Cancer-associated fibroblast senescence and its relation with tumour-infiltrating lymphocytes and PD-L1 expressions in intrahepatic cholangiocarcinoma.

BACKGROUND: Caveolin-1 (CAV1) in cancer-associated fibroblasts (CAFs) has pro- or anti-tumourigenic effect depending on the cancer type. However, its effect in intrahepatic carcinoma (ICC) remains unknown. Therefore, this study aimed to investigate the relationship between CAV1 in CAFs and tumour-infiltrating lymphocyte (TIL) numbers or PD-L1 levels in ICC patients. METHODS: Consecutive ICC patients (n = 158) were enrolled in this study. The levels of CAV1 in CAFs, CD8 + TILs, Foxp3+ TILs and PD-L1 in cancer cells were analysed using immunohistochemistry. Their association with the clinicopathological factors and prognosis were evaluated. The correlation between these factors was evaluated. RESULTS: CAV1 upregulation in CAFs was associated with a poor overall survival (OS) (P < 0.001) and recurrence-free survival (P = 0.008). Clinicopathological factors were associated with high CA19-9 levels (P < 0.001), advanced tumour stage (P = 0.046) and lymph node metastasis (P = 0.004). CAV1 level was positively correlated with Foxp3+ TIL numbers (P = 0.01). There were no significant correlations between CAV1 levels and CD8 + TIL numbers (P = 0.80) and PD-L1 levels (P = 0.97). An increased CD8 + TIL number and decreased Foxp3+ TIL number were associated with an increased OS. In multivariate analysis, positive CAV1 expression in CAFs (P = 0.013) and decreased CD8 + TIL numbers (P = 0.021) were independent poor prognostic factors. CONCLUSION: Cellular senescence, represented by CAV1 levels, may be a marker of CAFs and a prognostic indicator of ICC through Foxp3+ TIL regulation. CAV1 expression in CAFs can be a therapeutic target for ICC.

Preoperative serum CA19-9 predicts postoperative pancreatic fistula in PDAC patients: retrospective analysis at a single institution.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a critical complication of pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC). Recent papers reported that serum carbohydrate antigen (CA)19-9 levels predicted long-term prognosis. We investigated whether preoperative serum CA19-9 levels were associated with POPF in PDAC patients. METHODS: This cohort study was conducted at a single institution retrospectively. Clinicopathologic features were determined using medical records. RESULTS: Among of 196 consecutive patients who underwent pancreatectomy against PDAC, 180 patients whose CA19-9 levels were above the measurement sensitivity, were registered in this study. The patients consisted of 122 patients who underwent pancreaticoduodenectomy and 58 patients who underwent distal pancreatectomy. Several clinicopathological factors, including CA 19-9 level, as well as surgical factors were determined retrospectively based on the medical records. Patients with high CA19-9 levels had a significantly higher incidence of POPF than those with low levels (43.9 vs. 13.0%, P < 0.0001). The receiver operating characteristic curves calculated that the cutoff CA19-9 value to predict POPF was 428 U/mL. CA19-9, BMI, curability, and histology were statistically significant risk factors for POPF by univariate analysis. Multivariate analysis showed that CA19-9 and BMI levels were statistically significant independent risk factors for POPF. CA19-9 levels were correlated with both histology and curability. Disease free survival and overall survival of patients with higher levels of CA19-9 were significantly shorter than that of patients with lower levels of preoperative serum CA19-9. CONCLUSIONS: In patients undergoing pancreatectomy for PDAC, higher preoperative CA19-9 levels are a significant predictor for POPF.

PD-L1 expression enhancement by infiltrating macrophage-derived tumor necrosis factor-α leads to poor pancreatic cancer prognosis.

Immunotherapy using anti-PD-1/PD-L1 antibodies for several types of cancer has received considerable attention in recent decades. However, the molecular mechanism underlying PD-L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells has not been clearly elucidated. We investigated the clinical significance and regulatory mechanism of PD-L1 expression in PDAC cells. Among the various cytokines tested, tumor necrosis factor (TNF)-α upregulated PD-L1 expression in PDAC cells through NF-κB signaling. The induction of PD-L1 expression was also caused by co-culture with activated macrophages, and the upregulation was inhibited by neutralization with anti-TNF-α antibody after co-culture with activated macrophages. PD-L1 expression in PDAC cells was positively correlated with macrophage infiltration in tumor stroma of human PDAC tissues. In addition, survival analysis revealed that high PD-L1 expression was significantly associated with poor prognosis in 235 PDAC patients and especially in patients harboring high CD8-positive T-cell infiltration. These findings indicate that tumor-infiltrating macrophage-derived TNF-α could be a potential therapeutic target for PDAC.

Construction and validation of a simple scoring system for stage III colorectal cancer recurrence (SiS-SCORE). A case control study.

BACKGROUND: Stage III colorectal cancer is an indication for adjuvant chemotherapy; however, there is no definite view on the selection of regimen. If the recurrence can be predicted, it can serve as the indicator of regimen selection. The present study aimed to predict the recurrence of stage III colorectal cancer by constructing a simple scoring system. METHODS: The information of stage III cases that underwent curative surgery was obtained from two facilities and analyzed. A scoring system was constructed from the analysis results and evaluated based on the cases from a different facility. RESULTS: Five factors were extracted by multivariate analysis: age > 65, male, rectum, ≥pN2 and CA19-9 > 37. When these parameters were scored as 1 point each, the score was correlated with the cumulative recurrence rate. Additionally, when cases were divided into three groups (≤1 point, 2 points, ≥3 points), the 5-year recurrence rate was as follows:, ≤1 point: 33.3%, 2 points: 42.1%, ≥3 points: 78.6%. The cumulative recurrence rate of ≥3 points was significantly higher than that of ≤1 point (P < 0.001). Similar results were obtained by evaluating that cases at a different facility (P = 0.032). Both cases with 2 points were located between ≤1 point and ≥3 points, reflecting the average recurrence rate of each institution. CONCLUSION: As the SiS-SCORE presented the same result in the facility that was different from the base facility, it can be used widely. However, a prospective study is required to prove the usefulness of the SiS-SCORE.

Significance of lymph node metastasis in pancreatic neuroendocrine tumor.

PURPOSE: Pancreatic neuroendocrine tumor (PNET) is relatively rare and has a generally better prognosis than does pancreatic cancer. However, as its prognosis in patients with lymph node metastasis (LNM) is unclear, lymph node dissection for PNET is controversial. Our study aimed to clarify the significance of LNM in PNET. METHODS: We retrospectively examined 83 PNET patients who underwent pancreatic resections with lymph node dissection at Kumamoto University Hospital, Saiseikai Kumamoto Hospital, and Kumamoto Regional Medical Center from April 2001 to December 2014. Their clinicopathological parameters were analyzed by the absence or presence of LNM, and with regard to the disease-free survival (DFS) and overall survival (OS). A predictive score of LNM was also made using the age, tumor size, primary tumor location, and tumor function. RESULTS: Although the 5-year OS was 74.8% for LNM+ and 94.6% for LNM- (P = 0.002), LNM was not an independent risk factor for the OS in a multivariate analysis. However, tumors larger than 1.8 cm were found to be an independent prognostic factor, and the cut-off value for the predictive score was 1.69. CONCLUSIONS: Although LNM was not an independent prognostic factor, lymph node dissection is recommended for patients whose predictive score is larger than 1.69.

Residual total pancreatectomy: Short- and long-term outcomes.

BACKGROUND/OBJECTIVES: Because of limited numbers of patients, there are limited data available regarding outcomes after residual total pancreatectomy (R-TP). This study aimed to assess outcomes after the R-TP vs the one-stage total pancreatectomy (O-TP), especially focused on the pancreatic adenocarcinoma cases. METHODS: From 2005 to 2014, all patients who underwent the R-TP (n = 8) and the O-TP (n = 12) for pancreatic primary malignancy were prospectively enrolled. RESULTS: The median time from the initial operation to the R-TP was 30 months. Ten patients in the O-TP group and 8 in the R-TP had pancreatic adenocarcinoma. Postoperative complications occurred in two O-TP patients and one R-TP patient. There was no in-hospital mortality. At 12 months after surgery, the median insulin dose was 27 U/day after the O-TP and 24 U/day after the R-TP, the median hemoglobin A1c was 7.2% after the O-TP and 6.9% after the R-TP. There was a significantly larger reduction in body weight after the O-TP than after the R-TP. Postoperative fatty liver disease occurred in about half of the patients in each group. In patients with pancreatic adenocarcinoma, the 2-year overall survival rate was not significantly different (68.6% after the O-TP vs 71.4% after the R-TP). CONCLUSIONS: Although the postoperative morbidity and nutritional statuses should be improved, these favorable short- and long-term outcomes demonstrate that the R-TP is a feasible procedure for patients with malignant tumor in the remnant pancreas.

The modified Glasgow Prognostic Score (mGPS) is a good predictor of indication for palliative bypass surgery in patients with unresectable pancreatic and biliary cancers.

BACKGROUND: Patients with unresectable pancreatic and biliary cancers sometimes need decompression due to obstruction of the gastrointestinal tract and/or biliary tract. The aim of this study was to determine the prognostic factors associated with an indication for palliative bypass surgery in patients with unresectable pancreatic and biliary cancers. METHODS: Between April 2005 and September 2011, 37 patients with unresectable pancreatic and biliary cancers underwent palliative bypass surgery. Prognostic factors were searched for among clinical characteristics, operation-related factors, and tumor-related factors using a prospective database. RESULTS: The median survival time (MST) of these patients was 4.6 months, with a 6-month survival rate of 40.5 %. A multivariate Cox proportional hazards regression analysis revealed that mGPS >2 was the only independent prognostic factor for bypass surgery. Patients with an mGPS of 2 had an MST of 1.7 months, and they had a significantly worse prognosis than mGPS 0-1 patients with an MST of 6.3 months. CONCLUSIONS: The mGPS is useful for predicting survival after surgical decompression due to gastrointestinal obstruction in patients with unresectable pancreatic and biliary cancers. Patients with a poor mGPS may not be indicated for palliative bypass surgery.

No-touch pancreatectomy for invasive ductal carcinoma of the pancreas.

BACKGROUND: Pancreatectomy is the only effective treatment for cancers of the pancreas. Surgeons usually grasp tumors during pancreatectomy; however, this procedure may increase the risk of squeezing and shedding of the cancer cells into the portal vein, retroperitoneum, and/or peritoneal cavity. In an effort to overcome these problems, we have developed surgical techniques for no-touch pancreatectomy. METHODS: From April 2008 through September 2013, 52 patients have been operated on no-touch pancreatectomy for invasive ductal carcinoma of the pancreas by a single operator (M.H.). Among them, 40 received pancreatoduodenectomy (PD), and 12 did distal pancreatectomy (DP). Twenty two cases (42%) required SMV-PV resection. This is a study to see if pancreatectomy can be technically done using a no-touch surgical technique without deteriorating the post-operative prognosis. During the procedure, the pancreatic tumor is neither grasped nor squeezed by the surgeon. Furthermore, for improved dissection of the retroperitoneal tissue (leftward and posterior margins for PD and rightward and posterior margins for DP), we use a hanging and clamping maneuver and dissection behind Gerota fascia. RESULTS: Overall 2- and 5-year survival rates were 64 and 42% with mean follow-up periods of 34.4 months (range: 6-68 months). Recurrence free 2- and 5-year survival rates were 49 and 31%, respectively. The 5-year survival rates of patients with JPS-stage III and those with JPS-stage IV were 57 and 20%, respectively. The 5-year survival rates of patients with UICC-stage IIA and those with UICC- stage IIB were 49 and 39%, respectively. Patients with UICC-stage III or IV did not survive for more than 2 years. CONCLUSIONS: No-touch pancreatectomy has many theoretic advantages that merit further investigation in future randomized controlled trials.

Short-term outcome of new end-to-side inserting pancreatico-jejunostomy without stiches on the pancreatic cut end.

BACKGROUND/AIMS: Post-operative leakage from pancreatic anastomosis remains an important cause of morbidity in pancreaticoduodenectomy. It also contributes to prolonged hospitalization and mortality. We have developed a new inserting end-to -side pancreatico-jejunostomy without stiches on the pancreatic cut end or pancreatic duct. METHODOLOGY: In this novel anastomosis technique, the pancreatic stump is first sunk into jejunum deeply in an end-to-side manner and tightened with a purse string in the bowel serosa. The pancreatic stump could be inserted completely inserting into the jejunum, independent of the size of the pancreas and jejunum. We performed this new anastomosis to 21 patients prospectively in Kumamoto University Hospital from April to October in 2012. RESULTS: Postoperative pancreatic fistula was not observed at all in the 21 patients. There was no hospital death, whereas 6 patients developed postoperative complications. Importantly, one patient developed hemorrhage from pancreatic cut end into the jejunum. CONCLUSIONS: This new method would be expected to minimize leakage from pancreaticojejunostomy. Further studies should be planned in a randomized controlled trial compared with another traditional pancreatico-jejunostomy.

Pancreaticodigestive anastomosis and the postoperative management strategies to prevent postoperative pancreatic fistula formation after pancreaticoduodenectomy.

Over the past 100 years, advances in surgical techniques and perioperative management have reduced the morbidity and mortality after pancreaticoduodenectomy (PD). Many techniques have been proposed for the reconstruction of the pancreaticodigestive anastomosis to prevent the development of a postoperative pancreatic fistula (POPF), but which is the best approach is still highly debated. We carried out a systematic review to determine and compare the effectiveness of various methods of anastomosis after PD. A meta-analysis and most randomized controlled trials (RCTs) showed that the mortality, POPF rate and incidence of other postoperative complications were not statistically different between the pancreaticogastrostomy and pancreaticojejunostomy (PJ) groups. One RCT showed that a binding PJ significantly decreased the risk of POPF and other postoperative complications compared with conventional PJ. External duct stenting reduced the risk of clinically relevant POPF in a meta-analysis and RCTs. The prophylactic use of octreotide after PD does not result in a reduced incidence of POPF. In conclusion, our findings suggest that the successful management of pancreatic anastomoses may depend more on the meticulous surgical technique, surgical volume, and other management parameters than on the type of technique used. However, some new approaches, such as binding PJ, and the use of external stents should be considered in further RCTs.

Pancreatic cancer in the remnant pancreas following primary pancreatic resection.

PURPOSE: To clarify the clinical features of cancer in the pancreatic remnant. METHODS: We retrospectively reviewed the clinical and pathological findings of 10 patients who developed remnant pancreatic cancer in our hospital between 2002 and 2012. The KRAS sequences in both the initial pancreatic tumor and remnant pancreatic cancer were examined in two patients. RESULTS: Eight patients underwent a second pancreatectomy for remnant pancreatic cancer (resected group), while two patients were not operated on and underwent chemotherapy (unresected group). The remnant pancreatic cancer developed at the cut end of the pancreas (pancreaticogastrostomy site) in four patients. In the resected group, four patients died 17 months after the emergence of the remnant pancreatic cancer and four patients survived during the median 40.5-month observation period. The median survival of the unresected group after the emergence of the remnant pancreatic cancer was 10 months. The findings of the KRAS sequencing and immunohistological staining of the remnant pancreatic cancer for MUC1 and MUC2 in the two patients were consistent with those of the initial pancreatic tumor in one patient, and not consistent in the other. CONCLUSIONS: Our results suggest that both local recurrence and a new primary cancer can develop in the pancreatic remnant, and repeated pancreatectomy can prolong survival.

Advanced Cholangiocarcinoma With High Tumor Mutation Burden Achieving Complete Response to Immune Check Point Inhibitor.

BACKGROUND/AIM: Genomic examination of tumor tissue has been clinically accepted, and the identification of actionable mutations for molecular-targeted therapy may provide substantial survival benefit for patients with advanced malignancies. CASE REPORT: A female patient in her 60s showed a stenosis of the afferent loop of the small intestine because of circumferential metastatic tumor 14 months after curative surgery for hilar cholangiocarcinoma. Chemotherapy with gemcitabine plus cisplatin was administered for 18 months. An oncopanel examination was performed during chemotherapy, and a high tumor mutation burden was revealed. At 38 months after surgery, a new recurrent tumor, 2.7 cm in size, was observed in the abdominal wall, which was histologically proven to be metastatic adenocarcinoma. Atezolizumab was administered. After three cycles of treatment, treatment was switched to pembrolizumab because of its acceptance by healthcare insurance. The recurrent tumors in the abdominal wall and small intestine disappeared 6 months after the administration of immune checkpoint inhibitor, and the patient has continued pembrolizumab, surviving for 76 months after surgery without any clinical evidence of tumor. CONCLUSION: Immune checkpoint blockade successfully prolonged the survival of a patient with advanced hilar cholangiocarcinoma with high tumor mutation burden, although the optimal number of mutations for such a successful response needs to be clarified.

Combined Neutrophil-to-Lymphocyte Ratio Score Is Associated With Chemotherapeutic Response and Predicts Prognosis in Patients With Advanced Pancreatic Cancer.

BACKGROUND/AIM: Neutrophil-to-lymphocyte ratio (NLR) is a prognostic indicator for several malignancies, including pancreatic cancer. We developed a novel combined NLR score (cNLRS) based on baseline NLR and change in NLR after chemotherapy (ΔNLR), and examined its prognostic value and role in chemotherapeutic response in patients with advanced pancreatic cancer. PATIENTS AND METHODS: This study retrospectively assessed 210 advanced pancreatic cancer patients receiving chemotherapy between 2010 and 2021. The cNLRS was developed and its association with chemotherapeutic response and prognosis was investigated. RESULTS: The cNLRS consisted of baseline NLR ≥2.5 and ΔNLR ≥0, both of which were remained as independent poor predictors of prognosis adjusting for other traditional clinicopathological features. A high cNLRS served as an independent prognostic factor of reduced overall survival. Of note, the cNLRS was significantly associated with disease control rate and treatment duration not only in 1st line treatment but also in 2nd line treatment. CONCLUSION: The cNLRS established as a useful prognostic biomarker might be associated with chemotherapeutic response and could predict survival in advanced patients with pancreatic ductal adenocarcinoma treated with chemotherapy.

End-to-side pancreaticojejunostomy without stitches in the pancreatic stump.

In patients undergoing pancreaticoduodenectomy, leakage from the pancreatic anastomosis remains an important cause of morbidity and contributes to prolonged hospitalization and mortality. Recently, a new end-to-end pancreaticojejunostomy technique without the use of any stitches through the pancreatic texture or pancreatic duct has been developed. In this novel anastomosis technique, the pancreatic stump is first sunk into deeply and tightened with a purse string in the bowel serosa. We modified this method in an end-to-side manner to complete the insertion of the pancreatic stump into the jejunum, independent of the size of the pancreas or the jejunum. We tested this new anastomosis technique in four pilot patients and compared their outcomes with four control patients who underwent traditional pancreaticojejunostomy. No severe pancreatic fistulas were observed in either group. There were no differences in morbidity or hospital stay between the groups. This new method can be performed safely and is expected to minimize leakage from pancreaticojejunostomies.

A case of accessory hepatic duct entering cystic duct successfully treated by laparoscopic cholecystectomy for cholecystolithiasis.

Although laparoscopic cholecystectomy is a well-established surgical procedure, an accessory hepatic duct (AcHD) entering the cystic duct is poorly understood. A 77-year-old woman with symptomatic cholecystlithiasis was referred to our hospital. Abdominal ultrasonography indicated several small stones in the gall bladder. Magnetic resonance cholangiopancreatography (MRCP) did not reveal an anomalous cystic duct. Dissecting the gall bladder bed at operation, AcHD entering the cystic duct was suspected. Intraoperative cholangiography revealed that B5 branch entered the cystic duct. We ligated the AcHD, and divided it. Laparoscopic cholecystectomy was completed, and the patient was discharged without any complication. A week after the operation, MRCP showed that ventral branch of B5 was dilated. The patient showed no symptom for more than a year. The present case exhibited extremely rare AcHD entering the cystic duct, which was hardly recognized before surgery. It is possible to recognize such anomalous variants with standard laparoscopic approach based on 2018 Tokyo Guidelines and with attention to the possibilities of AcHD entering the cystic duct.

Hyaluronate carboxymethylcellulose-based bioresorbable membrane (Seprafilm) reduces adhesion under the incision to make unplanned re-laparotomy safer.

PURPOSE: Hyaluronate carboxymethylcellulose-based bioresorbable membrane (HC membrane; Seprafilm(®)) is used to prevent postoperative adhesion. We conducted this study to assess the effectiveness of the HC membrane in reducing the severity of adhesions in patients undergoing unplanned re-laparotomy. METHODS: Between February, 2002 and December, 2010, 123 patients underwent abdominal surgery followed by a re-laparotomy in Kumamoto Regional Medical Center. The HC membrane was placed under the first abdominal incision in 60 patients (HC membrane group), whereas it was not used in the other 63 patients (control group). We compared the medical and operative records of these two groups. RESULTS: At the second laparotomy, adhesion under the incision was severe in many of the control group patients, but was significantly reduced in the HC membrane group. Postoperative small-bowel obstruction was significantly less frequent in the HC membrane group. According to univariate analysis of the risk factors for adhesion, prolonged operation time, blood loss, and not using an HC membrane were significantly associated with severe adhesion. Multivariate analysis revealed that only not using the HC membrane was significant. CONCLUSION: The HC membrane effectively reduces the severity of wound adhesion, making unplanned repeated laparotomy safer.

Clinical features of strangulated small bowel obstruction.

PURPOSE: The causes of strangulated small bowel obstruction (SSBO) include a fibrous cord, torsion, and internal hernia. We conducted this study to define the clinical features of SSBO. METHODS: We reviewed the clinical course and preoperative data of 74 patients treated for SSBO in Kumamoto Regional Medical Center between January 2004 and September 2010. RESULTS: Twenty-one patients had no history of laparotomy. Computed tomography (CT) showed high positivity (86.3 %) of closed loops in the involved intestine. Postoperative complications developed in 23 patients, representing a morbidity rate of 31.1 %. Forty-four patients underwent resection of non-viable small intestine (non-viable group), and 30 did not require resection of the intestine (viable group). There were four hospital deaths in the non-viable group. The overall mortality rate and the mortality rate in the non-viable group were 5.4 and 9.1 %, respectively. CONCLUSION: These findings indicate that SSBO can occur without a history of laparotomy, CT is useful in its diagnosis, and its associated morbidity and mortality are high.

Adult transmesenteric hernia: report of two cases.

Transmesenteric hernia is a rare cause of bowel obstruction in adults. We herein describe two cases that occurred in adult women, ages 27 and 19. Both cases presented with abdominal pain without muscular defense signs. Computed tomography of both cases showed features of small bowel obstruction by an internal hernia. A laparotomy showed mesenteric defects of the mesentery of the ileum in the former case and the mesentery of the transverse colon in the latter case, with a herniating ileum. The involved small bowel was viable in both cases, and the bowel was pulled out of the mesenteric defect without resection. The mesenteric defects were then successfully repaired.

Perioperative intra-arterial and systemic chemotherapy for pancreatic cancer.

BACKGROUND: Even after curative resection of pancreatic cancer, there is a high probability of systemic recurrence. This indicates that subclinical metastases are already present at the time of operation. The purpose of this study was to assess the feasibility and outcomes of patients who received a novel multimodality therapy combining pancreatic resection and intraoperative radiation therapy (IORT) with pre- and postoperative chemotherapy for pancreatic cancer. METHODS: For eligible patients with pancreatic cancer, 5-FU was administered at a dose of 125 mg/m(2)/day on days 1-5 every week as a continuous pancreatic and hepatic arterial infusion, and gemcitabine was infused intravenously at a dose of 800 mg/m(2) per day once per week for 2 weeks for preoperative chemotherapy. Pancreatic resection combined with IORT was performed 1 week after preoperative chemotherapy. Postoperative chemotherapy was performed in the same way as preoperative chemotherapy. We performed an intention-to-treat analysis for all enrolled patients. RESULTS: This study enrolled 44 patients. The most common toxicities were hematological and gastrointestinal events. Grade 3/4 hematological toxicities were observed during preoperative chemotherapy, although there were no grade 3/4 nonhematological events. Postoperative chemotherapy-related toxicities were more critical and frequent than preoperative ones. There were no pre- or postoperative chemotherapy-associated deaths. Median overall survival was 36.5 months with 30.5% overall 5-year survival. CONCLUSIONS: This multimodality therapy is feasible and promises to contribute to survival. It should be evaluated in a phase III setting.