Multicenter Prospective Cohort Study of Neoadjuvant Chemotherapy for Borderline Resectable Pancreatic Cancer (YPB-001).

OBJECTIVES: The present multicenter prospective observational study investigated the effectiveness and safety of neoadjuvant chemotherapy (NAC) for patients with borderline resectable pancreatic cancer (BRPC) and those with RPC contacting major vessels, with respect to a historical control of upfront surgery. MATERIALS AND METHODS: Patients with BRPC and RPC contacting major vessels were prospectively registered and administered NAC with durations and regimens determined by the corresponding treating physician. Our primary aim was to assess the R0 resection rate, and secondary aim was to evaluate safety, resection rate, time to treatment failure, overall survival, and response rate. RESULTS: Fifty of 52 enrolled patients were analyzed; 2 with serious comorbidities died during treatment. Thirty-one patients underwent resection, with R0 resection being achieved in 26 (52% of total and 84% of all resected cases). Univariate and multivariate analyses indicated age (≥75 years) as the only independent predictor of nonresection. Median progression-free survival and median survival time were longer in the prospective cohort than in the historical cohort. CONCLUSIONS: Overall, NAC for BRPC in real-world setting might yield R0 resection rates similar to those reported in previous clinical studies. Development of safe regimens and management strategies that can maintain treatment intensity in geriatric patients is warranted.

Laparoscopic-assisted thoracoscopic repair of latent traumatic diaphragmatic hernia: A case report.

Surgical approaches for traumatic diaphragmatic hernia include transabdominal, transthoracic, and thoracoabdominal. Selection of the optimal approach depends on the timing and organ damage, often minimally invasive approaches with laparoscopy or thoracoscopy are performed. A 47-year-old man with blunt chest trauma was diagnosed with left traumatic diaphragmatic hernia 1 month after the trauma. The prolapsed omentum was detached from the chest wall and around the hernia orifice and returned to the abdominal cavity by coordinated thoracoscopic and laparoscopic manipulations. The 4 × 2 cm herniation in the diaphragm was sutured closed from the thoracic side while preventing re-prolapse of the omentum and abdominal organs from the abdominal side. A combined thoracoscopic and laparoscopic approach can be effective in confirming organ damage, repositioning of prolapsed organs, and safe repair of the diaphragm in latent traumatic diaphragmatic hernia.

Allogenic multilayered fibroblast sheets promote anastomotic site healing in a rat model of esophageal reconstruction.

OBJECTIVE: Anastomotic leakage is a common and severe complication of esophageal reconstruction. Accordingly, there is a clinical need for novel methods to prevent it. We developed multilayered, growth factor-secreting fibroblast sheets that promote wound healing and angiogenesis. The present study aimed to assess the utility of allogenic multilayered fibroblast sheets in preventing esophageal anastomotic leakage in a rat model of esophageal reconstruction. METHODS: Allogenic multilayered fibroblast sheets prepared from oral mucosal tissues were implanted at esophageal anastomotic sites. RESULTS: The allogenic multilayered fibroblast sheet group had significantly higher burst pressure and collagen deposition compared to a control group five days postoperatively. The expression levels of collagen type I and III mRNAs around esophageal suture sites were higher in the allogenic multilayered fibroblast sheet group compared to the control group on postoperative days 0, 3, and 5. There was a trend toward lower anastomotic leakage and lower abscess scores in the allogenic multilayered fibroblast sheet group compared to the control group; however, these differences did not reach statistical significance. Allogenic multilayered fibroblast sheets completely disappeared at ten days after implantation. Further, no inflammation was observed at suture sites with implanted allogenic multilayered fibroblast sheets at five days after surgery. CONCLUSION: Allogenic multilayered fibroblast sheets may represent a promising method of preventing esophageal anastomotic leakage.

A case of multiple glucagonomas with no clinical manifestations of excess glucagon despite hyperglucagonemia.

Herein we report the case of a patient with multiple glucagonomas that have been precisely described with endoscopic ultrasound. A 36-year-old woman was referred to our hospital for computed tomography investigation of multiple pancreatic masses. Physical examination was unremarkable; on contrast-enhanced computed tomography, mass lesions were evident in the head, body, and tail of the pancreas. The mass in the pancreatic head was poorly demarcated and exhibited a faint contrast effect, the one in the pancreatic body was a cystic lesion, and the one in the pancreatic tail was hypervascular. Blood investigations showed that serum glucagon was abnormally high at 7670 pg/ml; glucose tolerance was not impaired. There was no family history that suggested multiple endocrine neoplasia type 1 or von Hippel-Lindau disease. Endoscopic ultrasound revealed that there were additional masses, which were scattered isoechoic to hyperechoic lesions a few millimeters in size. Ultrasound-guided fine needle biopsy of the lesion in the pancreatic tail resulted in a diagnosis of a neuroendocrine tumor. Based on these pathologic findings, we performed a total pancreatectomy. A large number of nodules with tumor cells were evident in all cut surfaces of the surgical specimen. Immunostaining was positive for chromogranin A and glucagon, and glucagonoma was therefore diagnosed. It is conceivable that attenuated glucagon action could have contributed to the development of the multiple glucagonomas.

Portal vein embolization via the ipsilateral percutaneous transhepatic approach versus laparotomic transileocecal approach: complications, profile and changes in future liver remnant volume.

OBJECTIVE: Major liver resection is an effective treatment option for patients with liver malignancy. The future liver remnant (FLR) volume and complications after portal vein embolization (PVE) were compared between the ipsilateral right portal vein (PTPE) and transileocolic (TIPE) approaches. METHODS: A total of 42 patients (TIPE, n = 22; PTPE, n = 20) underwent right lobectomy after PVE. CT and hepatobiliary scintigraphy were repeated before and after PVE. The blood examination findings and the FLR values (FLRCT: calculated from CT, %FLRCT: FLRCT ratio, %FLRSPECT: FLR ratio using single photon emission CT, FLRCT/BS: FLRCT to body surface ratio) were compared between two approach sites. The complications and mortality were also analyzed after PVE and major right hepatectomy. RESULTS: There were no significant differences in the patient characteristics, blood examination findings or FLR values between two groups. Adequate liver regeneration was observed without significant differences between PTPE and TIPE (increased ratio of FLRCT: 8.7% vs 19.2%, p = 0.15 [25-75 percentile: 17.1-60.4], %FLRCT: 11.2% vs 8.3%, p = 0.25 [6.3-13.3], %FLRSPECT: 15.4% vs 19.2%, p = 0.09 [16.0-22.4], FLRCT/BS: 33.6% vs 47.1%, p = 0.19 [17.2-60.4], respectively), but TIPE required a significantly longer procedure time than PTPE [181.4 min vs 108.7 min, p < 0.01 (103.3-193.5)]. However, one patient was converted to TIPE due to bleeding during PTPE. After right lobectomy, portal vein stenosis or thrombosis was noted in three patients [two with TIPE (9.1%) and one with PTPE (5%)] and three TIPE patients died within 90 days (13.6%) after right hepatectomy. CONCLUSION: FLR volume significantly increased after PVE, regardless of the approach sites; however, PTPE is a useful technique with a shorter procedure time.

[Questionnaire Survey of Treatment Strategies for Gastric Cancer with Peritoneal Dissemination in Yamaguchi Prefecture].

The questionnaire survey was conducted on treatment strategies for gastric cancer with peritoneal dissemination at 7 institutions, including 5 designated cancer hospitals in Yamaguchi prefecture. Staging laparotomy was performed at 6 out of 7 institutions. Six out of 7 institutions selected the treatment strategy for P0CY1 cases", upfront resection and adjuvant therapy". The doublet chemotherapy was performed by S-1 plus platinum or taxane. Surgical treatment for P1 cases, conversion gastrectomy was considered at all institutions when it was judged that R0 resection was possible after induction chemotherapy. Chemotherapy for P1 cases was treated according to the guidelines at all institutions, and the regimen was not changed depending on the peritoneal dissemination.

Autologous transplantation of multilayered fibroblast sheets prevents postoperative pancreatic fistula by regulating fibrosis and angiogenesis.

INTRODUCTION: Postoperative pancreatic fistula (POPF) is a serious complication after gastrointestinal or pancreatic surgery. Despite intensive investigations, the occurrence has not significantly decreased in the past decades. The aims of this study were to clarify the pathophysiology of POPF and establish the preventive measures using multilayered fibroblast sheets. METHODS: We developed a pancreatic fistula (PF) model of rat with transection of the splenic duct and surrounding pancreatic parenchyma. Multilayered fibroblast sheets prepared from tails were autologously transplanted to this model. The preventive effect was biochemically and histologically evaluated by measuring the ascitic levels of pancreatic enzymes and conducting immunohistochemistry and real-time polymerase chain reaction analyses of pancreatic tissue. Findings were compared to those obtained with acellular materials simply sealing the wound. RESULTS: In the PF model, the ascitic levels of pancreatic enzymes were transiently up-regulated. Inflammation and necrosis were histologically observed in a wide range. Islets were damaged even in remote areas. Transplantation of multilayered fibroblast sheets dramatically reduced the ascitic leakage of enzymes, suppressed inflammation, and broadly preserved the islets. Compared with acellular materials, these sheets offered superior prevention of cellular activity through the spaciotemporal regulation of fibrosis and angiogenesis. Notably, the leakage hole appeared to have been plugged with the fibrotic matrix, which might have been the most crucial mechanism minimizing pancreatic damage. CONCLUSIONS: The autologous transplantation of multilayered fibroblast sheets significantly prevented PF and protected the pancreas, underscoring the potential utility of this approach for POPF prevention.

Nuclear ß-catenin expression is positively regulated by JAB1 in human colorectal cancer cells.

Wnt/ß-catenin signaling is important for development and progression of colorectal cancer (CRC). The degradation complex for ß-catenin is functionally impaired in CRC cells, thereby resulting in the accumulation of ß-catenin and its translocation into the nucleus. Nuclear ß-catenin interacts with and co-activates T cell factor4 (TCF4), resulting in ß-catenin/TCF4-dependent transcription. Therefore, nuclear ß-catenin has been categorized as the main driving force in the tumorigenesis of CRC. Recent studies reveal that Jun activation domain-binding protein 1 (JAB1) enhances the degradation of seven in absentia homolog-1 (SIAH-1), a putative E3 ubiquitin ligase of ß-catenin, and positively regulates the expression of total ß-catenin in human CRC cells. An another recent study also shows that nuclear ß-catenin is ubiquitinated and degraded by an E3 ubiquitin ligase, tripartite motif-containing protein 33 (TRIM33). However, the regulatory mechanism for the expression of nuclear ß-catenin remains to be fully understood. In this study, we have demonstrated that JAB1 positively regulates the expression of nuclear ß-catenin, c-MYC as a ß-catenin/TCF4 target, and cell cycle regulators, such as Ki-67 and topoisomerase IIα, in human CRC cells. Taken together, these results suggest that JAB1 is considered as a promising target for novel CRC therapy.

[Questionnaire Survey of Third-Line Chemotherapy for Gastric Cancer in Yamaguchi Prefecture].

A questionnaire survey was conducted on third-line chemotherapy of unresectable or recurrent gastric cancer for 23 doctors involved in gastric cancer treatment in Yamaguchi prefecture. Eighty-seven% of doctors replied that third-line chemotherapy transfer rate was less than 60% of patients, and 13% of doctors replied that third-line chemotherapy transfer rate was more than 60% of patients. Nivolumab was the first-choice regimen for third-line chemotherapy, with 87% of doctors, 4% of doctors each for CPT-11, trifluridine/tipiracil hydrochloride, and docetaxel. Timing of switching from the second-line therapy to the third-line therapy, RECIST PD was the highest in 61% of doctors, with other baseline PD in 43% of doctors, clinical PD in 43% of doctors, and tumor marker elevation in 39% of doctors. The timing of regimen switching after using the immune checkpoint inhibitor was PD at the first CT in 43% of doctors, PD at the second CT in 43% of doctors. Nivolumab was used as the first-choice in more than 80% of the regimens for gastric cancer third-line chemotherapy in Yamaguchi prefecture. There was a difference in consciousness among doctors regarding the timing of switching from second- line to third-line chemotherapy and the timing of switching from nivolumab to fourth-line therapy.

Establishment of a Screening Method for Epstein-Barr Virus-Associated Gastric Carcinoma by Droplet Digital PCR.

BACKGROUND: Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is classified as one of the molecular subtypes of gastric cancer. We used droplet digital polymerase chain reaction (ddPCR) to enable highly sensitive and quantitative detection of EBV. METHODS: EBV-DNA load was calculated based on the copy number of the BamH1-W fragment of EBV by ddPCR, and the cut-off value of EBV-DNA load was set. We conducted both ddPCR and EBER1 ISH to examine whether their results coincided in 158 gastric cancer specimens of unknown EBV status. We prepared 26 biopsy specimens and 49 serum samples including EBVaGC and assayed them by ddPCR. RESULTS: The median values of EBV-DNA load for EBVaGC and EBV-negative control were 17.0 and 0.00308, respectively. A cut-off value of 0.032 was determined for which the sensitivity was 1. Among the 158 gastric cancer specimens, 14 lesions were judged as EBV-positive by the 0.032 cut-off value determined by ddPCR. The results of ddPCR and EBER1 ISH were in complete agreement. Even when using a biopsy specimen as a sample for ddPCR, the EBV-DNA load of all EBVaGCs was larger than the cut-off value. CONCLUSIONS: We established a new method of diagnosing EBVaGC from tissue samples by ddPCR.

Determination of thymidine phosphorylase expression level facilitates recurrence risk stratification in stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines.

The present study aimed to prospectively clarify the prognostic effect of the expression of several genes that are known to modulate 5-fluorouracil effects in 63 patients who underwent curative resection for stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines between 2008 and 2012. Thymidine phosphorylase (TP) expression in primary tumours was significantly lower in the recurrence group compared with the no-recurrence group (P=0.03), whereas, expression levels of genes that encoded thymidylate synthase, dihydropyrimidine dehydrogenase, folylpolyglutamate synthase, γ-glutamyl hydrolase and dihydrofolate reductase were not statistically different in tumours from the recurrence and no-recurrence groups. In the multivariate analysis using stepwise Cox proportional hazards regression, the following factors were significantly associated with shorter relapse-free survival following adjuvant chemotherapy with oral fluoropyrimidines: Venous invasion [present; hazard ratio (HR)=6.51; 95% confidence interval (CI): 1.55-27.4; P=0.01), Tumour-Node-Metastasis stage (3b; HR=6.18; 95% CI: 1.36-28.2; P=0.02) and TP expression (low; HR=9.61; 95% CI: 1.81-51.0; P=0.04). Patients with two or more risk characteristics had significantly shorter 5-year relapse-free survival compared with patients with one or no risk characteristics (55.8 vs. 91.8%; log-rank P=0.0006). We concluded that low TP expression is an independent predictive factor for poor prognosis in colorectal cancer. Therefore, determining TP expression may help to improve recurrence risk stratification in patients with stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines.

Perioperative variations in indices derived from noninvasive assessments to detect postmastectomy lymphedema.

OBJECTIVE: This study aimed to clarify the variations in indices derived from noninvasive assessments for the early detection of postmastectomy lymphedema (LE) from 1 month preoperatively until 2 years postoperatively. METHODS: In total, 120 patients who underwent surgery for breast cancer in our institution were prospectively followed up with a questionnaire for arm swelling as well as with tape measurements, bioimpedance analysis (BIA), and skin and subcutaneous tissue ultrasound at 1 month before and 3, 6, 12, 18, and 24 months after surgery. RESULTS: Ninety-seven patients completed the study. Among 93 patients who did not present with LE, 9% complained of arm swelling even before surgery, and the incidence peaked at 17% at 6 months after surgery. There were no differences in the circumferences of the upper arm, forearm, and hand between sides throughout the study period. However, the postoperative circumference values of the upper arm only on the operation side were slightly increased compared with the preoperative values. The mean excess fluid in the arm on the operation side compared with the contralateral side, as assessed by BIA, was nearly zero throughout the study period. There were no differences in subcutaneous echogenicity or skin and subcutaneous thicknesses between the sides throughout the study period. However, time-dependent increases in subcutaneous thicknesses were noticed on both sides. Four patients (4.1%) developed LE. In three of these patients, abnormality in the BIA was recorded 6 to 12 months before presentation. Immediately after presentation, the common findings included BIA abnormality and increased subcutaneous echogenicity and skin thickness in the medial forearm. CONCLUSIONS: In this study, a complaint of arm swelling was not sensitive enough for detection of the early onset of LE because a certain number of patients constantly complained of this symptom. Measurements of circumference might help in the diagnosis of LE onset, but this method is not specific enough because these measurements are also affected by various factors. However, BIA and skin and subcutaneous ultrasound were identified as potential tools for the early detection of LE.

[Questionnaire Survey of Secondary Chemotherapy for Gastric Cancer in the Yamaguchi Prefecture].

A questionnaire survey was conducted on the administration of secondary chemotherapy for unresectable or recurrent gastric cancer by 43 doctors involved in gastric cancer treatment in the Yamaguchi prefecture. Seventy-one percent of doctors replied that the secondary chemotherapy transfer rate was more than 60%, and 29% of doctors replied that the secondary chemotherapy transfer rate was less than 60%. The reasons why patients could not be transferred to secondary chemotherapy included inferior performance status, poor general condition, and elderly age, among others. Weekly paclitaxel plus ramucirumab therapy was used as the major regimen of secondary chemotherapy by 95% of doctors. In addition, 93% of doctors indicated that weekly nab-paclitaxel would be an option for gastric cancer secondary chemotherapy. Secondary chemotherapy for gastric cancer in the Yamaguchi prefecture has a standard regimen selection according to guidelines.

[Five Cases of Ten-Year Survival after Surgical Treatment of Pancreatic Cancer in Yamaguchi Prefecture].

A questionnaire survey was conducted regarding the prognosis for pancreatic cancer at 8 major hospitals in Yamaguchi Prefecture. A total of 552 patients with pancreatic cancer who underwent radical surgery between 1997 and 2016 were identified. Five of them survived for more than 10 years. Among the 5 patients, none was treated with neoadjuvant chemotherapy: 4 underwent PD and 1 underwent DP-CAR. Two of them were treated with adjuvant chemotherapy. No complications occurred during their postoperative courses. All of them had no recurrence and survived. Here, we reported the longterm postoperative survival of patients with pancreatic cancer with literature review.

[Questionnaire Survey on Adjuvant Chemotherapy for Colorectal Cancer in Yamaguchi Prefecture].

A questionnaire survey on postoperative chemotherapy for colorectal cancer was conducted in 22 hospitals in Yamaguchi Prefecture. Adjuvant chemotherapy was performed in<95% of Stage Ⅲ cancer, and oxaliplatin(OX)combination therapy was selected depending on the risk of recurrence. However, the proportion of OX combination therapy was lower than that in other prefectures, which was 24% in Stage Ⅲa, 44% in Ⅲb, and 76% in Ⅲc. In addition, among the OX combination therapy regimens(FOLFOX or CAPOX), the proportion of FOLFOX administration was higher in Yamaguchi Prefecture than in other prefectures. In Stage Ⅱ, most hospitals set up high-risk factors for recurrence and underwent adjuvant chemotherapy. FU-based monotherapy was selected in 80% of hospitals. A few hospitals decided the requirement of OX combination therapy based on age alone. In Yamaguchi Prefecture, the indication of postoperative adjuvant chemotherapy for colorectal cancer was almost standard; however, the rate of administering OX combination therapy was low.

Dclk1 Inhibition Cancels 5-FU-induced Cell-cycle Arrest and Decreases Cell Survival in Colorectal Cancer.

BACKGROUND/AIM: 5-Fluorouracil (5-FU) is frequently used in colorectal cancer treatment, but with limited success. The aim of the present study was to explore the cytotoxic effects of 5-FU, in combination with inhibition of doublecortin-like kinase 1 (Dclk1), a tumor stem cell marker that regulates pro-survival signaling in colorectal cancer cells, in the human colon cancer cell line, COLO-320. MATERIALS AND METHODS: The effects of 5-FU treatment plus Dclk1 inhibition on the phosphorylation of checkpoint kinase 1 (Chk1), cell cycle, DNA damage, apoptosis, and cell survival in COLO-320 cells were evaluated. RESULTS: Combined treatment with 5-FU and a Dclk1 inhibitor, LRRK2-IN-1 (LRRK), decreased 5-FU-induced phosphorylation of Chk1 and canceled 5-FU-induced cell-cycle arrest at the S phase. Combined treatment with 5-FU and LRRK failed to induce poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, but tended to decrease cell survival compared to individual treatment with 5-FU or LRRK. CONCLUSION: These results indicate that a combination of 5-FU and LRRK may be an effective, novel approach for colorectal cancer therapy.

Loss of skeletal muscle mass after curative gastrectomy is a poor prognostic factor.

Sarcopenia has been reported to relate to poor prognosis in various malignant cancer types. The present study aimed to clarify the prognostic impact of skeletal muscle mass (SMM) loss after curative gastrectomy in patients with gastric cancer. A total of 119 patients who underwent curative gastrectomy for gastric cancer between 2009 and 2016 were analyzed. The SMM loss at 6 months postoperatively compared with the SMM prior to surgery was calculated using the hospital records. The median loss of SMM was 3.8%. Multivariate logistic regression analysis demonstrated that total gastrectomy was a significant and independent risk factor for SMM loss of ≥5% (odds ratio=2.58; P=0.02). Results from multivariate analysis using stepwise Cox proportional hazards regression indicated that the following factors were significantly associated with shorter overall survival after curative gastrectomy: Age [>70 years; hazard ratio (HR)=2.46, P=0.04], TNM stage (≥2; HR=2.65, P=0.04) and loss of SMM (≥5%; HR=2.57, P=0.03). The present findings suggested that loss of SMM after curative gastrectomy for gastric cancer is an independent predictive factor for poor prognosis.

Laparoscopic low anterior resection for rectal cancer after Whitehead's hemorrhoidectomy: A case report.

A 65-year-old man presented with bloody stool. Colonoscopy revealed a raised tumor in the rectum, above the peritoneal reflection. He underwent endoscopic mucosal resection, but the pathological findings suggested the possibility of residual cancer. We performed laparoscopic low anterior resection using a circular stapling instrument for additional curative surgery. However, we could not insert the shaft of the endoscopic circular stapler from the anus because of anal stenosis due to Whitehead's hemorrhoidectomy the patient had undergone 20 years earlier. Therefore, we planned to use a linear stapler to insert an anvil into the rectum. The cartridge-carrying instrument was inserted from the sigmoidal side, and we performed a side-to-end anastomosis. The patient was discharged without anastomotic leakage or defecation disorder. We present this case because laparoscopic low anterior resection for rectal cancer with anal stenosis has not been previously reported.

JAB1-STAT3 activation loop is associated with recurrence following 5-fluorouracil-based adjuvant chemotherapy in human colorectal cancer.

Jun activation domain-binding protein 1 (JAB1) has been shown to have multiple roles in tumorigenesis, including the degradation of tumor suppressor proteins such as p53, Smad7, Runx3 and the cyclin-dependent kinase inhibitor p27Kip1, and the activation of oncogenic transcription factors, such as c-Jun and hypoxia-inducible factor-1α. In addition, our previous study revealed that JAB1 positively regulates signal transducer and activator of transcription 3 (STAT3) DNA-binding activity in human colon cancer cells. In turn, the oncogenic transcription factor STAT3 positively regulates JAB1 expression, indicative of a positive feedback loop. Furthermore, high JAB1 expression is associated with a poor prognosis in numerous malignant carcinomas. However, the association between JAB1 expression and prognosis in colorectal cancer remains unclear. The aim of the present study was to elucidate the association between JAB1 and STAT3 expression and recurrence in colorectal cancer. In the present study, it was found that high JAB1 expression in primary colorectal cancer tissues is an independent predictor of recurrence following 5-fluorouracil (5-FU)-based adjuvant chemotherapy in colorectal cancer patients, and that high expression of both JAB1 and STAT3 in primary colorectal cancer tissues is associated with a lower recurrence-free survival rate following 5-FU-based adjuvant chemotherapy compared to high expression of only JAB1 or STAT3. Overall, these results suggest that JAB1 is a novel predictive marker of recurrence following 5-FU-based adjuvant chemotherapy in colorectal cancer patients, and that the JAB1-STAT3 activation loop may be a potential therapeutic target in recurrent colorectal cancer following 5-FU-based adjuvant chemotherapy.