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Apoptosis is a morphologically distinct form of programmed cell death that plays a major role in cancer treatments. This cellular suicide program is known to be regulated by many different signals from both intracellular and extracellular stimuli. Here we report that p53 suppressed expression of the cellular FLICE-inhibitory protein (FLIP) that potentially blocks apoptotic signaling in human colon cancer cell lines expressing mutated and wild-type p53. In contrast, the expression of the death receptor KILLER/DR5 (TRAIL-R2) had no effect on FLIP expression, although exogenous p53 is known to induce KILLER/DR5 expression. In line with these observations, FLIP-negative cancer cells were sensitive to both p53- and KILLER/DR5-mediated apoptosis, whereas cells containing high levels of FLIP underwent apoptotic cell death when triggered by ectopic p53 expression but not by KILLER/DR5 expression. Treating the cells with a specific inhibitor of the proteasome inhibited the decrease of FLIP by p53, suggesting that p53 enhances the degradation of FLIP via a ubiquitin-proteasome pathway. Thus, the data indicate that p53-mediated downregulation of FLIP may explain the potent sensitization of human cancer cells to the apoptotic suicide program induced by wild-type p53 gene transfer. Oncogene (2001) 20, 5225–5231. [ABSTRACT FROM AUTHOR]

Presents information on a study which used hepatocyte transplantation to correct metabolic defects and provide metabolic support in experimental animal models of hepatic failure. Methodology of the study; Results and discussion on the study; Conclusions.

The tumor suppressor gene p53 is a potent transcriptional regulator of genes which are involved in many cellular activities including cell cycle arrest, apoptosis, and angiogenesis. Recent studies have demonstrated that the activation of the transcriptional factor nuclear factor κB (NF-κB) plays an essential role in preventing apoptotic cell death. In this study, to better understand the mechanism reponsible for the p53-mediated apoptosis, the effect of wild-type p53 (wt-p53) gene transfer on nuclear expression of NF-κB was determined in human colon cancer cell lines. A Western blot analysis of nuclear extracts demonstrated that NF-κB protein levels in the nuclei were suppressed by the transient expression of the wt-p53 in a dose-dependent manner. Transduced wt-p53 expression increased the cytoplasmic expression of IκBα as well as its binding ability to NF-κB, thus markedly reducing the amount of NF-κB that translocated to the nucleus. The decrease in nuclear NF-κB protein correlated with the decreased NF-κB constitutive activity measured by electrophoretic mobility shift assay. Furthermore, parental cells transfected with NF-κB were better protected from cell death induced by the wt-p53 gene transfer. We also found that the wt-p53 gene transfer was synergistic with aspirin (acetylsalicylic acid) in inhibiting NF-κB constitutive activity, resulting in enhanced apoptotic cell death. These results suggest that the inhibition of NF-κB activity is a plausible mechanism for apoptosis induced by the wt-p53 gene transfer in human colon cancer cells and that anti-NF-κB reagent aspirin could make these cells more susceptible to apoptosis. Oncogene (2000) 19, 726–736. [ABSTRACT FROM AUTHOR]

Post-gastrectomy syndrome (PGS) and body weight loss (BWL) decrease quality of life (QOL) and survival of the patient undergoing gastrectomy. We have introduced perioperative and post-discharge continuous nutritional counseling (CNC) to prevent BWL and improve QOL after gastrectomy. In the present study, we evaluated the effect of CNC on QOL using the Post-gastrectomy Syndrome Assessment Scale-45 (PGSAS-45). Eighty-three patients with gastric cancer (GC) who underwent curative gastrectomy between March 2018 and July 2019 were retrospectively analyzed. Patients received either pre-discharge nutritional counseling alone (control group, n = 45) or CNC (CNC group, n = 38) after gastrectomy. QOL at 12 months after gastrectomy was compared between the two groups. In QOL assessment, change in body weight (−7.98% vs. −12.77%, p = 0.0057), ingested amount of food per meal (7.00 vs. 6.07, p = 0.042) and ability for working (1.89 vs. 2.36, p = 0.049) were significantly better in CNC group than control group. Multiple regression analysis showed that CNC was a significantly beneficial factor for abdominal pain subscale (p = 0.028), diarrhea subscale (p = 0.047), ingested amount of food per meal (p = 0.012), Ability for working (p = 0.031) and dissatisfaction at the meal (p = 0.047). Perioperative and postoperative CNC could improve QOL in the patient undergoing gastrectomy in addition to preventing postoperative BWL. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a critical role in tumor immunosuppression. However, targeted depletion of CAFs is difficult due to their diverse cells of origin and the resulting lack of specific surface markers. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that leads to rapid cell membrane damage. Methods: In this study, we used anti-mouse fibroblast activation protein (FAP) antibody to target FAP+ CAFs (FAP-targeted NIR-PIT) and investigated whether this therapy could suppress tumor progression and improve tumor immunity. Results: FAP-targeted NIR-PIT induced specific cell death in CAFs without damaging adjacent normal cells. Furthermore, FAP-targeted NIR-PIT treated mice showed significant tumor regression in the CAF-rich tumor model accompanied by an increase in CD8+ tumor infiltrating lymphocytes (TILs). Moreover, treated tumors showed increased levels of IFN-γ, TNF-α, and IL-2 in CD8+ TILs compared with non-treated tumors, suggesting enhanced antitumor immunity. Conclusions: Cancers with FAP-positive CAFs in their TME grow rapidly and FAP-targeted NIR-PIT not only suppresses their growth but improves tumor immunosuppression. Thus, FAP-targeted NIR-PIT is a potential therapeutic strategy for selectively targeting the TME of CAF+ tumors. [ABSTRACT FROM AUTHOR]

Normal cells in a culture enter a nondividing state after a finite number of population doubling, which is termed replicative senescence, whereas cancer cells have unlimited proliferative potential and are thought to exhibit an immmortal phenotype by escaping from senescence. The p21 gene (also known as stil1), which encodes the cyclin-dependent kinase inhibitor, is expressed at high levels in senescent cells and contributes to the growth arrest. To examine if the p21[sup sdi1] gene transfer could induce senescence in human cancer cells, we utilized an adenoviral vector-based expression system and four human cancer cell lines differing in their p53 status. Transient overexpression of p21[sup sdi1] on cancer cells induced quiescence by arresting the cell cycle at the G[sup 1] phase and exhibited morphological changes, such as enlarged nuclei as well as a flattened cellular shape, specific to the senescence phenotype. We also showed that p21[sup sdi1]-transduced cancer cells expressed β-galactosidase activity at pH 6.0, which is known to be a marker of senescence. Moreover, the polymerase chain reaction-based assay demonstrated that levels of telomerase activity were significantly lower in p21[sup sdi1]-expressing cells compared to parental cancer cells. These observations provide the evidence that p21[sup sdi1] overexpression could induce a senescence-like state and reduce telomerase activity in human cancer cells, suggesting that these novel p21[sup sdi1] functions may have important implications for anticancer therapy. [ABSTRACT FROM AUTHOR]

The CD95 (Fas/APO-1) system regulates a number of physiological and pathological processes of cell death. The ligand for CD95 induces apoptosis in sensitive target cells by interacting with a transmembrane cell surface CD95 receptor. We previously reported that the recombinant adenovirus-mediated transfer of the wild-type p53 gene caused apoptotic cell death in a variety of human cancer cells. To better understand the mechanism responsible for this cell death signaling, we have investigated the potential involvement of the CD95 receptor/ligand system in p53-mediated apoptosis. The transient expression of the wild-type p53 gene up-regulated the CD95 ligand mRNA as well as protein expression in H1299 human lung cancer cells deficient for p53 and in DLD-1 and SW620 human colon cancer cells with mutated p53, all of which constitutively expressed CD95 receptor as shown by a flow cytometric analysis, and induced rapid apoptotic cell death as early as 24 h after gene transfer. However, the sensitivity to the cytolytic effect of agonistic anti-CD95 antibody (CH11) varied among these cell lines: CH11 induced apoptosis in H1299 cells, but not in DLD-1 and SW620 cells despite their abundant CD95 receptor expression, suggesting that the CD95 receptors on DLD-1 and SW620 cells might be inactivated. In addition, an antagonistic anti-CD95 ligand antibody (4H9) that interfered with the CD95-receptor-ligand interaction partially reduced the apoptosis induced by the wild-type p53 gene transfer in H1299 cells, whereas apoptosis of DLD-1 and SW620 cells occurred in the presence of 4H9. Taken together, these findings led us to conclude that the CD95 receptor/ligand system is differentially involved in p53-mediated apoptosis, suggesting that the restoration of the wild-type p53 function may mediate apoptosis through CD95 receptor/ligand interactions as well as an alternative pathway. [ABSTRACT FROM AUTHOR]

Investigates the therapeutic efficacy of direct administration of a retroviral wild type p53 expression vector in an orthotopic human lung cancer model in nu/nu mice. Effect of LNp53B on the proliferation of H226Br cells in vitro.

The p21WAF1/CIP1 gene, which encodes a cyclin-dependent kinase inhibitor, may be critical for tumor suppressor gene p53-induced cell cycle arrest. The p53 gene is known to regulate G1 checkpoint, which can either induce G1 arrest or initiate apoptosis. To directly examine the role of p21WAF1/CIP1 in the control of p53 function, we have introduced human p21WAF1/CIP1 gene into a p53-deficient human non-small cell lung cancer cell line H1299 using a p21WAF1/CIP1-expressing adenoviral vector (AdCMVp21). Infection with AdCMVp21 resulted in high levels of p21WAF1/CIP1 expression and significantly suppressed the growth of H1299 cells through the G1 arrest of the cell cycle. In contrast, transient expression of the wild-type p53 gene by a recombinant adenoviral vector (AdCMVp53) in H1299 cells induced apoptotic cell death and resulted in a rapid loss of cell viability. We then examined the effects of combined infection with AdCMVp21 and AdCMVp53 on H1299 cells to explore the dominant function of these molecules. Interestingly, introduction of exogenous p53 overcame p21WAF1/CIP1-mediated cell cycle arrest at G1 and induced apoptosis, although viral-transduced p21WAF1/CIP1 expression level was unaffected. These observations suggest that p53 expression converts a p21WAF1/CIP1-mediated growth arrest into apoptosis. The result was repeated with two additional human colon adenocarcinoma cell lines with the different p53 status, mutant p53-expressing DLD-1 and wild-type p53-expressing LoVo, suggesting that this phemonenon is a general event among human cancer cells. Thus, p53-mediated apoptotic pathway is dominant over the growth arrest pathway, indicating that p53 may be an essential upstream mediator of p21WAF1/CIP1 in the regulation of a cell process leading either to growth arrest or to apoptotic suicide. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is an aggressive, immunologically "cold" tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702). Methods: We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps). Results: First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection. Conclusion: OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer. [ABSTRACT FROM AUTHOR]

A 52‐year‐old, Japanese man presented to the hospital with a complaint of anal bleeding, and detailed examination resulted in a diagnosis of locally advanced rectal cancer. The patient underwent total neoadjuvant therapy followed by short‐course radiation therapy and consolidation chemotherapy, which provided a partial response. After preoperative contrast‐enhanced computed tomography showed a horseshoe kidney, robot‐assisted, precise, laparoscopic, low anterior resection with D3 dissection and ileostomy construction was performed. The horseshoe renal isthmus was elevated surrounding the inferior mesenteric artery, and the left ureter and seminal vessels ran in front of the kidney. The hypogastric nerve traveled ventral to the horseshoe kidney. With robotic surgery, it was possible to perform more precise surgery while recognizing vascular and nerve anatomy in a rectal cancer patient with a horseshoe kidney due to good three‐dimensional visibility and articulated forceps manipulation. [ABSTRACT FROM AUTHOR]

Although the current trend in pancreatoduodenectomy (PD) has shifted from open surgery to minimally invasive surgery (MIS), evidence on the role of MIS as an element of Enhanced Recovery After Surgery (ERAS) in PD is limited. This study aimed to investigate the effect of robotic surgery using the ERAS protocol on the outcomes of patients undergoing PD. This retrospective study included 252 patients who underwent open PD (OPD) or robotic PD (RPD) managed using the ERAS protocol between January 2017 and March 2023. Outcomes stratified by the surgical approach were compared. Multivariable analyses were performed to evaluate the effect of ERAS items, including robotic surgery, on outcomes after PD. Of 252 patients, 202 (80.2%) underwent OPD, and 50 (19.2%) underwent RPD. Multivariable analyses demonstrated that perioperative management center support (odds ratio [OR], 2.85; 95% CI, 1.14-7.72; P =.025), robotic surgery (OR, 6.40; 95% CI, 1.94-26.1; P =.002), early solid intake (OR, 2.84; 95% CI, 1.46-5.63; P =.002), and early drain removal (OR, 3.77; 95% CI, 2.04-7.06; P <.001) were significant ERAS items related to early discharge after PD. Our study demonstrated that employing the ERAS protocol for OPD and RPD is feasible and safe. Moreover, our results suggested the role of robotic surgery as an element of the ERAS protocol for PD. A combination of ERAS protocols and MIS may be safe and feasible for accelerating postoperative recovery after PD. [ABSTRACT FROM AUTHOR]

Bone and soft-tissue sarcomas are rare malignancies with histological diversity and tumor heterogeneity, leading to the lack of a common molecular target. Telomerase is a key enzyme for keeping the telomere length and human telomerase reverse transcriptase (hTERT) expression is often activated in most human cancers, including bone and soft-tissue sarcomas. For targeting of telomerase-positive tumor cells, we developed OBP-301, a telomerase-specific replication-competent oncolytic adenovirus, in which the hTERT promoter regulates adenoviral E1 gene for tumor-specific viral replication. In this study, we present the diagnostic potential of green fluorescent protein (GFP)-expressing oncolytic adenovirus OBP-401 for assessing virotherapy sensitivity using bone and soft-tissue sarcomas. OBP-401-mediated GFP expression was significantly associated with the therapeutic efficacy of OBP-401 in human bone and soft-tissue sarcomas. In the tumor specimens from 68 patients, malignant and intermediate tumors demonstrated significantly higher expression levels of coxsackie and adenovirus receptor (CAR) and hTERT than benign tumors. OBP-401-mediated GFP expression was significantly increased in malignant and intermediate tumors with high expression levels of CAR and hTERT between 24 and 48 h after infection. Our results suggest that the OBP-401-based GFP expression system is a useful tool for predicting the therapeutic efficacy of oncolytic virotherapy on bone and soft-tissue sarcomas. [ABSTRACT FROM AUTHOR]

This study investigates methylation patterns in circulating cell-free DNA (ccfDNA) for their potential role in colorectal cancer (CRC) detection and the monitoring of treatment response. Through methylation microarrays and quantitative PCR assays, we analyzed 440 samples from The Cancer Genome Atlas (TCGA) and an additional 949 CRC samples. We detected partial or extensive methylation in over 85% of cases within three biomarkers: EFEMP1, SFRP2, and UNC5C. A methylation score for at least one of the six candidate regions within these genes' promoters was present in over 95% of CRC cases, suggesting a viable detection method. In evaluating ccfDNA from 97 CRC patients and 62 control subjects, a difference in methylation and recovery signatures was observed. The combined score, integrating both methylation and recovery metrics, showed high diagnostic accuracy, evidenced by an area under the ROC curve of 0.90 (95% CI = 0.86 to 0.94). While correlating with tumor burden, this score gave early insight into disease progression in a small patient cohort. Our results suggest that DNA methylation in ccfDNA could serve as a sensitive biomarker for CRC, offering a less invasive and potentially more cost-effective approach to augment existing cancer detection and monitoring modalities, possibly supporting comprehensive genetic mutation profiling. [ABSTRACT FROM AUTHOR]

Purpose: It remains unknown whether stroke volume variation (SVV), pulse pressure variation (PPV), and dynamic arterial elastance (Eadyn) are suitable for monitoring fluid management during thoracoscopic esophagectomy (TE) in the prone position with one-lung ventilation and artificial pneumothorax. Our study aimed to evaluate the accuracy of SVV, PVV, and Eadyn in predicting the fluid responsiveness in these patients. Methods: We recruited 24 patients who had undergone TE. Patients with a mean arterial blood pressure ≤ 65 mmHg received a 200-ml bolus of 6% hydroxyethyl starch over 10 min. Fluid responders showed the stroke volume index ≥ 15% 5 min after the fluid bolus. Receiver operating characteristic (ROC) curves were generated and area under the ROC curve (AUROC) was calculated. Results: We obtained 61 fluid bolus data points, of which 20 were responders and 41 were non-responders. The median SVV before the fluid bolus in responders was significantly higher than that in non-responders (18% [interquartile range (IQR) 13–21] vs. 12% [IQR 8–15], P = 0.001). Eadyn was significantly lower in responders than in non-responders (0.55 [IQR 0.45–0.78] vs. 0.91 [IQR 0.67–1.00], P < 0.001). There was no difference in the PPV between the groups. The AUROC was 0.76 for SVV (95% confidence interval [CI] 0.62–0.89, P = 0.001), 0.56 for PPV (95% CI 0.41–0.71, P = 0.44), and 0.82 for Eadyn (95% CI 0.69–0.95, P < 0.001). Conclusions: SVV and Eadyn are reliable parameters for predicting fluid responsiveness in patients undergoing TE. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) cells harboring KRAS or BRAF mutations show a more-malignant phenotype than cells with wild-type KRAS and BRAF. KRAS/BRAF–wild-type CRCs are sensitive to epidermal growth factor receptor (EGFR)-targeting agents, whereas KRAS/BRAF–mutant CRCs are resistant due to constitutive activation of the EGFR-downstream KRAS/BRAF signaling pathway. Novel therapeutic strategies to treat KRAS/BRAF mutant CRC cells are thus needed. We recently demonstrated that the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 exhibit therapeutic potential against KRAS-mutant human pancreatic cancer cells. In this study, we evaluated the therapeutic potential of OBP-301 and OBP-702 against human CRC cells with differing KRAS/BRAF status. Human CRC cells with wild-type KRAS/BRAF (SW48, Colo320DM, CACO-2), mutant KRAS (DLD-1, SW620, HCT116), and mutant BRAF (RKO, HT29, COLO205) were used in this study. The antitumor effect of OBP-301 and OBP-702 against CRC cells was analyzed using the XTT assay. Virus-mediated modulation of apoptosis, autophagy, and the EGFR-MEK-ERK and AKT-mTOR signaling pathways was analyzed by Western blotting. Wild-type and KRAS-mutant CRC cells were sensitive to OBP-301 and OBP-702, whereas BRAF-mutant CRC cells were sensitive to OBP-702 but resistant to OBP-301. Western blot analysis demonstrated that OBP-301 induced autophagy and that OBP-702 induced autophagy and apoptosis in human CRC cells. In BRAF-mutant CRC cells, OBP-301 and OBP-702 suppressed the expression of EGFR, MEK, ERK, and AKT proteins, whereas mTOR expression was suppressed only by OBP-702. Our results suggest that p53-armed oncolytic virotherapy is a viable therapeutic option for treating KRAS/BRAF-mutant CRC cells via induction of autophagy and apoptosis. [ABSTRACT FROM AUTHOR]

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity. [ABSTRACT FROM AUTHOR]

Background: The current status of site-specific cancer registry has not been elucidated, but sufficient system is found in some societies. The purpose of this study was to clear the present condition of site-specific cancer registries in Japan and to suggest for the improvement. Methods: The questionnaire was conducted by the study group of the Ministry of Health, Labor, and Welfare. It consisted of 38 questions, conflicts of interest, clinical research method, informed consent and funding for registry. We distributed this questionnaire to 28 academic societies, which had published the clinical practice guideline(s) assessed under Medical Information Network Distribution Service (MINDS). Results: The concept of the importance in assessment for medical quality by the data of the site-specific cancer registry was in good consensus. But the number of the society with the mature registry was limited. The whole-year registry with the scientific researches in the National Clinical Database (NCD) and in the Translational Research Informatics Center (TRI) might seem to be in success, because assured enhancement may be estimated. Now, academic societies have the structural factors, i.e., the financial limitation in the registry maintenance and the data analysis, and in the difficulty of employment of the researchers with skill and talent. Conclusions: To manage the site-specific cancer registry effectively, the scientific registry system will be essentially important. Each academic society had much experienced highly qualified clinical researches in past. Accordingly, the scientific suggestion and co-operation should be of great importance for the improvement. [ABSTRACT FROM AUTHOR]

Purpose: Biliary reconstruction remains a technically demanding and complicated procedure in minimally invasive hepatopancreatobiliary surgeries. No optimal hepaticojejunostomy (HJ) technique has been demonstrated to be superior for preventing biliary complications. This study aimed to investigate the feasibility of our unique technique of posterior double-layer interrupted sutures in robotic HJ. Methods: We performed a retrospective analysis of a prospectively collected database. Forty-two patients who underwent robotic pancreatoduodenectomy using this technique between September 2020 and November 2022 at our center were reviewed. In the posterior double-layer interrupted technique, sutures were placed to bite the bile duct, posterior seromuscular layer of the jejunum, and full thickness of the jejunum. Results: The median operative time was 410 (interquartile range [IQR], 388–478) min, and the median HJ time was 30 (IQR, 28–39) min. The median bile duct diameter was 7 (IQR, 6–10) mm. Of the 42 patients, one patient (2.4%) had grade B bile leakage. During the median follow-up of 12.6 months, one patient (2.4%) with bile leakage developed anastomotic stenosis. Perioperative mortality was not observed. A surgical video showing the posterior double-layer interrupted sutures in the robotic HJ is included. Conclusions: Posterior double-layer interrupted sutures in robotic HJ provided a simple and feasible method for biliary reconstruction with a low risk of biliary complications. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation. [ABSTRACT FROM AUTHOR]

Navigation surgery using indocyanine green (ICG) fluorescence imaging has been used in thoracoabdominal surgery, and its usefulness has been reported in many cases. In this study, laparoscopic lateral lymph node dissection was performed using ICG fluorescence imaging in a patient with left femoral spinous cell carcinoma with inguinal and external iliac lymph node metastases. Spinous cell carcinoma is classified as a rare cancer in Japan, and there is a scarcity of evidence for pelvic lymph node dissection, as well as a lack of studies that mention the dissection area. We hypothesized that visualization of lymph nodes and lymph flow using intraoperative ICG fluorescence imaging would indicate the area of dissection and lead to more efficient dissection. In conclusion, intraoperative ICG fluorescence imaging may be useful in this area where there is limited evidence, although there are some limitations. [ABSTRACT FROM AUTHOR]

Salvage surgery for esophageal cancer after definitive chemoradiotherapy (dCRT) is effective, but it is associated with a high rate of perioperative complications. The indications for robot‐assisted minimally invasive esophagectomy (RAMIE) are expanding. However, there are few reports of salvage RAMIE. A 73‐year‐old man was referred to our hospital for residual esophageal cancer with a mediastinal fistula after dCRT. The perioperative diagnosis was T3N1M0‐Stage III, and the salvage RAMIE was performed. Although the dissection was difficult due to fibrosis caused by dCRT and the esophageal mediastinal fistula, RAMIE was performed safely with no complications. Multiple features of RAMIE contributed to stable surgery. The monopolar dissection is effective for hard scar tissue caused by CRT and inflammation. [ABSTRACT FROM AUTHOR]

Simple Summary: In esophageal cancer, the 5-year survival rate for patients who underwent esophagectomy with chemoradiotherapy is poor, with an estimated rate of 32.4%. One reason for this outcome is the low response rate to preoperative chemotherapy or radiotherapy. In this study, we revealed that low-dose chemotherapy or radiotherapy causes malignant phenotypic changes, such as cancer-associated fibroblasts, in normal fibroblasts. Furthermore, radiotherapy-resistant fibroblasts significantly increased the total number of tumors in the peritoneal cavity compared to the control group in peritoneal-disseminated tumor models. Thus, conventional cancer therapy has anti-therapeutic effects via activation of fibroblasts, and it is important to determine which modality of esophageal cancer treatment is selected or combined, recognizing that inappropriate radiotherapy and chemotherapy can lead to tumor resistance. Esophageal cancer is one of the most aggressive tumors, and the outcome remains poor. One contributing factor is the presence of tumors that are less responsive or have increased malignancy when treated with conventional chemotherapy, radiotherapy, or a combination of these. Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Focusing on conventional cancer therapies, we investigated how CAFs acquire therapeutic resistance and how they affect tumor malignancy. In this study, low-dose chemotherapy or radiotherapy-induced normal fibroblasts showed enhanced activation of CAFs markers, fibroblast activation protein, and α-smooth muscle actin, indicating the acquisition of malignancy in fibroblasts. Furthermore, CAFs activated by radiotherapy induce phenotypic changes in cancer cells, increasing their proliferation, migration, and invasion abilities. In in vivo peritoneal dissemination models, the total number of tumor nodules in the abdominal cavity was significantly increased in the co-inoculation group of cancer cells and resistant fibroblasts compared to that in the co-inoculation group of cancer cells and normal fibroblasts. In conclusion, we demonstrated that conventional cancer therapy causes anti-therapeutic effects via the activation of fibroblasts, resulting in CAFs. It is important to select or combine modalities of esophageal cancer treatment, recognizing that inappropriate radiotherapy and chemotherapy can lead to resistance in CAF-rich tumors. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte–macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation. [ABSTRACT FROM AUTHOR]

Studies remain limited on the role of the Pfannenstiel incision in minimally invasive hepato-pancreato-biliary (HPB) surgery, especially robotic surgery. The role of various extraction sites in robotic HPB surgery should be understood. Herein, we describe the surgical techniques, outcomes, advantages, and disadvantages of the Pfannenstiel incision in robotic pancreatic surgery. Seventy patients underwent robotic pancreatectomy at our institution between September 2020 and October 2022. The Pfannenstiel incision was used for specimen retrieval in 55 patients. Advantages of the Pfannenstiel incision include less pain, cosmetic benefits, and a lower incidence of complications. Moreover, the specimen could be removed using the robotic system docked. However, all complex reconstructions should be performed intra-abdominally during robotic pancreatoduodenectomies. The incidence of mortality and postoperative pancreatic fistula (grade B) was 0% and 9.1%, respectively. During the median follow-up (11.2 months) after surgery, complications at the Pfannenstiel incision site included surgical site infection (n = 1, 1.8%) and incisional hernia (n = 1, 1.8%). The Pfannenstiel incision can be a useful option for specimen retrieval in minimally invasive HPB surgery, according to the surgeon's preferences and the patient's condition. [ABSTRACT FROM AUTHOR]

Adenosine-to-inosine RNA editing is a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family. It has been discovered recently as an epigenetic modification dysregulated in human cancers. However, the clinical significance of RNA editing in patients with liver metastasis from colorectal cancer (CRC) remains unclear. The current study aimed to systematically and comprehensively investigate the significance of adenosine deaminase acting on RNA 1 (ADAR1) expression status in 83 liver metastatic tissue samples collected from 36 patients with CRC. The ADAR1 expression level was significantly elevated in liver metastatic tissue samples obtained from patients with right-sided, synchronous, or RAS mutant-type CRC. ADAR1-high liver metastasis was significantly correlated with remnant liver recurrence after hepatic metastasectomy. A high ADAR1 expression was a predictive factor of remnant liver recurrence (area under the curve = 0.72). Results showed that the ADAR1 expression level could be a clinically relevant predictive indicator of remnant liver recurrence. Patients with liver metastases who have a high ADAR1 expression requires adjuvant chemotherapy after hepatic metastasectomy. [ABSTRACT FROM AUTHOR]

Introduction: Gastric cancer is divided into four subtypes by their molecular features linked with genetic alterations, e.g., Epstein-Barr virus (EBV), microsatellite instability-high (MSI-high), chromosomal instability (CIN), and genomically stable (GS), called as TCGA classification. In this study, we tried to clarify the epigenetic features of the four GC subtypes according to aberrant methylation status in 23 loci. Methods: A total of 98 gastric cancers and their normal gastric mucosa samples were included in this study. We divided gastric cancers into TCGA subtypes which were determined in line with MSI-high, EBV, CIN, to GS by their molecular features. The 13 loci of polymorphic microsatellite sequences were used to determine loss of heterogeneity for the detection of CIN. The MSI status was determined by three mononucleotide repeat markers. Infection of EBV was determined by recovering EBV BNRF1 sequence from genomic DNA collected from gastric cancers. Methylation status of 23 loci was investigated by the combined bisulfite restriction analysis. Status of other findings, e.g., KRAS mutations, HER2 expression status, and infection of helicobacter pylori were confirmed. Results: Gastric cancers were divided into MSI (13%), EBV (7%), CIN (53%), and GS (27%). By histological classification, poorly differentiated adenocarcinoma was more in tumors categorized in MSI-high, and GS and signet-ring cell carcinoma (sig) were more in GS. Among the 23 loci investigated their methylation status, 18 loci were significantly hypermethylated in caner tissues. An unsupervised clustering divided gastric cancers into two clusters and revealed that most GS tumors clustered together in a cluster that exhibited lower methylation levels, distinct from the other subtypes. The inter-variable clustering revealed that a cluster contained the three loci (SFRP2-region 1/2 and APC) belonging to the Wnt signal cascade (Wnt-associated loci). The mean methylation score of Wnt-associated loci was the lowest in GS tumors (MSI-high: 2.7 [95% confidence interval, 2.3–2.9]; EBV: 2.1 [1.2–3.1]; CIN: 2.4 [2.2–2.7]; GS: 1.3 [0.8–0.7]). In contrast, the mean methylation score of the other 15 loci was significantly higher in MSI-high, while that in GS was as same as that in EBV or CIN (MSI-high: 10.4 [8.3–12.4]; EBV: 5.7 [1.7–9.7]; CIN: 4.4 [3.6–5.1]; GS: 3.4 [2.2–4.6]). Additionally, the lower methylation score of Wnt-associated loci was observed only in sig tumors. Conclusions: GS subtype tumors have the potential to possess distinct signatures in DNA hypomethylation profiles in Wnt signaling pathway, especially in sig. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Delayed gastric emptying (DGE) is a major complication of pancreatoduodenectomy (PD). Several efforts have been made to decrease the incidence of DGE. However, the optimal anastomotic method for gastro/duodenojejunostomy (GJ) remains debatable. Moreover, few studies have reported the impact of GJ surgical techniques on outcomes following robotic pancreatoduodenectomy (RPD). This study aimed to investigate the surgical outcomes of robot-sewn and stapled GJ anastomoses in RPD. Methods: Forty patients who underwent RPD at the Okayama University Hospital between September 2020 and October 2022 were included. The outcomes between robot-sewn and stapled anastomoses were compared. Results: The mean [standard deviation (SD)] operative and GJ time were 428 (63.5) and 34.0 (15.0) minutes, respectively. Postoperative outcomes included an overall incidence of DGE of 15.0%, and the mean postoperative hospital stays were 11.6 (5.3) days in length. The stapled group (n = 21) had significantly shorter GJ time than the robot-sewn group (n = 19) (22.7 min versus 46.5 min, p < 0.001). Moreover, stapled GJ cases were significantly associated with a lower incidence of DGE (0% versus 21%, p = 0.01). Although not significant, the stapled group tended to have shorter postoperative hospital stays (9.9 days versus 13.5 days, p = 0.08). Conclusions: Our findings suggest that stapled GJ anastomosis might decrease anastomotic GJ time and incidence of DGE after RPD. Surgeons should select a suitable method for GJ anastomosis based on their experiences with RPD. [ABSTRACT FROM AUTHOR]

The concept of the superior mesenteric artery (SMA)-first approach has been widely accepted in pancreatoduodenectomy. However, few studies have reported surgical approaches to the SMA in robotic pancreatoduodenectomy (RPD). Herein, we present our surgical strategies to dissect around the SMA in RPD. Among the various approaches, our standard protocol for RPD included the right approach to the SMA, which can result in complete tumor resection in most cases. In patients with malignant diseases requiring lymphadenectomy around the SMA, we developed a novel approach by combining the left and right approaches in RPD. Using this approach, circumferential dissection around the SMA can be achieved through both the left and right sides. This approach can also be helpful in patients with obesity or intra-abdominal adhesions. The present study summarizes the advantages and disadvantages of both the approaches during RPD. To perform RPD safely, surgeons should understand the different surgical approaches and select the best approach or a combination of different approaches, depending on demographic, anatomical, and oncological factors. [ABSTRACT FROM AUTHOR]

Background: Remnant gastric cancer (RGC) has been increasing for various reasons such as a longer life span, medical progress, and others. It generally has a poor prognosis, and its mechanism of occurrence is unknown. The purpose of this study was to evaluate the clinicopathological features of and clarify the oncological features of RGC. Methods: Between January 2002 and January 2017, 39 patients with RGC following distal gastrectomy underwent curative surgical resection at the Okayama University Hospital; their medical records and immunohistochemically stained extracted specimens were used for retrospective analysis. Results: On univariate analysis, initial gastric disease, pathological lymph node metastasis, and pathological stage were the significant factors associated with poor overall survival (p=0.014, 0.0061, and 0.016, respectively). Multivariate analysis of these 3 factors showed that only initial gastric disease caused by malignant disease was an independent factor associated with a poor prognosis (p=0.014, hazard ratio: 4.2, 95% confidence interval: 1.3–13.0). In addition, tumor-infiltrating CD8+ T cells expression was higher in the benign disease group than in the malignant group (p=0.046). Conclusions: Initial gastrectomy caused by malignant disease was an independent poor prognostic factor of RGC, and as one of the causes, lower level of tumor-infiltrating CD8+ T cells in RGC may involve in. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT, targeting cancer cells and CAFs, could be a therapeutic strategy. A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, P < 0.001 and P = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. We demonstrated the relationship between EGFR/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-targeted NIR-PIT might be a promising therapeutic strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

Survival remains poor even after resection of pancreatic cancer and the postoperative recurrence rate is extremely high. Thus, neoadjuvant treatment may improve outcomes for resectable pancreatic cancer (RPC). This study evaluated the efficacy of neoadjuvant therapy for radiologically judged RPC. A prospectively maintained institutional database was reviewed to identify patients who underwent potentially curative resection of radiologically judged RPC. Patient characteristics and intermediate-term outcomes were compared between groups that received neoadjuvant treatment or upfront surgery (UFS). We identified 353 eligible patients, including 55 patients who received neoadjuvant chemoradiotherapy (CRT group), 53 patients who received neoadjuvant gemcitabine plus nab-paclitaxel (GnP group), and 245 patients who underwent UFS (UFS group). The cumulative rates of pancreatic cancer recurrence at 2 years after pancreatic surgery were 49.5% in the UFS, 48.1% in the CRT group, and 52.7% in the GnP group. The recurrence rate tended to be improved after neoadjuvant treatment, although the difference was not significant at this follow-up point. While the clinical TNM classifications were noticeably different from the final pathological findings, the clinical and pathological TNM classifications were more similar in the groups that underwent neoadjuvant treatment. Neoadjuvant treatment can help identify good surgical candidates and avoid unnecessary laparotomy. Our results also suggest that neoadjuvant therapy might help improve the preoperative diagnostic accuracy for patients with RPC. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence indicates that immunogenicity plays an important role in intrahepatic cholangiocarcinoma (ICC). Herein, we systematically evaluated the clinical relevance of immunogenicity in ICC.Methods: Highly immunogenic ICCs identified in the public dataset and the Cancer Immunome Atlas (TCIA) were assessed to determine the prognostic impact of immunogenicity in ICC and key components after curative resection. We also investigated the clinical relevance of the immune milieu in ICC.Results: Using the Gene Expression Omnibus dataset 89749 and TCIA, we identified CD8+/forkhead box P3 (FoxP3)+ tumour-infiltrating lymphocytes (TILs), T-cell immunoglobulin and mucin domain 3 (TIM-3) and human leukocyte antigen-A (HLA-A) in highly immunogenic ICCs. Immunohistochemical analysis of the in-house cohort showed that intratumoral FoxP3+ TILs correlated with CD8+ TILs (P = 0.045, Fisher's exact test) and that high FoxP3+/CD8+ ratio (FCR) was an important marker for poor survival (P < 0.001, log-rank test). Furthermore, the FCR was higher in tumour-free lymph nodes in ICCs with lymph node metastases than in those without lymph node metastases (P = 0.003, Mann-Whitney U test).Conclusions: FCR should be considered an important biomarker that represents the immune environment of ICC based on its potentially important role in tumour progression, especially lymph node metastasis. [ABSTRACT FROM AUTHOR]

Background: Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking. Methods: We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort. Results: In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50–1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74–1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28–0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53–1.07). Conclusion: Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC. [ABSTRACT FROM AUTHOR]

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability–high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p < 0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p < 0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX–CRT regimen. CRT can promote proteomic diversity via RNA editing. [ABSTRACT FROM AUTHOR]

Purpose: To investigate if early exercise can help prevent skeletal muscle loss and improve the clinical outcomes of esophageal cancer patients receiving preoperative neoadjuvant chemotherapy (NAC). Methods: This was a single-center, retrospective observational cohort study of 110 patients with advanced esophageal cancer. We analyzed the effect of early exercise on the risk of skeletal muscle loss (defined as > 2.98%) during NAC and the subsequent clinical outcomes. Patients in the early exercise group (n = 71) started exercise therapy 8 days earlier than those the late exercise group (n = 39). Results: The median age of the patients was 65.4 years, the mean BMI was 21.1 kg/m2, and 92 (84%) of the 110 patients were men. Skeletal muscle loss occurred in 34% and 67% of the early and late exercise groups, respectively (p < 0.001). There was a lower risk of surgical site infection in the early exercise group (1% vs 16%, p = 0.021). Multivariate analysis revealed that early exercise reduced the risk of skeletal muscle loss (OR = 0.25, 95% CI 0.09–0.65, p = 0.006). Conclusions: Our results suggest that early exercise reduces the risk of both skeletal muscle loss during NAC and subsequent surgical site infection in patients with esophageal cancer. [ABSTRACT FROM AUTHOR]

The reconstruction procedure was almost the same as in LTG, whereas the assistant surgeon carried out procedures such as resection and suturing using the LS. This method prevents unintentional suturing of the posterior wall because the anterior walls of the esophagus and jejunum are only sutured after being lifted and thus clearly separated from the posterior wall. [Extracted from the article]

Minimally invasive spleen-preserving distal pancreatectomy (SPDP) is technically challenging, and only a few reports have described surgical approaches for minimally invasive SPDP. This report demonstrates our novel gastrohepatic ligament approach in robotic SPDP with preservation of the splenic vessels (the superior window approach in the Kimura technique). Our gastrohepatic ligament approach for robotic SPDP included four steps. First, the gastrohepatic ligament was divided extensively, and the pancreas was confirmed (step 1). In this step, we did not lift the stomach, nor did we divide the gastrocolic ligament. Next, the superior and inferior borders of the pancreas were dissected, and the tunneling of the pancreas on the superior mesenteric vein was performed (step 2). Following the division of the pancreas (step 3), the pancreatic body and tail were dissected from the medial to the lateral side with preservation of the splenic vessels (step 4). Using this approach, the pancreas can be directly accessed via the gastrohepatic ligament route and dissected without division of the gastrocolic ligament or retraction of the stomach. The present approach for robotic SPDP preserves splenic vessels, facilitating easy access to the pancreas with minimal dissection, and may be optional in selected patients, including those with low body mass index. [ABSTRACT FROM AUTHOR]

Background: The optimal management for peritoneal dissemination in patients with hepatocellular carcinoma remains unclear. Although several reports have described the usefulness of surgical resection, the indications should be carefully considered. Herein, we report the case of a patient with hepatocellular carcinoma with peritoneal recurrence who underwent surgical resection using an indocyanine green fluorescence navigation system and achieved favorable disease control.Case Presentation: A 45-year-old Asian woman underwent left hemihepatectomy for a ruptured hepatocellular carcinoma. Seventeen months after the initial surgery, a single nodule near the cut surface of the liver was detected on computed tomography, along with elevation of tumor markers. The patient was diagnosed with peritoneal metastasis and underwent a surgical resection. Twelve months later, a single nodule on the dorsal side of the right hepatic lobe was detected on computed tomography, and we performed surgical resection. Indocyanine green (0.5 mg/kg) was intravenously administered 3 days before surgery, and the indocyanine green fluorescence imaging system revealed clear green fluorescence in the tumor, which helped us perform complete resection. Indocyanine green fluorescence enabled the detection of additional lesions that could not be identified by preoperative imaging, especially in the second metastasectomy. There was no further recurrence at 3 months postoperatively.Conclusion: When considering surgical intervention for peritoneal recurrence in patients with hepatocellular carcinoma, complete resection is mandatory. Given that disseminated nodules are sometimes too small to be detected by preoperative imaging studies, intraoperative indocyanine green fluorescence may be an essential tool for determining the indications for surgical resection. [ABSTRACT FROM AUTHOR]

Purpose: Centralization of high-risk surgeries has become a widespread strategy. However, whether or not the hospital volume affects the outcomes of common surgeries remains unclear. This study explored the association between hospital volume and short-term outcomes of common surgeries, as represented by appendectomy, cholecystectomy, and pneumothorax surgery, by analyzing data from a Japanese nationwide database. Methods: All hospitals were categorized into four groups (very low-, low-, high-, and very high-volume) according to the annual hospital volume of all gastrointestinal surgeries or all respiratory surgeries in 2017. Patient demographic data and surgical outcomes were evaluated across hospital volume categories. Results: We analyzed 2392 facilities which performed 771,182 gastrointestinal surgeries, and 992 facilities which performed 98,656 respiratory surgeries. Short-term outcomes of patients who underwent appendectomy (n = 50,568), cholecystectomy (n = 104,262), and pneumothorax surgery (n = 11,723) were evaluated. The incidences of postoperative complications, reoperation, and readmission were similar among the groups. Multivariable logistic regression analyses revealed hospital volume to have no association with these short-term outcomes. Conclusion: Analyses of a Japanese nationwide database revealed that the hospital volume was not associated with short-term outcomes of appendectomy, cholecystectomy, and pneumothorax surgery. These common surgical procedures may not require centralization into high-volume hospitals. [ABSTRACT FROM AUTHOR]

Background: Adenomatoid mesothelioma is a rare subtype of malignant mesothelioma that can be confused with adenomatoid tumors, which are classified as benign. The clinical features and optimal management of adenomatoid mesothelioma have not been elucidated in the literature. In this report, we present an extremely rare case of adenomatoid mesothelioma that developed on the peritoneal surface of the diaphragm as well as a literature review of adenomatoid mesothelioma in the abdominal cavity.Case Presentation: The patient was a 61-year-old Japanese woman who had undergone resection of a malignant peripheral nerve sheath tumor of the hand 18 years prior. She was diagnosed with clinical stage I lung adenocarcinoma on follow-up chest radiography. Simultaneously, a 20-mm enhancing nodule with slow growth on the right diaphragm was detected on contrast-enhanced computed tomography. She presented no specific clinical symptoms. At this point, the lesion was suspected to be a hypervascular tumor of borderline malignancy, such as a solitary fibrous tumor. After a left upper lobectomy for lung adenocarcinoma, she was referred to our department, and laparoscopic tumor resection was performed. Adenomatoid tumors were also considered based on the histopathological and immunohistochemical analyses, but we made the final diagnosis of adenomatoid mesothelioma using the results of the genetic profile. The patient remains alive, with no recurrence noted 6 months after surgery.Conclusion: We encountered a valuable case of adenomatoid mesothelioma of peritoneal origin. There are some previously reported cases of adenomatoid mesothelioma and adenomatoid tumors that may need to be recategorized according to the current classification. It is important to accumulate and share new findings to clarify the clinicopathological characteristics and genetic status of adenomatoid mesothelioma. [ABSTRACT FROM AUTHOR]

Background: The international consensus guidelines for intraductal papillary mucinous neoplasm of the pancreas (IPMN) presented clinical features as indications for surgery. Whereas surveillance for recurrence, including de novo lesions, is essential, optimal surveillance protocols have not been established. Aim and methods: This study aimed to assess the clinical features of recurrence at the remnant pancreas (Rem-Panc) and extra-pancreas (Ex-Panc) after surgery for IPMN. Ninety-one patients of IPMN that underwent detailed preoperative assessment and pancreatectomy were retrospectively analyzed, focusing especially on the type of recurrence. Results: The IPMNs were finally diagnosed as low-grade dysplasia (LDA, n = 42), high-grade dysplasia (HAD, n = 19), and invasive carcinoma (IPMC, n = 30). Recurrence was observed in 26 patients (29%), of which recurrence was seen at Rem-Panc in 19 patients (21%) and Ex-Panc in 7 patients (8%). The frequency of Rem-Panc recurrence was 10% in LDA, 21% in HDA, and 37% in IPMC. On the other hand, Ex-Panc recurrence was observed only in IPMC (23%). Ex-Panc recurrence showed shorter median recurrence-free survival (RFS) and overall survival (OS) than Rem-Panc recurrence (median RFS 8 months vs. 35 months, p < 0.001; median OS 25 months vs. 72 months, p < 0.001). Regarding treatment for Rem-Panc recurrence, repeat pancreatectomy resulted in better OS than no repeat pancreatectomy (MST 36 months vs. 15.5 months, p = 0.033). On multivariate analysis, main duct stenosis or disruption as a preoperative feature (hazard ratio [HR] 10.6, p = 0.002) and positive surgical margin (HR 4.4, p = 0.018) were identified as risk factors for Rem-Panc recurrence. Conclusions: The risk factors for Rem-Panc and Ex-Panc recurrence differ. Therefore, optimal surveillance on these features is desirable to ensure that repeat pancreatectomy for Rem-Panc recurrence can be an appropriate surgical intervention. [ABSTRACT FROM AUTHOR]

Background: The international consensus guidelines for intraductal papillary mucinous neoplasm of the pancreas (IPMN) presented clinical features as indications for surgery. Whereas surveillance for recurrence, including de novo lesions, is essential, optimal surveillance protocols have not been established.Aim and Methods: This study aimed to assess the clinical features of recurrence at the remnant pancreas (Rem-Panc) and extra-pancreas (Ex-Panc) after surgery for IPMN. Ninety-one patients of IPMN that underwent detailed preoperative assessment and pancreatectomy were retrospectively analyzed, focusing especially on the type of recurrence.Results: The IPMNs were finally diagnosed as low-grade dysplasia (LDA, n = 42), high-grade dysplasia (HAD, n = 19), and invasive carcinoma (IPMC, n = 30). Recurrence was observed in 26 patients (29%), of which recurrence was seen at Rem-Panc in 19 patients (21%) and Ex-Panc in 7 patients (8%). The frequency of Rem-Panc recurrence was 10% in LDA, 21% in HDA, and 37% in IPMC. On the other hand, Ex-Panc recurrence was observed only in IPMC (23%). Ex-Panc recurrence showed shorter median recurrence-free survival (RFS) and overall survival (OS) than Rem-Panc recurrence (median RFS 8 months vs. 35 months, p < 0.001; median OS 25 months vs. 72 months, p < 0.001). Regarding treatment for Rem-Panc recurrence, repeat pancreatectomy resulted in better OS than no repeat pancreatectomy (MST 36 months vs. 15.5 months, p = 0.033). On multivariate analysis, main duct stenosis or disruption as a preoperative feature (hazard ratio [HR] 10.6, p = 0.002) and positive surgical margin (HR 4.4, p = 0.018) were identified as risk factors for Rem-Panc recurrence.Conclusions: The risk factors for Rem-Panc and Ex-Panc recurrence differ. Therefore, optimal surveillance on these features is desirable to ensure that repeat pancreatectomy for Rem-Panc recurrence can be an appropriate surgical intervention. [ABSTRACT FROM AUTHOR]

A 43-year-old female underwent pelvic magnetic resonance imaging for uterine myoma that incidentally revealed a 4.6 × 2.8 cm soft tissue mass in the anorectal region. Rectal endoscopy showed a submucosal tumor just above the anal canal. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed an anorectal tumor with very high FDG uptake. Aspiration cytology and needle biopsy were inconclusive, and the patient underwent trans-perineal tumor resection. The excised tumor was a 4.6 × 3.5 × 2.7 cm gray–white bifurcated nodular tumor. Light microscopy revealed fenestrated growth of poorly dysmorphic short spindle-shaped cells with eosinophilic sporophytes. Immunohistochemical staining was positive for αSMA and desmin, negative for CD117 (KIT) and S100, and the patient was diagnosed with benign leiomyoma. Tumor cells were also positive for glucose transporter-1 (GLUT1) immunohistochemically. It is important to keep in mind that FDG-PET/CT may show false-positive results even in benign anal leiomyoma for various reasons, including GLUT1 overexpression. [ABSTRACT FROM AUTHOR]

This article, published in the Journal of Gastrointestinal Surgery, discusses the use of the right posterior superior mesenteric artery (SMA) approach in robotic pancreaticoduodenectomy (RPD). The authors describe the technical aspects of this approach, which involves dissecting the posterior, right, and anterior sides of the SMA to detach the pancreatic neck from the mesenteric vessels. They highlight the advantages of this approach, such as early identification of SMA and superior mesenteric vein involvement, and adequate retropancreatic lymphadenectomy. However, they also note that there may be technical difficulties in patients with peripancreatic inflammation and adhesions around the pancreatic head. The authors conclude that surgeons should choose the best approach based on demographic, anatomical, and oncological factors. [Extracted from the article]

Purpose: Although D2 lymphadenectomy is currently considered a standard procedure for advanced gastric cancer (GC) worldwide, there is room for discussion about the appropriate range of suprapancreatic D2 lymphadenectomy. Focusing on the posterior hepatic plexus (PHP), which is not well recognized, we developed a surgical technique of suprapancreatic D2 lymphadenectomy, which we have called PHP-D2, and its short-term and long-term efficacies were evaluated in comparison with non-PHP-D2. Methods: GC patients who underwent distal gastrectomy with D2 lymphadenectomy between July 2006 and May 2013 were enrolled, from which patients who had peritoneal metastasis and/or were peritoneal cytology-positive during surgery were excluded. Their medical records were retrospectively reviewed. Results: Ninety-two patients (non-PHP-D2: 48, PHP-D2: 44) were enrolled. Shorter operation time (330 min vs 275 min, p < 0.0001) and less blood loss (290 mL vs 125 mL, p < 0.0001) were observed in PHP-D2, and no pancreatic fistulas were observed in PHP-D2. More lymph nodes of #11p (1 vs 1.5, p = 0.0328) and #12a lymph nodes (0 vs 1, p = 0.0034) were retrieved in PHP-D2, with no significant differences in #8a and #9 lymph nodes. Lymphatic recurrence was significantly less in PHP-D2 (p = 0.0166), and univariate and multivariate analyses showed that non-PHP-D2 was a significant risk factor for lymphatic recurrence (p = 0.0158), although there were no significant differences between non-PHP-D2 and PHP-D2 in 5-year overall survival and 5-year relapse-free survival. Conclusion: PHP-D2 was a safe and feasible procedure that had the potential to reduce lymphatic recurrence, and it can be a standard procedure of D2 lymphadenectomy for advanced GC. [ABSTRACT FROM AUTHOR]

Background: To aid in the oncological management of multiple bilobar colorectal liver metastases (CRLMs), we describe a new surgical procedure, VEssel-Skeletonized PArenchyma-sparing Hepatectomy (VESPAH). Study design: Of 152 patients with CRLMs treated with hepatectomy, 33 patients had multiple bilobar liver metastases (≥8 liver metastases); their surgical procedures and clinical outcomes were retrospectively summarized and compared between those who underwent VESPAH and those who underwent major hepatectomy (Major Hx). Results: Of the 33 patients, 20 patients were resected by VESPAH (the VESPAH group) and 13 patients by major hepatectomy (Major Hx group). The median number of CRLMs was 13 (range, 8–53) in the VESPAH group and 10 (range, 8–41) in the Major Hx group (P=0.511). No operative mortality nor severe morbidity was observed in either group. The VESPAH group showed earlier recovery of remnant liver function after surgery than the Major Hx group; the incidence of grade B/C post hepatectomy liver failure was 5% in the VESPAH group and 38% in the Major Hx group, P=0.048). Intrahepatic tumor recurrence was confirmed in 14 (70%) and 7 (54%) patients in the VESPAH and Major Hx groups, respectively (P=0.416). There was no significant difference in median overall survival (OS) after hepatectomy between the two groups; the median OS was 47 months in the VESPAH group and 33 months in the Major Hx group (P=0.481). The VESPAH group showed the higher induction rate of adjuvant chemotherapy within 2 months after surgery (P=0.002) and total number of repeat hepatectomy for intrahepatic recurrence (P=0.060) than the Major Hx group. Conclusions: VESPAH enables us to clear surgical navigation by hepatic vessel skeletonization and may enhance patient tolerability of not only adjuvant chemotherapy but also repeat hepatectomies during the patients' lifetimes. [ABSTRACT FROM AUTHOR]

Background and Aim: Recently, artificial intelligence (AI) has been used in endoscopic examination and is expected to help in endoscopic diagnosis. We evaluated the feasibility of AI using convolutional neural network (CNN) systems for evaluating the depth of invasion of early gastric cancer (EGC), based on endoscopic images. Methods: This study used a deep CNN model, ResNet152. From patients who underwent treatment for EGC at our hospital between January 2012 and December 2016, we selected 100 consecutive patients with mucosal (M) cancers and 100 consecutive patients with cancers invading the submucosa (SM cancers). A total of 3508 non‐magnifying endoscopic images of EGCs, including white‐light imaging, linked color imaging, blue laser imaging‐bright, and indigo‐carmine dye contrast imaging, were included in this study. A total of 2288 images from 132 patients served as the development dataset, and 1220 images from 68 patients served as the testing dataset. Invasion depth was evaluated for each image and lesion. The majority vote was applied to lesion‐based evaluation. Results: The sensitivity, specificity, and accuracy for diagnosing M cancer were 84.9% (95% confidence interval [CI] 82.3%–87.5%), 70.7% (95% CI 66.8%–74.6%), and 78.9% (95% CI 76.6%–81.2%), respectively, for image‐based evaluation, and 85.3% (95% CI 73.4%–97.2%), 82.4% (95% CI 69.5%–95.2%), and 83.8% (95% CI 75.1%–92.6%), respectively, for lesion‐based evaluation. Conclusions: The application of AI using CNN to evaluate the depth of invasion of EGCs based on endoscopic images is feasible, and it is worth investing more effort to put this new technology into practical use. [ABSTRACT FROM AUTHOR]

Multidisciplinary therapy centered on radical surgery for resectable pancreatic cancer is expected to prolong prognosis, but relies on CA19-9 biomarker levels to determine treatment strategy. Boron neutron capture therapy (BNCT) is a chemoradiotherapy using tumor hyperaccumulator boron drugs and neutron irradiation. The purpose of this study is to investigate novel boron drug agents for BNCT for pancreatic cancer. Bioinformatics was used to evaluate the uptake of current boron amino acid (BPA) drugs for BNCT into pancreatic cancer. The expression of the amino acid transporter LAT1, a BPA uptake transporter, was low in pancreatic cancer and even lower in high CA19-9 pancreatic cancer. In contrast, the glucose transporter was high in high CA19-9 pancreatic cancers and inversely correlated with LAT1 expression. Considering the low EPR effect in pancreatic cancer, we synthesized a small molecule Glucose-BSH, which is boron BSH bound to glucose, and confirmed its specific uptake in pancreatic cancer. uptake of Glucose-BSH was confirmed in an environment compatible with the tumor microenvironment. The therapeutic efficacy and safety of Glucose-BSH by therapeutic neutron irradiation were confirmed with BNCT. We report Glucose-BSH boron drug discovery study of a Precision Medicine BNCT with application to high CA19-9 pancreatic cancer. • Boron neutron capture therapy (BNCT) is a chemoradiotherapy using boron agents and neutron irradiation; the cancer accumulation capacity of boron agents is the key to its application in pancreatic cancer. • We successfully developed a boron-based drug targeting a glucose transporter that is highly expressed in pancreatic cancer. • BNCT using the sugar-binding boron drug developed in this study is a novel therapy as BNCT targeting pancreatic cancer with high CA19-9 levels. [ABSTRACT FROM AUTHOR]