performed. The postoperative course was uneventful. Histopathological examination of the resected specimen revealed no tumor cells in the gastric mesentery or the round ligament of the liver. The pathological diagnosis was gastric cancer [M, U, L, Less, Ant, Post, type4, T3(SS), N0, M0 (H0, P0, CY0), ypStage IIA]. Adjuvant chemotherapy (S-1) was commenced. The patient is still alive 7 months later with no evidence of recurrence.


Metabolic surgeryのインパクト 肥満・糖尿病の治療が変わる

Metabolic surgeryのインパクト 肥満・糖尿病の治療が変わる


Visualization of the pelvic nerves using magnetic resonance imaging for rectal cancer surgery.

This study evaluated the visualization of the pelvic nerves using magnetic resonance imaging (MRI) combined with computed tomography (CT) to synthesize three-dimensional (3D) reconstruction images of the pelvic organs. The CT and MRI scans were performed for patients with rectal cancer who underwent surgery. The out-of-phase image of LAVA-Flex was used to identify the pelvic nerves. The images of the pelvic nerves were extracted from the MRI scans, and those of the arteries and rectum and pelvis were extracted from the CT scans. Each extracted organ image was used to synthesize 3D reconstruction images. The MRI scan allowed adequate visualization of the pelvic splanchnic nerves, inferior hypogastric plexus, and obturator nerves. The comparison of 3D reconstruction images and intraoperative findings showed matched images. We visualized the pelvic nerves using MRI and synthesized 3D reconstruction images of the pelvic organs. Preoperative confirmation of the location of the pelvic organs is important to prevent unanticipated injury during rectal cancer surgery.


Utility of robotic surgery for Siewert type II/III adenocarcinoma of esophagogastric junction: transhiatal robotic versus laparoscopic approach.

Robotic surgery (RS) has been rapidly adopted for gastric cancer and adenocarcinoma of the esophagogastric junction (AEG). However, the utility of RS for Siewert type II/III AEG remains unclear. Forty-one patients who underwent either transhiatal RS (n = 15) or laparoscopic surgery (LS) (n = 26) for Siewert type II/III AEG were enrolled in this study. The surgical outcomes of the two groups were compared. In the entire cohort, there were no significant intergroup differences in the operative time, blood loss volume, or number of retrieved lymph nodes. The length of the postoperative hospital stay was shorter in the RS group than in the LS group (14.20 ± 7.10 days vs. 18.73 ± 17.82 days, respectively; p = 0.0388). The morbidity rate (Clavien-Dindo grade ≥ 2) was similar between the groups. In the Siewert II cohort, there were no significant intergroup differences in short-term outcomes. In the entire cohort, there was no significant difference between the RS and LS groups in the 3-year overall survival rate (91.67% vs. 91.48%, N.S.) or 3-year disease-free survival rate (91.67% vs. 91.78%, N.S.), respectively. Likewise, in the Siewert type II cohort, there was no significant difference between the RS and LS groups in the 3-year overall survival rate (80.00% vs. 93.33%, N.S.) or 3-year disease-free survival rate (80.00% vs. 94.12%, N.S.), respectively. Transhiatal RS for Siewert II/III AEG was safe and contributed to similar short-term and long-term outcomes compared with LS.


The application of enhanced recovery after surgery in total gastrectomy: a propensity score-matched analysis.

This study aimed to investigate the feasibility and safety of our enhanced recovery after surgery protocol including early oral intake and omitting nasogastric tube (NGT) placement after total gastrectomy. We analyzed 182 consecutive patients who underwent total gastrectomy. The clinical pathway was changed in 2015, and patients were divided into 2 groups (conventional group and modified group). Postoperative complications, bowel movement, and postoperative hospital stays were compared in the two groups in all cases and propensity score matching (PSM). Flatus and defecation were significantly earlier in the modified group compared with those in the conventional group (flatus: 2 (1-5) days vs 3 (2-12) days, p = 0.03; defecation: 4 (1-14) days vs 6 (2-12) days p = 0.04). The postoperative hospital stay was 18 (6-90) days in the conventional group and 14 (7-74) days in the modified group (p = 0.009). Days until discharge criteria were met were earlier in the modified group compared with that in the conventional group (10 (7-69) days vs 14 (6-84) days p = 0.01). Overall and severe complications occurred in nine patients (12.6%) and three patients (4.2%) in the conventional group and twelve patients (10.8%) and four patients (3.6%) in the modified group, respectively (p = 0.70 and p = 0.83) in all cases. In PSM, there is no significant difference between the two groups concerning the postoperative complications (overall complication 6 (12.5%) vs 8 (16.7%) p = 0.56, severe complications 1 (2%) vs 2 (4.2%) p = 0.83). Modified ERAS for total gastrectomy may be feasible and safe.


Surgical Outcomes of Gastrectomy in Hemodialysis Patients with Gastric Cancer.


TU-100 Antagonizes the M2 Polarization Phenotype of Macrophages in the Tumor Microenvironment by Suppressing the TLR4/NF-B/STAT3 Axis.

Macrophages are the most abundant immune cells in the tumor stroma, and their polarization states within the tumor microenvironment (TME) exert critical roles in tumorigenesis. TU-100 (Daikenchuto) is a commonly prescribed Japanese herbal medicine that has shown anti-cancer effects by regulating cancer-associated fibroblasts (CAFs) in the TME. However, its effects on tumor-associated macrophages (TAMs) remain unclear. TAMs were generated by macrophage exposure to tumor-conditioned medium (CM), and their polarization states were evaluated after TU-100 treatment. The underlying mechanism was further studied. TU-100 exhibited little cytotoxicity over a range of doses in M0 macrophages and TAMs. However, it could antagonize the M2-like polarization of macrophages evoked by tumor-CM exposure. These effects might be caused by the inhibition of TLR4/NF-B/STAT3 signaling in the M2-like phenotype of macrophages. Interestingly, TU-100 antagonized the malignancy promoting effects of M2 macrophages on hepatocellular carcinoma cell lines in vitro. Mechanistically, the administration of TU-100 restrained the high expression of MMP-2, COX-2, and VEGF in TAMs. TU-100 may alleviate the progression of cancer by regulating the M2 polarization of macrophages within the TME, suggesting a viable therapeutic approach.


Transanal lateral lymph node dissection with intraoperative hologram support in low rectal cancer.

In Japan, the standard treatment for stage II/III advanced low rectal cancer is total mesorectal excision plus lateral lymph node dissection (LLND). There are also recent reports on the use of transanal LLND. However, the transanal anatomy is difficult to understand, and additional support tools are required to improve the surgical safety. The present study examined the utility of holograms with mixed reality as an intraoperative support tool for assessing the complex pelvic anatomy. Polygon (stereolithography) files of patients' pelvic organs were created and exported from the SYNAPSE VINCENT imaging system and uploaded into the Holoeyes MD virtual reality software. Three-dimensional images were automatically converted into patient-specific holograms. Each hologram was then installed into a head mount display (HoloLens2), and the surgeons and assistants wore the HoloLens2 when they performed transanal LLND. Twelve digestive surgeons with prior practice in hologram manipulation evaluated the utility of the intraoperative hologram support by means of a questionnaire. Intraoperative hologram support improved the surgical understanding of the lateral lymph node region anatomy. In the questionnaire, 75% of the surgeons answered that the hologram accurately reflected the anatomy, and 92% of the surgeons answered that the anatomy was better understood by simulating the hologram intraoperatively than preoperatively. Moreover, 92% of the surgeons agreed that intraoperative holograms were a useful support tool for improving the surgical safety. Intraoperative hologram support improved the surgical understanding of the pelvic anatomy for transanal LLND. Intraoperative holograms may represent a next-generation surgical tool for transanal LLND.


術前に肝細胞癌との鑑別が困難であった筋腫型肝血管筋脂肪腫の1例

術前に肝細胞癌との鑑別が困難であった筋腫型肝血管筋脂肪腫の1例

患者は40代女性.検診で肝から突出する15cmの巨大腫瘤を指摘され,精査加療目的に当科紹介となった.既往歴や背景肝に特記事項なく,腫瘍マーカーは正常であったが,造影CTの動脈・門脈相で肝右葉に15cm大の早期濃染と遅延相でwashoutを認めた.EOB-MRI肝細胞相ではdefectとして描出され肝細胞癌が疑われた.破裂の危険性を考慮し,まずTACEを行い,その後拡大肝右葉切除を施行した.病理組織学的には腫瘍の大半が平滑筋様細胞で構成されており,脂肪細胞は認めず,免疫組織化学染色にてVimentin,αSMA,HMB-45,melan Aが陽性であり,Perivascular epithelioid cell tumor(PEComa)として包括される腫瘍群の中の筋腫型の肝血管筋脂肪腫(Angiomyolipoma;AML)と診断した.今回我々は,術前に肝細胞癌との鑑別が困難であった,若年女性に発生した肝原発筋腫型AMLを経験したため報告する.(著者抄録)


Usefulness of Diagnostic Staging Laparoscopy for Advanced Gastric Cancer.

For advanced gastric cancer (AGC), peritoneal metastasis is the most common determinant of unresectability, but accurate preoperative diagnosis for peritoneal metastasis is challenging. Staging laparoscopy (SL) can detect unsuspected peritoneal metastasis. This study retrospectively evaluated the utility of SL and its indication in patients with AGC. In this study, we enrolled 114 patients with pathologically diagnosed gastric adenocarcinoma who underwent SL. Of the 114 patients, 43 (37.7%) had peritoneal metastasis (P1 or CY1). Higher age, larger tumor size, type 4 GC, deeper tumor depth, elevated CA125, and ascites findings in preoperative CT were found to be significant predictors of peritoneal metastasis. In multivariate analysis, peritoneal metastasis was associated with type 4 GC (odds ratio [OR]: 6.11; 95% confidence interval [CI]: 1.87-19.8; P < .01) and ascites in CT (OR: 4.25; 95% CI: 1.48-12.1; P < .01). Staging laparoscopy is an effective tool to detect peritoneal metastasis from AGC. It can increase the curative resection rate and decrease unnecessary laparotomies.


Transoral Anvil Delivery System With Tension-Free Method for Esophagojejunostomy After Laparoscopic Total Gastrectomy Prevents The Postoperative Stenosis.


Lineage of drug discovery research on fluorinated pyrimidines: chronicle of the achievements accomplished by Professor Setsuro Fujii.

Prof. Setsuro Fujii achieved significant results in the field of drug discovery research in Japan. He developed nine well-known drugs: FT, UFT, S-1 and FTD/TPI are anticancer drugs, while cetraxate hydrochloride, camostat mesilate, nafamostat mesilate, gabexate mesilate and pravastatin sodium are therapeutic drugs for various other diseases. He delivered hope to patients with various diseases across the world to improve their condition. Even now, drug discovery research based on Dr. Fujii's ideas is continuing.

International Journal of Clinical Oncology


Stapler insertion angle toward the esophagus reduces the incidence of early postoperative Roux stasis syndrome after distal gastrectomy in minimally invasive surgery.

Roux stasis syndrome (RSS) after Roux-en-Y (RY) reconstruction significantly prolongs the hospital stay and decreases the quality of life. The purpose of the present study was to evaluate the incidence of RSS in patients who underwent distal gastrectomy for gastric cancer and to identify the factors related to the development of RSS after mechanical RY reconstruction in minimally invasive surgery (MIS). This study included 134 patients who underwent distal gastrectomy in MIS with mechanical RY anastomosis. RSS was defined as the presence of symptoms such as nausea, vomiting, or abdominal fullness, and the confirmation of delayed gastric emptying on imaging or gastrointestinal fiber testing. Clinical data were checked, including body mass index, operative procedure, age, sex, operative time, blood loss volume, extent of lymph node dissection, final stage, stapler insertion angle, method of entry hole closure. The relationship between the incidence of RSS and these factors was analyzed. RSS occurred in 24 of 134 patients (17.9%). RSS occurred significantly more frequently in patients with D2 lymphadenectomy than in patients with D1 + lymphadenectomy (p = 0.04). All patients underwent side-to-side anastomosis via the antecolic route. The incidence of RSS was significantly greater in patients with a stapler insertion angle toward the greater curvature (n = 20, 22.5%) versus the esophagus (n = 4, 8.9%) (p = 0.04). The multivariate logistic regression model revealed that the stapler insertion angle to the greater curvature is identified as independent risk factor for RSS (OR 3.23, 95%Cl 1.01-10.3, p = 0.04). Stapler insertion angle toward the esophagus may reduce the incidence of early postoperative RSS rather than toward the greater curvature.


Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2021 version (5th JSH-HCC Guidelines).

The fifth version of the Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine and partly to the Grading of Recommendations Assessment, Development and Evaluation system, which was published in October 2021 in Japanese. In addition to surveillance-diagnostic and treatment algorithms, a new algorithm for systemic therapy has been created, as multiple drugs for hepatocellular carcinoma can be currently selected. Here, new or revised algorithms and evidence on which the recommendations are based are described.


Curcumin and Andrographis Exhibit Anti-Tumor Effects in Colorectal Cancer via Activation of Ferroptosis and Dual Suppression of Glutathione Peroxidase-4 and Ferroptosis Suppressor Protein-1.

Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide. The limitations of current chemotherapeutic drugs in CRC include their toxicity, side effects, and exorbitant costs. To assess these unmet needs in CRC treatment, several naturally occurring compounds, including curcumin and andrographis, have gained increasing attention due to their multi-targeted functionality and safety vs. conventional drugs. In the current study, we revealed that a combination of curcumin and andrographis exhibited superior anti-tumor effects by inhibiting cell proliferation, invasion, colony formation, and inducing apoptosis. Genome-wide transcriptomic expression profiling analysis revealed that curcumin and andrographis activated the ferroptosis pathway. Moreover, we confirmed the gene and protein expression of glutathione peroxidase 4 (GPX-4) and ferroptosis suppressor protein 1 (FSP-1), the two major negative regulators of ferroptosis, were downregulated by this combined treatment. With this regimen, we also observed that intracellular accumulation of reactive oxygen species and lipid peroxides were induced in CRC cells. These cell line findings were validated in patient-derived organoids. In conclusion, our study revealed that combined treatment with curcumin and andrographis exhibited anti-tumorigenic effects in CRC cells through activation of ferroptosis and by dual suppression of GPX-4 and FSP-1, which have significant potential implications for the adjunctive treatment of CRC patients.


Carcinogenic risk in the biliary epithelium of children with congenital biliary dilatation via the DNA damage repair pathway.

Congenital biliary dilatation (CBD) is a high-risk factor for biliary tract cancer (BTC). We previously reported the potential for carcinogenesis in the biliary epithelium of patients with CBD. In this study, we investigated potential carcinogenetic pathways, focusing on the DNA damage repair response, in children with CBD and compared the findings with those in adults. We enrolled 6 children with CBD and 10 adults with CBD without BTC who underwent extrahepatic bile duct resections, plus 4 control patients who underwent pancreaticoduodenectomy for non-biliary cancer. Levels of phosphorylated histone H2AX (γH2AX), MRE11, and Ku-70 in the biliary tract epithelium were evaluated by immunohistochemistry. The levels of γH2AX, MRE11, and Ku-70 were significantly higher in the gallbladder epithelium and bile duct epithelium of both children and adults than in controls. Children and adults with CBD might develop BTC via the DNA damage repair pathway, as evidenced by increased γH2AX, MRE11, and Ku-70 expression.


Curcumin-Mediated Resistance to Lenvatinib via EGFR Signaling Pathway in Hepatocellular Carcinoma.

Lenvatinib is a multi-kinase inhibitor approved as a first-line treatment for patients with unresectable advanced hepatocellular carcinoma (HCC). However, its response rate is unsatisfactory, primarily due to the acquisition of resistance, which limits its clinical significance for treating patients with HCC. Recent evidence suggests that epidermal growth factor receptor (EGFR) activation can trigger Lenvatinib-resistance; and is considered an important therapeutic target in HCC. Curcumin, one of the most studied naturally occurring botanicals with robust anti-cancer activity, is also reported to be a potent tyrosine kinase inhibitor. In this study, we hypothesized that the anti-EGFR potential of Curcumin might help overcome Lenvatinib resistance in HCC. We established two Lenvatinib-resistant cells and discovered that a combination of Curcumin and Lenvatinib exhibited a synergistic anti-tumor efficacy in the resistant HCC cell lines. In line with previous reports, Lenvatinib-resistant cell lines revealed significant activation of the EGFR, and genomewide transcriptomic profiling analysis identified that the PI3K-AKT pathway was associated with Lenvatinib resistance. The combination treatment with Curcumin and Lenvatinib dramatically suppressed gene and protein expression of the EGFR-PI3K-AKT pathway, suggesting Curcumin overcomes Lenvatinib resistance via inhibition of EGFR. We further validated these findings in tumor spheroids derived from resistant cell lines. In conclusion, we, for the first time, report that Curcumin reverses Lenvatinib resistance in HCC, and that their combination has clinical application potential for adjunctive treatment in HCC.


Multiplication of tumor maximum diameter and number as a new surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage hepatocellular carcinoma.

Recent advances in treatment modalities have been made, limiting the indication of hepatic resection in the treatment strategy for hepatocellular carcinoma (HCC) patients. This retrospective study investigated the significance of multiplication of tumor maximum diameter and number (MDN) as a surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage HCC. A total of 49 patients with Barcelona Clinic Liver Cancer intermediate-stage HCC who underwent curative hepatic resection between 2000 and 2020 were enrolled in this study. Prognostic factors of overall survival and disease-free survival, including the product of MDN, were analyzed. Patients with MDN >12 experienced significantly worse prognosis compared with those with MDN ≤12 (p = 0.0395), and 5-year overall survival rates after hepatic resection were 60.0% and 23.4%, respectively. Furthermore, the disease-free survival rate of patients with MDN >12 was significantly worse compared with those with MDN ≤12 (p = 0.0049), and all patients with MDN >12 experienced recurrence within 3 years after hepatic resection. In the multivariate analysis, MDN >12 was identified as the only independent prognostic factor of both overall survival and disease-free survival. In addition, patients with MDN >12 suffered from uncontrollable recurrence by locoregional treatment, such as more than four intrahepatic and extrahepatic recurrences, after hepatic resection. MDN index might be a new surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage HCC, and influence clinical decision-making for individual treatment strategies.


Impact of the hospital volume and setting on postoperative complications of surgery for gastroenterological cancers in a regional area of Western Japan.

A research subgroup was established by the Japanese Society of Gastroenterological Surgery to improve the health care quality in the Chushikoku area of Western Japan. The records of four surgical procedures were extracted from the Japanese National Clinical Database and analyzed retrospectively to establish the association between hospital characteristics, defined using a combination of hospital case-volume and patients' hospital travel distance, and the incidences of perioperative complications of ≥ Grade 3 of the Clavien-Dindo classification after gastroenterological surgery. This study analyzed 11,515 cases of distal gastrectomy for gastric cancer, 4,705 cases of total gastrectomy for gastric cancer, 4,996 cases of right hemicolectomy for colon cancer, and 5,243 cases of lower anterior resection for rectal cancer, with composite outcome incidences of 5.6%, 10.2%, 5.5%, and 10.7%, respectively. After adjusting for patient characteristics and surgical procedures, no association was identified between the hospital category and surgical outcomes. The findings of our study of the Chushikoku region did not provide positive support for the consolidation and centralization of hospitals, based solely on hospital case volume. Our grouping was unique in that we included patient travel distance in the analysis, but further investigations from other perspectives are needed.


Pleomorphic type undifferentiated gastric sarcoma, report of a case.

Reports on pleomorphic type of undifferentiated sarcoma (PUS) originating from the gastrointestinal tract, especially the stomach, are extremely rare. We herein report a case of pleomorphic type undifferentiated gastric sarcoma. The patient was a 67-year-old woman. The chief complaint was upper abdominal pain. Upper gastrointestinal endoscopy, ultrasonography, and contrast-enhanced computed tomography showed two submucosal tumors at the greater curvature of the fundus and the lesser curvature of the gastric angle. Endoscopic ultrasound-guided fine-needle aspiration revealed a c-kit-negative spindle cell tumor at the greater curvature of the fundus. Total gastrectomy, splenectomy, and partial resection of the diaphragm and liver were performed. One lesion had invaded the lateral segment of the liver, left diaphragm and spleen. The postoperative course was uneventful. Histopathological and immunohistochemical examinations of the resected specimen revealed PUS. Peritoneal dissemination was detected at 8 months after surgery. However, no effective therapeutic agents were adopted for chemotherapy. The patient had poor performance status due to disease progression and underwent best supportive care. The patient died 10 months after surgery. This case highlights the imaging, histological diagnosis, and treatment strategy for PUS originating from the stomach. Surgeons should be aware of PUS as a differential diagnosis in cases with submucosal tumor of the stomach.


Impact of apparent diffusion coefficient on prognosis of early hepatocellular carcinoma: a case control study.

We investigated the usefulness of apparent diffusion coefficients (ADC) from diffusion-weighted images (DWI) obtained using magnetic resonance imaging (MRI) for prognosis of early hepatocellular carcinoma (HCC): Barcelona Clinic Liver Cancer (BCLC) stage 0 and A. We enrolled 102 patients who had undergone surgical resection for early HCC: BCLC stage 0 and A, and calculated their minimum ADC using DWI-MRI. We divided patients into ADC (n = 72) and ADC (n = 30) groups, and compared clinicopathological factors between the two groups. The ADC group showed higher protein induced by vitamin K absence-II (PIVKA-II) levels (p = 0.02) compared with the ADC group. In overall survival, the ADC group showed significantly worse prognosis than the ADC group (p < 0.01). Univariate analysis identified multiple tumors, infiltrative growth, high PIVKA-II, and low ADC value as prognostic factors. Multivariate analysis identified infiltrative growth and low ADC value as an independent prognostic factor. ADC values can be used to estimate the prognosis of early HCC.


An exosome-based liquid biopsy signature for pre-operative identification of lymph node metastasis in patients with pathological high-risk T1 colorectal cancer.

According to current guidelines, more than 70% of patients with invasive submucosal colorectal cancer (T1 CRC) undergo a radical operation with lymph node dissection, even though only ~ 10% have lymph node metastasis (LNM). Hence, there is imperative to develop biomarkers that can help robustly identify LNM-positive patients to prevent such overtreatments. Given the emerging interest in exosomal cargo as a source for biomarker development in cancer, we examined the potential of exosomal miRNAs as LNM prediction biomarkers in T1 CRC. We analyzed 200 patients with high-risk T1 CRC from two independent cohorts, including a training (n = 58) and a validation cohort (n = 142). Cell-free and exosomal RNAs from pre-operative serum were extracted, followed by quantitative reverse-transcription polymerase chain reactions for a panel of miRNAs. A panel of four miRNAs (miR-181b, miR-193b, miR-195, and miR-411) exhibited robust ability for detecting LNM in the exosomal vs. cell-free component. We subsequently established a cell-free and exosomal combination signature, successfully validated in two independent clinical cohorts (AUC, 0.84; 95% CI 0.70-0.98). Finally, we developed a risk-stratification model by including key pathological features, which reduced the false positive rates for LNM by 76% without missing any true LNM-positive patients. Our novel exosomal miRNA-based liquid biopsy signature robustly identifies T1 CRC patients at risk of LNM in a preoperative setting. This could be clinically transformative in reducing the significant overtreatment burden of this malignancy.


Fontan associated liver disease(FALD)関連肝癌に対しての腹腔鏡肝切除の1例 Fontan循環における肝離断対策

30代男性,3歳時に単心房・単心室症を背景にFontan手術を受けた.Fontan associated liver disease(FALD)として肝臓内科にフォローを開始されて以来3年後にFALD関連肝癌を疑われ,腹腔鏡肝切除を施行した.肝離断中は,Central venous pressure(CVP)圧を下げるため,positive end expiratory pressureをオフし,最小限の輸液量,利尿剤併用しながらの麻酔管理を行うも,Fontan循環の影響でCVPコントロールは不良で,静脈性出血が継続したままの肝離断となった.本症例は,術後合併症なく経過したものの,FALD関連肝癌症例は,Fontan循環による高CVP下での肝離断を余儀なくされるため,そのジレンマを解決する必要があり,その対策に関して考察を加え報告する.(著者抄録)


The Impact of the Pre-operative Neutrophil-lymphocyte Ratio as the Predictive Marker of Post-operative Weight Loss and Improving Diabetes in Sleeve Gastrectomy.

The aim was to investigate the impact of the neutrophil-lymphocyte ratio (NLR) in sleeve gastrectomy (SG). 15 obese patients were enrolled in this study ; mean body weight (BW) 127.5kg ; mean body mass index (BMI) 46.7kg/m. 10 of these were diabetics who underwent a SG. The impact of the pre-operative NLR on the percentage of excess weight loss (%EWL) and remission of diabetes 1 year post-operative were examined. The %EWL at 1 year post-operative were 46.3%. Improvements were also evident in the diabetes at 1 year post-operative : complete remission (CR) 40%, partial remission (PR) 20% and Improve 40%. Comparing pre-operative NLR in %EWL<50% and ≧50% in 1 year post-operative, <50% was 2.64 and ≧50% was 2.03. The NLR in CR and PR was significantly lower than that in Improve. The pre-operative NLR may be a predictive marker of weight loss and improving diabetes after SG. J. Med. Invest. 70 : 140-144, February, 2023.

The Journal of Medical Investigation : JMI


Intestinal hypomotility due to longitudinal enterotomy can be alleviated by transverse closure.

Heineke-Mikulicz (HM) strictureplasty is commonly used to treat short stenoses in Crohn's disease. However, the degree to which intestinal motility is maintained remains unclear. We compared the peristalsis and transport capacity of the sutured intestines with HM configuration and transverse (TS) and longitudinal (LS) incisions. The intestinal diameter, intraluminal pressure, and bead transit time of each sutured group were compared with that of the non-treatment (NT) group in the isolated proximal colon of rats. Propulsive contractions were induced using hydroxy-?-sanshool (HAS), a constituent of Japanese pepper. There was no change in the intestinal diameter between HM, TS, and NT groups ; however, it was significantly narrowed at the suture site and its distal side in the LS group. After HAS administration, the intestinal diameter at the suture site in the HM group was higher than that in the LS group. The intraluminal pressure was higher and the transit time was shorter in the HM group compared to those in the LS group. The HM configuration, which widens the incision site and distal diameter and shortens the cut surface of the circular muscle in the longitudinal direction, may help maintain basal and HAS-induced intestinal peristalsis and motility. J. Med. Invest. 70 : 180-188, February, 2023.


Prognostic impact of frailty after gastrectomy in elderly gastric cancer patients.

Frailty plays a crucial role in cancer patients who have received surgery in this recent aging society. We aimed to investigate frailty as a prognostic factor in elderly gastric cancer (GC) patients who underwent curative gastrectomy. We analyzed 86 elderly (over 75 years old) GC patients who underwent curative gastrectomy. Patients were assigned to two groups;frailty group (n=29) and no-frailty group (n=57). Clinicopathological values were compared between the two groups. The OS rate of the frailty group was significantly poorer than that of the no-frailty group (5-yr OS rate;frailty group 52.49% vs. no-frailty group 74.87%, p<0.05). Multivariate analysis of the OS showed that frailty tended to be significant prognostic factor (p=0.09). The DFS rate of the frailty group was significantly poorer than that of the no-frailty group (5-yr DFS rate;frailty group 42.30% vs. no-frailty group 71.55%, p<0.05). Multivariate analysis of the DFS showed that frailty tended to be significant prognostic factor (p=0.14). We identified the clinical impact of frailty prognostic factor for elderly GC patients who underwent gastrectomy. J. Med. Invest. 70 : 423-429, August, 2023.


Impact of pancreatic resection in patients with liver cirrhosis.

Several reports have shown a high mortality rate in patients with liver cirrhosis (LC) who undergo pancreaticoduodenectomy, however, there are few reports on its long-term prognosis. Twelve patients with LC who had undergone pancreatic resection were enrolled. To compare clinicopathological variables, 159 non-LC patients who had undergone resection for pancreatic cancer were enrolled. Pancreaticoduodenectomy (PD) was performed in 5 LC patients and distal pancreatectomy (DP) was performed in 7 LC patients. Patients in the LC group had more co-morbidities, lower platelet counts and higher Fib4 index than the non-LC group. The postoperative complication rate was higher in the LC group (83.3% vs 47.8%). While the postoperative hospital stay and 30-day mortality rate were not different, the 90-day mortality rate was higher in the LC group (25.0% vs 2.5% ; p<0.01). Comparison by operative procedure showed no significant differences of postoperative outcomes in DP cases. However, in PD cases, postoperative complications were more frequent (100% vs 42.3%) and 90-day mortality was higher (40.0% vs 2.9% ; p<0.01) in the LC group. PD resulted in higher postoperative morbidity and mortality rates in patients with LC compared with non-LC patients. DP could be tolerated in the LC patients. J. Med. Invest. 70 : 189-194, February, 2023.


Impact of L-type amino acid transporter 1 on intrahepatic cholangiocarcinoma.

Amino acid transporters, such as L-type amino acid transporter 1 (LAT1), have an effect on tumor growth, metastasis, and survival of various solid tumors. However, the role of LAT1 in patients with intrahepatic cholangiocarcinoma (IHCC) remains unknown. Forty-six patients who had undergone initial hepatic resection for IHCC at Tokushima University Hospital were enrolled in this study. Immunohistochemical analysis of LAT1 and phosphorylated Akt (p-AKT) was performed using resected specimens. Clinicopathological factors, including prognosis, were analyzed between LAT1-high and LAT1-low groups. The LAT1-high group showed a higher proportion of periductal infiltrating type and higher carcinoembryonic antigen/carbohydrate antigen 19-9 levels compared with the LAT1-low group. Multivariate analysis revealed that LAT1-high expression was an independent prognostic factor for disease-free survival. Furthermore, the proportion of p-AKT positivity was higher in the LAT1-high group than in the LAT1-low group. LAT1 expression was associated with poor prognosis of IHCC and higher p-Akt expression. J. Med. Invest. 70 : 160-165, February, 2023.


Short- and long-term outcomes of pancreatectomy in patients with hemodialysis.

Several reports have shown the high mortality rate of pancreatic resection in patients with hemodialysis (HD), however, its long-term outcome remains unclear. In this study, we examined cases of pancreatic resection in patients with HD and conducted a literature review. Four patients with HD who underwent pancreatic resection from 2004 to 2019 were enrolled. To compare the clinicopathological variables of HD and non-HD patients, 161 non-HD patients who had undergone surgical resection for pancreatic cancer were enrolled. Among four cases of pancreatic resection with HD, three cases were malignant diseases. All patients with HD had some co-morbidities (100% in HD group, 45.3% in the non-HD group) and postoperative complications (100% in the HD group, vs 46.6% in the non-HD group). Although one patient had severe postoperative complications and length of postoperative hospital stay was longer, the 30- and 90-day mortality rates were both 0% in patients with HD. However, three cases in the HD group (75%) died approximately 6 months after surgery, including one cancer-related death. Pancreatic surgery in patients with HD should be carefully indicated, especially pancreaticoduodenectomy or total pancreatectomy, because of the poor prognosis induced by non-cancer-related causes of death. J. Med. Invest. 70 : 105-109, February, 2023.


Role of IDO expression in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy.

The role of the immune system in locally advanced rectal cancer (LARC) following preoperative chemoradiotherapy (CRT) has been widely investigated in recent years. This study examined the prognostic significance of indoleamine-pyrrole 2,3-dioxygenase (IDO) expression in patients with LARC who received preoperative CRT. Ninety patients with LARC who underwent preoperative CRT and curative resection were enrolled. IDO and programmed death-ligand 1 (PD-L1) expression was evaluated by immunohistochemistry. Clinicopathological factors did not significantly differ between patients with positive or negative IDO expression, excluding the correlation of positive IDO expression with better tumor differentiation (p = 0.02). IDO expression was not associated with pathological response (p = 0.44), but it was associated with PD-L1 expression. The 5-year overall survival (OS) rate was significantly worse in the IDO-positive group than in the IDO-negative group (64.8% vs. 85.4%, p = 0.02). Univariate analysis identified IDO and PD-L1 expression (p = 0.02), surgical procedure (p = 0.01), final pathological stage (p = 0.003), lymph node metastasis (p < 0.001), and lymphatic invasion (p = 0.002) as significant prognostic factors for OS. Multivariate analysis revealed that IDO expression (HR: 7.10, p = 0.0006), surgical procedure (HR: 5.03, p = 0.01), lymph node metastasis (HR: 2.37, p = 0.04) and lymphatic invasion (HR: 4.97, p = 0.01) were independent prognostic indicators. Disease-free survival was not correlated with IDO or PD-L1 expression. IDO expression in patients with LARC who received preoperative CRT could be a potential prognostic indicator. IDO expression could be a useful marker for specifying individual treatment strategies in LARC.


【胆膵疾患と最新テクノロジーの融合】胆膵疾患における最新の術前術中手術支援システム

胆膵手術における術前シミュレーションは,腫瘍進展範囲あるいは主要脈管解剖をいかに正確にイメージできるかが,ポイントとなる．空間認識力という意味で,extended realityは有用である．また,術中ナビゲーションに関しては,ICG蛍光法がゴールドスタンダードとなるが,人工知能を駆使した最新の知見,ならびに自験例も踏まえて,本稿で紹介する．(著者抄録)


Essential amino acids as diagnostic biomarkers of hepatocellular carcinoma based on metabolic analysis.

Metabolomics, defined as the comprehensive identification of all small metabolites in a biological sample, has the power to shed light on phenotypic changes associated with various diseases, including cancer. To discover potential metabolomic biomarkers of hepatocellular carcinoma (HCC), we investigated the metabolomes of tumor and non-tumor tissue in 20 patients with primary HCC using capillary electrophoresis-time-of-flight mass spectrometry. We also analyzed blood samples taken immediately before and 14 days after hepatectomy to identify associated changes in the serum metabolome. Marked changes were detected in the different quantity of 61 metabolites that could discriminate between HCC tumor and paired non-tumor tissue and additionally between HCC primary tumors and colorectal liver metastases. Among the 30 metabolites significantly upregulated in HCC tumors compared with non-tumor tissues, 10 were amino acids, and 7 were essential amino acids (leucine, valine, tryptophan, isoleucine, methionine, lysine, and phenylalanine). Similarly, the serum metabolomes of HCC patients before hepatectomy revealed a significant increase in 16 metabolites, including leucine, valine, and tryptophan. Our results reveal striking differences in the metabolomes of HCC tumor tissue compared with non-tumor tissue, and identify the essential amino acids leucine, valine, and tryptophan as potential metabolic biomarkers for HCC.


オンライン時代は女性医師キャリア形成の追い風となる

オンライン時代は女性医師キャリア形成の追い風となる

新型コロナウイルス感染症の拡大が,これまで停滞していた医師の働き方改革の推進へとつながっている.その中でも,学会のオンライン化は医師の働き方に大きな変化をもたらした.学会のリモート参加は,自宅に居ながら参加でき,地方からも参加しやすく,移動時間と費用の大きな削減となる.オンデマンド配信は,時間・場所にかかわらず学ぶ機会を得られる非常に有効なツールとなる.また,学会の委員活動など,習慣的に行われていた対面での会議が,現在はほぼ遠隔で行われている.これまで時間的制約により,積極的に学会活動に手を挙げることができなかった女性医師の同分野での活躍推進が期待される.特に子育て中の女性医師にとって,オンライン化はワーク・ライフ・バランスを維持しながらキャリアを形成していく有効なツールとなりうる.この変化を逃さず女性活躍推進へとつなげるための,オンライン学会(ハイブリット形式)の継続を強く要望したい.(著者抄録)

The Japanese Journal of Gastroenterological Surgery


【膵・胆管合流異常-先天性胆道拡張症の最新トピックス-】膵・胆管合流異常 先天性胆道拡張症の分類と臨床的意義

本邦で先天性胆道拡張症は,膵・胆管合流異常を合併するものと定義されていることから,戸谷分類のI型(Ibは除く)とIV-A型が対象となり,このため拡張胆管形態の分類に加えて,膵管胆管合流形態の分類も診断する必要がある．膵管胆管合流形態については,これまで合流形態のみの分類にとどまっていたが,臨床症状をより反映する分類が日本膵・胆管合流異常研究会診断基準検討委員会によって2015年に提案され,分類に応じて術中対処法も異なってくる．また拡張胆管に関しては,戸谷分類が広く引用されており,戸谷分類に応じて術中対処法だけでなく術後合併症も異なる．しかしながら,これまでの分類は一定の臨床的意義を示すものの,発生や病態,臨床症状,治療法すべてに対応する分類は依然確立されておらず,今後の検討課題と思われる．(著者抄録)


【術前画像の読み解きガイド-的確な術式選択と解剖把握のために】胆道 先天性胆道拡張症に対する胆管切除+胆道再建 解剖把握と術中所見

<文献概要>先天性胆道拡張症は,戸谷分類で5型に分類され,戸谷I型(Ibは除く)とIV-A型では,膵・胆管合流異常を合併する.膵液の胆道内への逆流(膵液胆道逆流現象)の防止および胆道癌発生予防の目的のため,(肝外)胆管切除+胆道再建術が標準術式として確立されているが,拡張胆管の切除が不十分であったり,肝門部胆管形成が不適切であれば,難治性胆管炎や肝内結石,遺残胆管癌などの術後合併症が危惧される.本稿では,先天性胆道拡張症における(肝外)胆管切除+胆道再建の術中・術後合併症を回避するための基本手技とともに,理解すべき術前・術中画像による解剖把握のポイントについて概説する.


Impact of L-type amino acid transporter 3 on the prognosis of hepatocellular carcinoma.

The aim of the present study was to investigate the impact of L-type amino acid transporter 3 (LAT3) expression on the prognosis of hepatocellular carcinoma (HCC). A total of 135 patients who had undergone initial hepatic resection for HCC at Tokushima University Hospital (Tokushima, Japan) were enrolled in the present study. Immunohistochemical analysis of LAT3 and phosphorylated AKT (p-AKT) was performed using resected specimens. Clinicopathological factors, including prognosis, were compared between the LAT3-high and -low expression groups. The results demonstrated that the LAT3-high group showed significantly higher protein induced by vitamin K absence-II levels (P=0.01) compared with the LAT3-low group. The LAT3-high group showed significantly worse prognosis compared with the LAT3-low group regarding cancer-specific survival and disease-free survival (P<0.05). Multivariate analysis revealed that high LAT3 expression and multiple tumors were independent prognostic factors for cancer-specific survival. Furthermore, the rate of p-AKT-positive cases was higher in the LAT3-high group than in the LAT3-low group. Overall, these findings suggested that LAT3 expression was associated with poor prognosis of HCC and high p-AKT expression.


Lymph node response to neoadjuvant chemotherapy as an independent prognostic factor in gastric cancer.

Previous studies have revealed the usefulness of neoadjuvant chemotherapy (NAC) followed by surgery for clinical stage III gastric cancer (GC). The tumor volume at the primary tumor site (PT) is sometimes difficult to measure because of the luminal structure; therefore, evaluation of the lymph node (LN) response to NAC may help to more accurately predict survival outcomes. The present study therefore evaluated the LN response to NAC for prediction of survival outcomes in patients with GC. The study involved 160 patients with clinical stage III GC who underwent NAC (n=14) and upfront surgery (n=146). PT and LN responses to NAC were evaluated, various clinicopathological factors were evaluated and Cox proportional hazard regression analyses were performed to determine survival outcomes. Overall survival (OS) and disease-free survival (DFS) were not significantly different between patients who underwent NAC and those who underwent upfront surgery (OS, P=0.71; DFS, P=0.50). However, although there were no significant differences in PT responses, patients classified as LN non-responders to NAC had a significantly worse prognosis compared with patients classified as LN responders in terms of DFS (PT, P=0.93; LN, P<0.01) and OS (PT, P=0.84; LN, P<0.01). Moreover, a higher neutrophil-lymphocyte ratio tended to be associated with poor DFS [univariate: hazard ratio (HR)=4.23, P=0.06; multivariate: HR=6.45, P=0.04]. Finally, an LN response to NAC was significantly better for prediction of recurrence (univariate, HR=7.79, 95% confidence interval=1.16-63.51, P=0.02; multivariate, HR=7.44, P=0.01). Overall, the current study revealed the clinical importance of the LN response to NAC for predicting survival outcomes in patients with GC. These findings highlight the potential clinical impact of optimizing treatment strategies to improve the selection and management of patients.


Computed tomography texture analysis for the prediction of lateral pelvic lymph node metastasis of rectal cancer.

This study aimed to investigate the usefulness of computed tomography (CT) texture analysis in the diagnosis of lateral pelvic lymph node (LPLN) metastasis of rectal cancer. This was a retrospective cohort study of 45 patients with rectal cancer who underwent surgery with LPLN dissection at Tokushima University Hospital from January 2017 to December 2021. The texture analysis of the LPLNs was performed on preoperative CT images, and 18 parameters were calculated. The correlation between each parameter and pathological LPLN metastasis was evaluated. The texture parameters were compared between pathologically metastasis-positive LPLNs and metastasis-negative LPLNs. A total of 40 LPLNs were extracted from 25 patients by preoperative CT scans. No LPLNs could be identified in the remaining 19 patients. Eight of the 25 patients had pathologically positive LPLN metastasis. Extracted LPLNs were analyzed by the texture analysis. Pathologically metastasis-positive LPLNs had significantly lower mean Hounsfield unit, gray-level co-occurrence matrix (GLCM) energy, and GLCM Entropy_log2 values, and a significantly larger volume than pathologically metastasis-negative LPLNs. Multivariate analysis revealed that the independent predictive factors for LPLN metastasis were volume (a conventional parameter) (odds ratio 7.81, 95% confidence interval 1.42-43.1, p value 0.018) and GLCM Entropy_log2 (a texture parameter) (odds ratio 12.7, 95% confidence interval 1.28-126.0, p value 0.030). The combination of both parameters improved the diagnostic specificity while maintaining the sensitivity compared with each parameter alone. Combining the CT texture analysis with conventional diagnostic imaging may increase the accuracy of the diagnosis of LPLN metastasis of rectal cancer.


腹腔鏡下切除を行った限局性盲腸壊死の1例

腹腔鏡下切除を行った限局性盲腸壊死の1例

症例は82歳,男性.来院前日から腹痛が出現し,血便も認めたため当院紹介となった.腹部は平坦・硬で腹部全体に圧痛を認め,反跳痛,筋性防御も伴っていた.腹部単純CTで回盲部から上行結腸に著明な壁肥厚,周囲の炎症所見,腸管外ガスを認め,また血液生化学所見では白血球数とCRPの上昇を認めた.結腸穿孔と診断し同日腹腔鏡下に緊急手術を行い,術中所見で盲腸に虚血壊死所見を認めたため腹腔鏡下回盲部切除術を行った.術後経過は問題なく術後11日目に退院となった.稀な疾患である限局性盲腸壊死に対し腹腔鏡下に切除を行った1例を経験したので,若干の文献的考察を加えて報告する.(著者抄録)


Impact of osteopenia and neutropenia in patients with colorectal cancer treated with FOLFOXIRI: a retrospective cohort study.

This study was performed to assess the impact of osteopenia on chemotherapy-induced neutropenia and the prognosis for patients treated with FOLFOXIRI for colorectal cancer. In total, 77 patients who underwent FOLFOXIRI for un-resectable metastatic and advanced colorectal cancer were retrospectively evaluated. Osteopenia was evaluated by the bone mineral density, which was measured using the average pixel density of the trabecular bone in the 11th thoracic vertebra by computed tomography before the introduction of chemotherapy. The relationship between osteopenia and neutropenia was evaluated. Progression-free survival and overall survival of patients with osteopenia and patients with neutropenia were evaluated. Grade ≥ 3 neutropenia was significantly more common in patients with than without osteopenia (p = 0.002). The multivariate analysis showed that osteopenia was a significant independent predictive factor for grade ≥ 3 neutropenia (p = 0.016). There was no significant difference in progression-free survival or overall survival between patients with and without osteopenia. Patients with grade ≥ 3 neutropenia tended to have a higher progression-free survival rate than others (p = 0.059). The overall survival rate was significantly higher in patients with grade ≥ 3 neutropenia than in others (p = 0.011). Osteopenia might be a predictor of chemotherapy-induced neutropenia, and neutropenia might be a prognostic factor for progression-free survival and overall survival in patients with colorectal cancer treated with FOLFOXIRI.

International Journal of Clinical Oncology


Intraoperative holographic image-guided surgery in a transanal approach for rectal cancer.

Urethral injury is one of the most important complications in transanal total mesorectal excision (TaTME) in male patients with rectal cancer. The purpose of this study was to investigate holographic image-guided surgery in TaTME. Polygon (stereolithography) files were created and exported from SYNAPSE VINCENT, and then uploaded into the Holoeyes MD system (Holoeyes Inc., Tokyo, Japan). After uploading the data, the three-dimensional image was automatically converted into a case-specific hologram. The hologram was then installed into the head mount display, HoloLens (Microsoft Corporation, Redmond, WA). The surgeons and assistants wore the HoloLens when they performed TaTME. In a Wi-Fi-enabled operating room, each surgeon, wearing a HoloLens, shared the same hologram and succeeded in adjusting the hologram by making simple hand gestures from their respective angles. The hologram contributed to better comprehension of the positional relationships between the urethra and the surrounding pelvic organs during surgery. All surgeons were able to properly determine the dissection line. This first experience suggests that intraoperative holograms contributed to reducing the risk of urethral injury and understanding transanal anatomy. Intraoperative holograms have the potential to become a new next-generation surgical support tool for use in spatial awareness and the sharing of information between surgeons.

Langenbeck's Archives of Surgery / Deutsche Gesellschaft für Chirurgie


Preoperative nutrition and exercise intervention in frailty patients with gastric cancer undergoing gastrectomy.

The frailty was associated with the worse surgical outcomes and poor prognosis in several cancers. Therefore, we aimed to identify the usefulness of nutrition and exercise intervention (NEI) in frailty patients with GC. We analyzed 58 frailty patients with GC who underwent radical surgery. Among these, 15 patients were performed NEI by nutritional and rehabilitation support team. We compared the surgical outcomes between NEI and non-NEI groups with frailty patients and evaluated the nutrition and rehabilitation markers in pre- and post-NEI groups. The postoperative complication of NEI groups was 6.7% and less than that of non-NEI groups (p = 0.08). The mean postoperative hospital stay of NEI groups was 13.0 ± 1.0 days for NEI groups and significantly shorter than that of non-NEI groups (p = 0.03). The NLR was 4.3 ± 0.6 for pre-NEI and significantly improved by NEI between pre- and post-NEI (p = 0.03). We identified the clinical importance of NEI for improving the surgical outcomes in frailty patients with GC. Our findings highlight the potential clinical impact of optimizing treatment strategies to select and manage the frailty patients.


The TTYH3/MK5 Positive Feedback Loop regulates Tumor Progression via GSK3-β/β-catenin signaling in HCC.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and identification of novel targets is necessary for its diagnosis and treatment. This study aimed to investigate the biological function and clinical significance of tweety homolog 3 (TTYH3) in HCC. TTYH3 overexpression promoted cell proliferation, migration, and invasion and inhibited HCCM3 and Hep3B cell apoptosis. TTYH3 promoted tumor formation and metastasis . TTYH3 upregulated calcium influx and intracellular chloride concentration, thereby promoting cellular migration and regulating epithelial-mesenchymal transition-related protein expression. The interaction between TTYH3 and MK5 was identified through co-immunoprecipitation assays and protein docking. TTYH3 promoted the expression of MK5, which then activated the GSK3β/β-catenin signaling pathway. knockdown attenuated the activation of GSK3β/β-catenin signaling by TTYH3. TTYH3 expression was regulated in a positive feedback manner. In clinical HCC samples, TTYH3 was upregulated in the HCC tissues compared to nontumor tissues. Furthermore, high TTYH3 expression was significantly correlated with poor patient survival. The CpG islands were hypomethylated in the promoter region of in HCC tissues. In conclusion, we identified TTYH3 regulates tumor development and progression via MK5/GSK3-β/β-catenin signaling in HCC and promotes itself expression in a positive feedback loop.

International Journal of Biological Sciences


クリニカルカンファレンスから(第23回) 徳島大学病院の症例 高度肥満による続発性無月経に対し腹腔鏡下スリーブ状胃切除術を施行し妊娠・出産に至った一例


A Hepatectomy Based on a Hybrid Concept of Portal Perfusion of Anterior Segment and Venous Drainage Area of Superior Right Hepatic Vein.

Right hepatic vein sometimes could not be a reliable landmark between the anterior and posterior segment. The aim of this study was to clarify the portal perfusion area of the anterior segment and to propose a less invasive hepatectomy based on both the portal perfusion and the hepatic venous drainage. Three-dimensional computerized tomography images of 66 patients were constructed. A case, in which the perfusion area of the anterior segment crossed over superior right hepatic vein (SRHV), was called as SRHV-inclusion. It was defined as inclusion of more than 1 cm of the proximal site of SRHV surrounded by the portal perfusion area of the anterior segment. SRHV-inclusion was observed in 26%. The cases with large inferior right hepatic vein (IRHV) had more frequent SRHV-inclusion (47%). The elderly patient with hepatic disorder, who had hepatocellular carcinoma near the root of the SRHV, underwent a less invasive hepatectomy (anterior segment + SRHV drainage area) resulting in the preservation of the IRHV. The perfusion area of the anterior segment crossed over SRHV in one fourth of patients in the study. Our proposed less invasive hepatectomy based on a hybrid concept might be an alternative operative procedure other than right hepatectomy.


Polymethoxylated flavone sudachitin is a safe anticancer adjuvant that targets glycolysis in cancer-associated fibroblasts.

Sudachitin is a polymethoxylated flavone found in the peel of , a unique specialty citrus fruit in Tokushima Prefecture, Japan. Previous reports have demonstrated that sudachitin has anti-inflammatory and metabolic regulatory activities. However, to the best of our knowledge, no studies have explored whether sudachitin can act as an antitumor therapeutic agent by regulating metabolic functions in the tumor microenvironment. In the present study, cell proliferation and cytotoxicity assays were used to determine whether sudachitin inhibited the growth of liver cancer and pancreatic carcinoma, cholangiocarcinoma and colorectal cancer cells and to compare its toxicity against normal fibroblasts and induced cancer-associated fibroblasts (CAFs). Using lactate assays and reverse transcription-quantitative PCR, the effects of sudachitin on glycolysis in CAFs were investigated. The effects of CAFs on malignant tumor cells were evaluated using cell proliferation, wound healing and invasion assays. As result, sudachitin inhibited various types of tumor cells with different half-maximal inhibitory concentrations. Treatment with 50 µM sudachitin for 48 h suppressed tumor and CAFs proliferation but was not cytotoxic against normal fibroblasts. This dose also inhibited glycolysis in CAFs and, thus, diminished their pro-tumorigenic activities. Overall, the present study revealed that sudachitin has promise as a safe and widely available natural antitumor adjuvant.


Intraoperative support with three-dimensional holographic cholangiography in hepatobiliary surgery.

This study was performed to investigate the potential of intraoperative three-dimensional (3D) holographic cholangiography, which provides a computer graphics model of the biliary tract, with mixed reality techniques. Two patients with intraductal papillary neoplasm of the bile duct were enrolled in the study. Intraoperative 3D cholangiography was performed in a hybrid operating room. Three-dimensional polygon data using the acquired cholangiography data were installed into a head mount display (HoloLens; Microsoft Corporation, Redmond, WA, USA). Upon completion of intraoperative 3D cholangiography, a hologram was immediately and successfully made in the operating room using the acquired cholangiography data, and several surgeons wearing the HoloLens succeeded in sharing the same hologram. Compared with usual two-dimensional cholangiography, this 3D holographic cholangiography technique contributed to more accurate reappearance of the bile ducts, especially the B1 origination site, and moving the hologram from the respective operators' angles by means of easy gesture-handling without any monitors. Intraoperative 3D holographic cholangiography might be a new next-generation operation-support tool in terms of immediacy, accurate anatomical reappearance, and ease of handling.


Pincer Approach to Gastrosplenic Ligament in Robotic Total Gastrectomy for Gastric Cancer.


Vascular variations encountered during laparoscopic surgery for transverse colon, splenic flexure, and descending colon cancer: a retrospective cohort study.

Laparoscopic surgery for cancer located in the transverse colon or splenic flexure is difficult because of vascular variability in this region and adjacent vital organs such as the pancreas, spleen, and duodenum. This retrospective cohort study involved 51 patients who underwent laparoscopic surgery for colon cancer at Tokushima University Hospital from July 2015 to December 2020. Variations of the middle colic artery (MCA), left colic artery (LCA), middle colic vein (MCV), and first jejunal vein (FJV) and short-term outcomes of laparoscopic surgery in patients with each vascular variation were evaluated. Variations of the MCA, LCA, MCV, and FJV were classified into four, three, five, and three patterns, respectively. The short-term outcomes of laparoscopic surgery for transverse colon cancer in patients with MCA variations and those with FJV variations were evaluated, and no significant difference was found in the operation time, blood loss, postoperative complication rate, time from surgery to start of dietary intake, or time from surgery to discharge among the different variations. Additionally, no significant differences were found in the short-term outcomes of laparoscopic surgery for descending colon cancer in patients with LCA variations. Preoperative assessment of vascular variations may contribute to the stability of short-term outcomes of laparoscopic surgery for transverse colon, splenic flexure, and descending colon cancer.


【1型糖尿病-診療と研究の最前線】治療研究 膵β細胞再生医療の可能性 脂肪由来幹細胞の有用性

1型糖尿病治療としての再生医療はいまだ研究段階の域をでていないが，本領域は急速に発展しており，さまざまなコンセプトのもとで臨床応用も目前に迫っている．本稿では，再生医療における幹細胞の役割，分類(分化能力，その起源)を明らかにし，現在，最も臨床応用が近いと考えられる体性幹細胞(なかでも脂肪由来幹細胞)における筆者らの研究成果と，医師主導治験確立に向けた取り組みを示すとともに，すでに行われている1型糖尿病に対する幹細胞を用いた臨床研究など(幹細胞を直接投与するもの，幹細胞からβ細胞様細胞へ分化誘導させるもの)をレビューし，将来，再生医療がどのように1型糖尿病治療にコミットメントしていくかの展望を示す．(著者抄録)

Journal of Clinical and Experimental Medicine