Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC.

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.

Prognostic Impact of Margin Status in Distal Cholangiocarcinoma.

BACKGROUND: A positive ductal margin is strongly associated with poor survival in patients with distal cholangiocarcinoma. However, the significance of the radial margin status and its effect on survival are not fully clarified. METHODS: All patients with distal cholangiocarcinoma who underwent pancreatoduodenectomy between January 2000 and December 2018 at Tokai University Hospital were retrospectively analyzed. Positive margins were divided into positive ductal margin and positive radial margin. RESULTS: One hundred and eight consecutive patients with distal cholangiocarcinoma underwent pancreatoduodenectomy. Margin-negative R0 resection was performed in 85 patients (79%). Twenty-three patients (21%) had a positive resection margin (R1 resection). The 5-year survival rate and median overall survival for patients with R0 resection and those with R1 resection was 64%, 98 months and 25%, 26 months, respectively. There was a significant difference in survival between patients with R0 resection and those with R1 resection (p < 0.001). Patients with positive radial margin (n = 10) had a significantly worse outcome than those with positive ductal margin (n = 13) (p = 0.016). Univariate analysis showed that R1 resection, lymph node metastasis, tumor depth, portal vein invasion, pancreatic invasion, lymphatic invasion, and venous invasion were significant prognostic factors. Multivariate analysis confirmed that R1 resection and nodal involvement were significant independent prognostic indicators after surgical resection for distal cholangiocarcinoma. CONCLUSIONS: Positive surgical margin and nodal involvement were the strongest predictors of poor survival in patients with distal cholangiocarcinoma. Patients with a positive radial margin had a significantly worse outcome than those with a positive ductal margin.

Neoadjuvant and Adjuvant Treatments for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma: The Current Status of Pancreatic Ductal Adenocarcinoma Treatment in Japan.

Resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Although the outcome of technically resectable PDAC has improved with advances in surgery and adjuvant therapy, the 5-year survival rate remains low at 20% to 40%. More effective therapy is needed. Almost 15 years ago, the National Comprehensive Cancer Network guidelines proposed a resectability classification of PDAC based on preoperative imaging. Since then, treatment strategies for PDAC have been devised based on resectability. The standard of care for resectable PDAC is adjuvant chemotherapy after R0 resection, as shown by the results of pivotal clinical trials. With regard to neoadjuvant treatment, several recent clinical trials comparing neoadjuvant treatment with upfront resection have been conducted on resectable PDAC and borderline resectable PDAC, and the benefits and efficacy of neoadjuvant treatment for pancreatic cancer has become clearer. The significance of neoadjuvant treatment for resectable PDAC remains controversial, but in borderline resectable PDAC the efficacy of neoadjuvant treatment has been further recognised, although the standard of care has not yet been established. Several promising clinical trials for PDAC are ongoing. This review presents previous and ongoing trials of perioperative treatment for resectable and borderline resectable PDAC, focusing on the difference between Asian and Western countries.

Prognostic Impact of Positive Peritoneal Lavage Cytology on Resectable Pancreatic Body and Tail Cancer: A Retrospective Study.

BACKGROUND: The prognostic impact of positive peritoneal lavage cytology on pancreatic cancer is unclear. Therefore, this study aimed to evaluate its impact in resectable pancreatic body and tail cancer. METHODS: Between January 2006 and December 2019, 97 patients with pancreatic body and tail cancer underwent peritoneal lavage cytology and curative resection at our institution. We analyzed the impact of positive peritoneal lavage cytology on clinicopathological factors and on the prognosis of pancreatic body and tail cancer. RESULTS: Malignant cells were detected in 14 patients (14.4%) using peritoneal lavage cytology. In these patients, the tumor diameter was significantly larger (p < 0.001) and anterior serosal invasion (p = 0.034), splenic artery invasion (p = 0.013), lympho-vessel invasion (p = 0.025), and perineural invasion (p = 0.008) were significantly more frequent. The R1 resection rate was also significantly higher in patients with positive peritoneal lavage cytology than in negative patients (p = 0.015). Positive peritoneal lavage cytology had a significantly poor impact on overall survival (p = 0.001) and recurrence-free survival (p < 0.001). This cytology was also an independent poor prognostic factor for recurrence (p = 0.022) and was associated with peritoneal dissemination and liver metastasis. CONCLUSIONS: Positive peritoneal lavage cytology is considered to be indicative of more systemic disease in patients with resectable pancreatic body and tail cancer than in patients with negative peritoneal lavage cytology. Early detection of pancreatic cancer before it develops micrometastases is important to improve prognosis, and CY+ patients require more intensive multimodality treatment than standard treatment for resectable pancreatic cancer.

Induction Chemotherapy with FOLFIRINOX for Locally Advanced Pancreatic Cancer: A Simple Scoring System to Predict Effect and Prognosis.

BACKGROUND: Effective chemotherapy (CTx) protocols as induction treatment provide increasing opportunities for surgical resection of locally advanced pancreatic cancer (LAPC). Although improved survival after resection of LAPC with CTx has been reported for selected patients, reliable recommendations on the indication for conversion surgery after induction treatment are currently lacking. We investigated the factors predictive of prognosis in resected LAPC after FOLFIRINOX. METHODS: Consecutive patients with LAPC undergoing curative resection after FOLFIRINOX between 2011 and 2018 were identified from a prospectively maintained database. Relevant clinical parameters and CT findings were examined. A scoring system was developed based on the ratio of hazard ratios for overall survival of all significant predictors. RESULTS: A total of 62 patients with LAPC who underwent oncologic resection after FOLFIRINOX were analyzed. Tumor shrinkage, tumor density, and postchemotherapy CA19-9 serum levels were independently associated with overall survival (multivariate analysis: HR = 0.31, 0.17, and 0.18, respectively). One, two, and two points were allocated to these three factors in the proposed scoring system, respectively. The median overall survival of patients with a score from 0 to 2 was significantly shorter than that of patients with a score from 3 to 5 (22.1 months vs. 53.2 months, P < 0.001). CONCLUSIONS: Tumor density is a novel predictive marker for the prognosis of patients with resected LAPC after FOLFIRINOX. A simple scoring model incorporating tumor density, the tumor shrinkage rate, and CA 19-9 levels identifies patients with a low score, who may be candidates for additional treatment.

Indications for resection of recurrent lesions in patients with distal cholangiocarcinoma based on prognostic factors: a single-institute retrospective study and brief literature review.

BACKGROUND: To evaluate the effectiveness of surgery for recurrent distal cholangiocarcinoma and determine surgical indications based on prognostic factors for the recurrence of distal cholangiocarcinoma. METHODS: We analysed the outcomes of 101 patients who underwent surgical resection for distal cholangiocarcinoma between 2000 and 2018. The clinicopathological factors and prognosis of primary and recurrent distal cholangiocarcinoma were investigated. RESULTS: Of the 101 patients with resected distal cholangiocarcinoma, 52 (51.5%) had relapsed. Seven (13.5%) and 45 patients (86.5%) underwent resection of recurrent lesions and palliative therapy, respectively. There were no major complications requiring therapeutic intervention after metastasectomy. The median overall survival in patients with and without surgery for recurrent lesions was 83.0 (0.0-185.6) and 34 months (19.0-49.0), respectively. Therefore, patients who had undergone surgery for recurrent lesions had a significantly better prognosis (p = 0.022). Multivariate analyses of recurrent distal cholangiocarcinoma revealed that recurrence within one year was an independent predictor of poor survival. Resection of recurrent lesions improved prognosis. CONCLUSIONS: Radical resection in recurrent distal cholangiocarcinoma may improve the prognosis in selected patients. Although time to recurrence is considered an important factor, the small number of cases of recurrence and resection of recurrent lesions in this study makes it difficult to conclude which patients are best suited for resection of recurrent lesions. This issue requires clarification in a multicentre prospective study, considering patients' background, such as the recurrence site and number of metastases.

True Carcinosarcoma of the Gallbladder: A Case Report and Brief Review of the Literature.

INTRODUCTION: Carcinosarcoma of the gallbladder (CSGB) is very rare, accounting for less than 1% of gallbladder malignancies. Therefore, the biological behavior is not well known. We report the case of a patient with CSGB who showed long-term survival after treatment with surgery and postoperative adjuvant chemotherapy. CASE PRESENTATION: A 79-year-old man was referred to our department with suspected gallbladder cancer after undergoing positron emission tomography-computed tomography (PET-CT) scan for preoperative examination of lung cancer, which showed strong accumulation in the gallbladder. Abdominal contrast-enhanced computed tomography (CT) demonstrated a heterogeneous enhanced, 25-mm mass in the anterior wall of the gallbladder fundus. Cholecystectomy and hepatoduodenal mesenteric lymph node sampling revealed a polypoid tumor. Histopathological findings showed a mixture of adenocarcinoma and sarcoma with spindle-shaped cells. Immunohistochemical s taining of the s arcoma s howed negative results for the epithelial markers and positive results for the mesenchymal markers, leading to a diagnosis of true CSGB. We administered S-1 as postoperative adjuvant chemotherapy and was reported to be alive 45 months after surgery without recurrence. CONCLUSION: CSGB has a poor prognosis, but if radical resection can be performed, there is a possibility of long-term survival. Further case studies and treatment options are needed to help understand this disease.

Enucleation for benign or borderline tumors of the pancreas: comparing open and minimally invasive surgery.

BACKGROUND: The feasibility and safety of minimally invasive enucleation (ME) for benign or borderline pancreatic tumors is still unclear. The aim of this study was to compare outcomes between ME and open enucleation (OE). METHODS: All patients undergoing pancreatic enucleation between October 2001 and January 2020 were analyzed from a prospective database. Consecutive patients undergoing ME were compared with patients undergoing OE in a matched-pair analysis (1:2). RESULTS: Of 358 patients, undergoing enucleation, 120 matched patients (ME n = 40, OE n = 80) were included. Patients undergoing ME had less blood loss (median 50 vs. 100 ml, P = 0.025) and had a higher proportion of patients discharged by 7 days, than patients undergoing OE (38% vs. 18%, P = 0.016). The rates of clinically relevant postoperative pancreatic fistula (POPF) and major complications (Clavien grade ≥ 3) were similar between both groups. Risk factor analysis for POPF B/C showed no significant parameters associated with POPF, including tumor size and proximity to the main pancreatic duct. CONCLUSION: Compared with conventional OE, ME reduces the amount of bleeding and allows earlier postoperative discharge, without increasing the incidence of major complications. Thus, minimally invasive enucleation should be considered for benign tumors of the pancreas when technically and oncologically feasible.

A prospective feasibility study of one-year administration of adjuvant S-1 therapy for resected biliary tract cancer in a multi-institutional trial (Tokyo Study Group for Biliary Cancer: TOSBIC01).

BACKGROUND: Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial. METHODS: The inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m2/day orally twice daily on days 1-28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS), and overall survival (OS). RESULTS: Forty-six patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade 3/4). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporary therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered more than 3 courses of S-1, only one patient discontinued because of adverse events. CONCLUSIONS: One-year administration of adjuvant S-1 therapy for resected BTC was feasible and may be a promising treatment for those with resected BTC. Now, a randomized trial to determine the optimal duration of S-1 is ongoing. TRIAL REGISTRATION: UMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347.

Methylated promoter DNA of CDO1 gene and preoperative serum CA19-9 are prognostic biomarkers in primary extrahepatic cholangiocarcinoma.

BACKGROUND: Promoter DNA methylation of Cysteine dioxygenase type1 (CDO1) gene has been clarified as a molecular diagnostic and prognostic indicator in various human cancers. The aim of this study is to investigate the clinical relevance of CDO1 methylation in primary biliary tract cancer (BTC). METHODS: CDO1 DNA methylation was assessed by quantitative methylation-specific PCR in 108 BTC tumor tissues and 101 corresponding normal tissues. BTC was composed of extrahepatic cholangiocarcinoma (EHCC) (n = 81) and ampullary carcinoma (AC) (n = 27). RESULTS: The CDO1 methylation value in the tumor tissues was significantly higher than that in the corresponding normal tissues (p<0.0001). The overall survival (OS) in EHCC patients with hypermethylation was poorer than those with hypomethylation (p = 0.0018), whereas there was no significant difference in AC patients. Multivariate analysis identified that CDO1 hypermethylation, preoperative serum CA19-9 and perineural invasion were independent prognostic factors in EHCC. The EHCC patients with CDO1 hypermethylation exhibited more dismal prognosis than those with hypomethylation even in low group of CA19-9 level (p = 0.0006). CONCLUSIONS: Our study provided evidence that promoter DNA methylation of CDO1 gene could be an excellent molecular diagnostic and prognostic biomarker in primary EHCC. The combination of CDO1 methylation and preoperative serum CA19-9 effectively enriched EHCC patients who showed the most dismal prognosis. These markers would be beneficial for clinical clarification of the optimal strategies in EHCC.

Neutrophil-to-lymphocyte ratio as a predictor of postoperative morbidity in patients with distal cholangiocarcinoma.

Systemic inflammatory-, immunological- and nutritional-based indices, such as the neutrophil-to-lymphocyte ratio (NLR), the prognostic nutritional index (PNI) and the Glasgow prognostic score (GPS), are drawing considerable research attention to predict the long-term prognosis of many types of cancer. Recently, these parameters have also been reported to be useful in predicting postoperative morbidity in several fields, including colorectal and otolaryngological cancer. However, while distal cholangiocarcinoma exhibits a high morbidity rate, its risk factors of morbidity have not yet been established. This is because previous studies have analyzed distal cholangiocarcinoma as periampullary tumors combined with pancreatic head cancer. Therefore, the aim of the present study was to investigate the application of the NLR, the PNI and the GPS in evaluating risk factors for postoperative morbidity in patients with distal cholangiocellular or ampullary carcinoma. Eighty-four patients who underwent pancreaticoduodenectomy (PD) for distal cholangiocellular or ampullary carcinoma at the Department of Surgery in Kitasato University Hospital between 2008 and 2016 were enrolled. Associations between perioperative characteristics (NLR, PNI and GPS) and postoperative complications (Clavien-Dindo classification grade III or higher) were retrospectively analyzed. In the univariate analysis, neutrophil and lymphocyte counts, body mass index (BMI) and the NLR were associated with postoperative complications (P<0.05). In the multivariate analysis, BMI [>23.0 kg/m2; odds ratio (OR): 3.80, 95.0% confidence interval (CI): 1.35-11.83; P=0.011] and the NLR (>2.0; OR: 6.77, 95.0% CI: 2.44-21.13; P<0.001) were independent risk factors for postoperative complications. BMI and the NLR are valuable predictors of postoperative morbidity following PD in patients with distal cholangiocarcinoma. It would be beneficial to determine treatment strategies for distal cholangiocarcinoma based on the NLR to reduce postoperative complications.

The potentiality of laparoscopic partial liver excisional biopsy using analysis of the liver surface based on preoperative 3D simulation imaging: A case report.

INTRODUCTION: The imaging diagnostics of liver tumor are difficult. There are no effective biopsy examinations for liver tumors that cannot be detected even by ultrasonography (US) and computed tomography (CT). We report a remarkably useful biopsy method for such tumors. PRESENTATION OF CASE: A 67-year-old man with hepatitis C underwent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, and the images revealed multiple delayed enhanced masses that showed high signal intensity in the hepatobiliary phase. The possibility of malignancy could not be ruled out due to the trend towards increased size of the masses. Percutaneous liver biopsy was considered impossible because CT and US could not detect the masses. Laparoscopic liver biopsy with preoperative simulation using 3D imaging was performed. The 3D imaging provided accurate information of liver surface irregularities with cirrhosis change. The tumor location was confirmed, and adequate tumor excisional biopsy was performed. Histological assessment revealed the tumor to be a focal nodular hyperplasia-like nodule. DISCUSSION AND CONCLUSIONS: Laparoscopic liver biopsy has been widely used because of its safety and accuracy. It enables accurate resection of tumors that are undetectable with CT and US by employing preoperative 3D imaging while maintaining the less-invasiveness.

Effects of Addition of Early Enteral Nutritional Support During the Postoperative Phase in Patients after Living-Donor Liver Transplantation.

BACKGROUND: Early initiation of enteral nutrition is recommended after some surgical procedures. This study retrospectively analyzed the effects of addition of early enteral nutrition (EEN) support during the postoperative phase in patients after living-donor liver transplantation (LDLT). MATERIAL AND METHODS: The subjects were adult patients who underwent LDLT in our department and received either total parenteral nutrition (TPN) or EEN for postoperative nutritional support. We retrospectively compared clinical parameters between the TPN group (n=50) and the EEN group (n=45). RESULTS: There were no significant differences in preoperative demographic data between the EEN and TPN groups with the exception of the follow-up period after surgery. In the EEN group, EEN was provided uneventfully; the daily amount of enteral nutrition was 996±465 kcal on postoperative day 7. Central venous catheters were removed significantly earlier in the EEN group than in the TPN group (postoperative day 11±7 vs. 28±18). The postoperative C-reactive protein level and the incidence of bacterial infection were significantly lower in the EEN group than in the TPN group. The postoperative length of hospital stay was significantly shorter and 6-month survival was significantly higher in the EEN group than in the TPN group. A multivariate analysis indicated that EEN was a significant factor for both shorter hospital stay and 6-month survival. CONCLUSIONS: Our retrospective analyses suggest that introduction of EEN had a great impact on postoperative short-term outcomes of LDLT.

Long-term complete response of advanced hepatocellular carcinoma treated with multidisciplinary therapy including reduced dose of sorafenib: case report and review of the literature.

An 83-year-old man underwent computed tomography during a routine check-up due to a history of surgical treatment for pancreatic cancer. Two tumors were detected in the anterior segment of the liver. A needle biopsy of the larger tumor was performed, and pathological examination showed that the tumor was a poorly differentiated hepatocellular carcinoma. Resection was not performed considering the patient's poor physical condition. Thus, transcatheter arterial chemoembolization and radiofrequency ablation of the tumors were performed. Three months later, residual tumor of the larger lesion and multiple pulmonary metastases were detected. This time, continuous hepatic arterial infusion chemotherapy was performed. Although the pulmonary metastases markedly reduced, tumor thrombi appeared in the right portal vein on computed tomography. Finally, sorafenib was administered, which led to disappearance of the tumor thrombi and no other signs of recurrence 8 months after initiation of sorafenib on computed tomography. Although sorafenib administration has continued at reduced doses of 200 mg per day or less due to hypertension, complete response has persisted for the past 34 months. It is noteworthy that sorafenib has been given at reduced doses, but a long-term complete response is maintained in a patient who had portal tumor thrombi and distant metastasis. Herein, we present this rare case of advanced hepatocellular carcinoma controlled with reduced doses of sorafenib following multidisciplinary therapy, describe our single center experience with sorafenib use in patients with hepatocellular carcinoma, and review previous reports that focused on dose reduction of sorafenib.

Cryoablation provides superior local control of primary hepatocellular carcinomas of >2 cm compared with radiofrequency ablation and microwave coagulation therapy: an underestimated tool in the toolbox.

BACKGROUND: Although cryoablation (Cryo) has been advocated as an effective locoregional therapy for hepatocellular carcinoma (HCC), few studies have compared the outcomes with those of radiofrequency ablation (RFA) and microwave coagulation therapy (MCT). METHODS: Consecutive patients with primary HCCs of <5 cm received Cryo or RFA/MCT between 1998 and 2011 and were monitored for local recurrence (defined as a recurrent tumor at or in direct contact with the ablated area) and overall complication rates. RESULTS: The median tumor size was 2.5 cm in the Cryo group (n = 55) and 1.9 cm in the RFA/MCT group (n = 64; P < 0.001), but other patient characteristics were similar. Multivariate Cox regression analysis revealed Cryo as the only independent factor for improved 2-year local recurrence-free survival, with a hazard ratio (HR) of 0.3 (95 % confidence interval, 0.1-0.9; P = 0.02). Tumor diameter was a negative indicator of local recurrence-free survival (HR, 2.0; 95 % confidence interval, 1.1-3.5; P = 0.02). Subgroup analysis of patients with tumors of >2 cm demonstrated significantly better local recurrence rates in the Cryo group compared with the RFA/MCT group (21 vs. 56 % at 2 years; P = 0.006). Overall complication rates and incidences of Clavien-Dindo classification grade ≥ III were identical (both P = 1.00). No in-hospital mortality occurred. CONCLUSIONS: Appropriate use of Cryo, as shown in this series, is safe and provides significantly improved local control for the treatment of primary HCCs of >2 cm compared with RFA/MCT.

[Pathological complete response in advanced gastric carcinoma by S-1/CDDP combination chemotherapy].

A59 -year-old woman was referred to our hospital for a close examination and treatment of an advanced gastric carcinoma. A physical examination and CT scan showed that the right cervical and axillar lymph nodes were swelling, and a histopathological examination of the axillar lymph node revealed metastatic growth of the gastric carcinoma (Stage IV). Then, we started S-1/CDDP combination chemotherapy. S-1 (80 mg/m2/day)was orally administered for 3 weeks followed by 2 weeks of rest, and CDDP (60 mg/m2) was administered by drip on day 8. Since the distant metastases were greatly reduced after 6 courses of combination therapy, a distal gastrectomy with lymph nodes dissection (D2) was performed. Histopathological examination of the resected tissues revealed no residual cancer cells, suggesting a pathologically complete response. The clinical course after the operation went well without any complications, and the patient is alive with no evidence of recurrence 1 year after surgery. S-1/CDDP combination chemotherapy appears to be one of the effective treatments for advanced gastric carcinoma.