Results of a Randomized Clinical Study of Gemcitabine Plus Nab-Paclitaxel Versus Gemcitabine Plus S-1 as Neoadjuvant Chemotherapy for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma (RCT, CSGO-HBP-015).

BACKGROUND: The optimal neoadjuvant chemotherapy (NAC) regimen for patients with localized pancreatic ductal adenocarcinoma (PDAC) remains uncertain. This trial aimed to evaluate the efficacy and safety of two neoadjuvant chemotherapy (NAC) regimens, gemcitabine plus nab-paclitaxel (GA) and gemcitabine plus S-1 (GS), in patients with resectable/borderline-resectable (R/BR) PDAC. PATIENTS AND METHODS: Treatment-naïve patients with R/BR-PDAC were enrolled and randomly allocated. They received two cycles (2 months) of each standard protocol, followed by radical surgery for those without tumor progression in general hospitals belonging to our intergroup. The primary endpoint was to determine the superior regimen on the basis of achieving a 10% increase in the rate of patients with progression-free survival (PFS) at 2 years from allocation. RESULTS: A total of 100 patients were enrolled, with 94 patients randomly assigned to the GS arm (N = 46) or GA arm (N = 48). The 2-year PFS rates did not show the stipulated difference [GA, 31% (24-38%)/GS, 26% (18-33%)], but the Kaplan-Myer analysis showed significance (median PFS, GA/GS 14 months/9 months, P = 0.048; HR 0.71). Secondary endpoint comparisons yielded the following results (GA/GS arm, P-value): rates of severe adverse events during NAC, 73%/78%, P = 0.55; completion rates of the stipulated NAC, 92%/83%, P = 0.71; resection rates, 85%/72%, P = 0.10; average tumor marker (CA19-9) reduction rates, -50%/-21%, P = 0.01; average numbers of lymph node metastasis, 1.7/3.2, P = 0.04; and median overall survival times, 42/22 months, P = 0.26. CONCLUSIONS: This study found that GA and GS are viable neoadjuvant treatment regimens in R/BR-PDAC. Although the GA group exhibited a favorable PFS outcome, the primary endpoint was not achieved.

Exploratory prospective, randomized phase II study of neoadjuvant transcatheter arterial chemoembolization plus surgery versus surgery alone for large hepatocellular carcinoma (CSGO-HBP-005): Clinical Study Group of Osaka University, Hepato-Biliary-Pancreatic Group.

AIM: Neoadjuvant transcatheter arterial chemoembolization (TACE) for large tumors is controversial, especially in the minimally invasive surgery era. The aim of this study was to compare features between groups treated with neoadjuvant TACE followed by surgery (TACE + surgery) or upfront surgery for hepatocellular carcinoma >5 cm. METHODS: In this exploratory, multicenter, randomized phase I study, the primary measure was 2-year disease-free survival (DFS). Secondary measures were resection rate, necrosis rate by TACE, 2-year overall survival, and site of recurrence. A total of 30 patients were randomly allocated to each arm. RESULTS: The two arms did not differ in patient characteristics. The median time to surgery from randomization was 48 days for TACE + surgery and 29 for surgery only (p < 0.001). Postoperative morbidities did not differ between arms. The 2-year DFS, overall survival, and resection rates were 56.7%, 80.0%, and 93.3%, respectively, in the TACE + surgery arm, and 56.1%, 89.9%, and 90.0% in the upfront surgery arm. Minimally invasive surgery was carried out in 35.7% in the TACE + surgery arm and in 29.6% in the upfront surgery arm. The median necrosis rate by TACE was 90.0%. In resected specimens, invasion to the hepatic vein was less with TACE + surgery (3.6% vs. 22.2%, p = 0.0380). In cases of 100% necrosis with TACE, 2-year DFS was 100%. Site of recurrence did not differ between groups. CONCLUSION: Neoadjuvant TACE did not improve 2-year DFS, and neoadjuvant TACE allowed delay of surgical treatment without increased morbidity and cancer progress. CLINICAL TRIAL REGISTRATION: UMIN: 000005241.

Impact of the perioperative assessment of deglutition on postoperative respiratory complications in elderly patients undergoing gastrectomy for gastric cancer.

PURPOSE: To investigate the association between perioperative deglutition screening and postoperative respiratory complications (PRCs) in elderly patients undergoing gastrectomy for gastric cancer. METHODS: We analyzed data from 86 patients with gastric cancer (aged ≥ 70 years) who underwent gastrectomy between October, 2016 and November, 2018. Videofluoroscopic swallowing examinations (VFSEs) were performed before and after surgery. We examined the association of these results with postoperative respiratory complications, as well as the relationships between demographic, operative, and swallowing function assessment data. RESULTS: PRCs were identified in 16 patients. The results of pre- and postoperative VFSE showed abnormalities in 28 and 32 patients, respectively. Multivariate analysis revealed that abnormalities in the postoperative VFSEs were strongly associated with the development of PRCs (P = 0.002). The findings of this analysis suggests that ventilatory impairment, a Charlson comorbidity index score ≥ 3, and an open surgical approach are independent risk factors for PRCs. CONCLUSION: This is the first study to demonstrate the efficacy of perioperative assessment of swallowing function using VFSE for predicting PRCs in elderly patients undergoing gastrectomy for gastric cancer.

A Multicenter Survey on Eligibility for a Randomized Phase III Trial of Adjuvant Chemotherapy for Resected Biliary Tract Cancer (JCOG1202, ASCOT).

BACKGROUND: The Adjuvant S-1 for Cholangiocarcinoma Trial (JCOG1202, [ASCOT]) was a multicenter, randomized controlled trial aimed at investigating the efficacy and safety of adjuvant chemotherapy (AC) with S-1 for resected biliary tract cancer (BTC). This trial reported that overall survival was prolonged with AC compared with observation. METHODS: With the aim of increasing enrollment, the present survey biannually recorded the number of patients eligible for enrollment into ASCOT and reasons for ineligibility among patients who had undergone surgery for BTC from April 2015 to September 2017 at 36 institutions participating in ASCOT. RESULTS: Of 2039 patients who underwent surgery for BTC, 211 (10.3%) were already enrolled, 166 (8.1%) were eligible but had not been enrolled, and 1662 (81.5%) were ineligible. Among ineligible patients, the predominant reasons for ineligibility were patient refusal (n = 332, 20.0%), pathologic stage (pT1N0; n = 248, 14.9%), age (≥ 81 years; n = 196, 11.8%), and prolonged postoperative complications (n = 176, 10.6%). CONCLUSIONS: Patients undergoing surgery for BTC are a heterogeneous cohort comprising patients with earlier pathologic stage, advanced age, and prolonged postoperative complications. These factors should be considered during the design of future clinical trials of perioperative treatments for resectable BTC.

[A Case of Hepatic Encephalopathy Caused by Portal Vein Thrombosis after Surgery for Perihilar Cholangiocarcinoma].

A female in her 70s underwent right hepatectomy with resection of caudate lobe and extrahepatic bile duct for perihilar cholangiocarcinoma(T2aN0M0, Stage Ⅱ: Biliary Cancer Treatment Regulations, 7th edition). On the 4th postoperative day, the patient had impaired consciousness, which worsened to almost coma on the 5th postoperative day. On the same day, a blood test showed high ammonia level, thus the state was thought to be hepatic encephalopathy. Contrast -enhanced CT on the same day showed thrombus from the main trunk of the portal vein to the remnant left branch, narrowing of the lumen of the vessel. Simultaneously, enlarged portosystemic shunt in the pelvic floor due to portal hypertension induced by the thrombosis. Plasmapheresis was performed, and anticoagulation with sodium heparin and antithrombin Ⅲ were started. Then, the portal vein thrombus was reduced, and encephalopathy was improved. She was discharged from the hospital on postoperative day 48. She was treated with edoxaban as an outpatient, and anticoagulation therapy was terminated after a CT scan 6 months after surgery, which confirmed no recurrence of thrombus. She is now alive without recurrence of thrombus or tumor for about 2 years after the surgery.

[A Case of Rectal Cancer in Which Total Pelvic Organ Excision Could Be Avoided by TNT Therapy and Robotic Surgery].

The patient is a 50s year old man. He visited his local doctor with complaints of anal pain and bloody stools, and a rectal examination revealed a tumor on the anterior wall of the rectal canal. CT imaging showed tumors invading the prostate, urethra, and anorectal muscles, and a 3 mm-sized nodule was found in the lungs. The patient was diagnosed as cT4bN1M1a, Stage Ⅳ, and total neoadjuvant chemotherapy was planned as preoperative treatment. The 5 Gy×5 times radiation therapy followed by 5 courses of CAPOX plus BEV as preoperative chemotherapy and CAPOX. CAPOX was administered. After completion of treatment, the colonoscopy showed PR, and MRI showed clear boundary between the prostate and tumor but invasion into the anorectal muscles; CT showed no lung metastasis, and preoperative diagnosis was ycT4bN0M0, ycStage Ⅱ. Robotic-assisted rectal amputation and left lateral lymph node dissection were performed under general anesthesia. Pathologically, the patient was diagnosed as ycT4bN0M0, Stage Ⅱ, and the efficacy was determined as TRG 1(AJCC). Vertical dissection was negative and radical resection was possible.

[A Case of Rectal Cancer with Enlarged Lateral Lymph Nodes Treated with Total Neoadjuvant Therapy and Robotic Surgery].

A 70s woman with advanced rectal cancer(AV 3 cm, type 2)was diagnosed as cT3N2M1a, Stage Ⅳ(UICC, TNM 8th) and underwent total neoadjuvant therapy(TNT)consisted of preoperative 5 Gy×5 short course RT followed by 5 courses of CAPOX plus BEV and CAPOX. Post-treatment endoscopy revealed nearCR, MRI failed to identify the primary tumor, and the mesenteric and lateral lymph node enlargement had disappeared. The patient underwent robot-assisted low anterior resection, bilateral lymph node dissection, and temporary ileal colostomy. Postoperative pathological findings were ypT0N0M0, Stage 0, and the efficacy evaluation was TRG 0(AJCC)with no residual tumor including lateral lymph nodes. The patient was discharged on the 16th day without any postoperative complications and is currently alive 6 months postoperatively without recurrence.

[A Case of Locally Advanced Sigmoid Colon Cancer Invading the Urinary Bladder Treated with Neoadjuvant Chemotherapy and Robot Assisted Urinary Bladder-Conserving Surgery].

We report a case of 72s male with locally advanced sigmoid colon cancer. Colonoscopy revealed an advanced sigmoid colon cancer(AV 15 cm, type 2, semi-peripheral, deeper than T3). He was diagnosed as cT4bN2M0, cStage Ⅲc(Japanese Classification of Colorectal, appendiceal, and, Carcinoma, 9th edition), and was given chemotherapy as preoperative treatment. He was treated with CAPOX plus BEV as neoadjuvant chemotherapy. Preoperative diagnosis was ycT4bN0M0, ycStage Ⅱc. The robot assisted high anterior resection and partial bladder resection were performed. The bladder was sutured under robotic assistance. The residual bladder capacity was 100 mL. Postoperative diagnosis was ypT0N0M0, ypStage 0, TRG 0 (AJCC). We experienced a case of neoadjuvant chemotherapy for rectosigmoid colon cancer with bladder invasion, which resulted in pCR.

[A Case of Conversion Surgery after Chemotherapy for Locally Advanced Unresectable Rectal Cancer].

We report a case of locally advanced rectal cancer that could not be curatively resected, in which the patient underwent conversion surgery after chemotherapy. The patient is a 70-year-old woman. She came to our hospital with a chief complaint of lower abdominal pain, and a close examination revealed rectal cancer with invasion of the external iliac artery and pelvic wall. She was treated with mFOLFOX6 plus cetuximab for locally advanced rectal cancer that was not amenable to surgical resection. After 11 courses of chemotherapy, significant shrinkage of the tumor was observed, and robot assisted laparoscopic high-anterior resection was performed. The patient didn't relapse at 12 months after surgery without adjuvant chemotherapy.

[A Case of Single Hole Ileal Resection for Ascendiry Colon Cancer with Ureterocutaneous Fistula in the Right Lower Abdomen].

The patient is a 70s woman. She underwent cystectomy for bladder cancer 6 years ago and had a ureterocutaneous fistula in the right lower abdomen. After colonoscopy for positive fecal occult blood, a type 1 elevated lesion was found in the ascending colon, which was diagnosed as a well-differentiated adenocarcinoma on biopsy. Surgery was performed with a single hole. The approach from the right lower abdomen, where the ureterocutaneous fistula and ureter are located, was avoided, and the approach from the hepatic flexure of the transverse colon was used first. After the right colon was mobilized, the large mesh adhesions around the ureter were carefully dissected, and the right ureter was identified and preserved, extending from the lateral ascending colon to the abdominal wall. The ileal artery was dissected at the root and after dissection of the D3 lymph node, the intestine was dissected and anastomosed extracorporeally. The operative time was 246 minutes with small amount of blood loss. The patient was discharged on the 6th postoperative day without any postoperative complications. The pathology result was pT3N0M0, pStage Ⅱa, and radical resection had been performed. The patient is currently undergoing recurrence-free follow-up.

[A Case of Pathological Complete Response for MSI-High Locally Advanced Unresectable Transverse Colon Cancer Treated with Nivolumab plus Ipilimumab Combination Therapy].

74-year-old woman was diagnosed with locally advanced unresectable transverse colon cancer. She started CAPOX therapy as first-line therapy after ileostomy. After second course, MSI-high was detected, so nivolumab plus ipilimumab combination therapy was started as second-line therapy. After 4 courses of combination therapy, she was judged to be in partial response and surgery was performed. Histopathological diagnosis of the surgical specimen showed complete response, and she is still alive without recurrence 15 months after surgery.

[A Case of Response to Pembrolizmab in Unresectable MSI-High Transverse Colon Cancer].

A 80s man was diagnosed circulated type 2 colon cancer at the transverse colon, and pathological findings was adenocarcinoma( por1). Genomic findings were microsatellite instability-high(MSI-H), all RAS wild type and BRAFV600E mutated. Contrast-enhanced CT showed an enlarged lymph nodes(#221, #222, #223, #214)along the middle colic and superior mesenteric artery. Clinical diagnosis was a locally advanced unresectable transverse colon cancer, cT4aN3M1a(LYM), cStage Ⅳa. Drug therapy with pembrolizumab was prescribed. Six months later, contrast-enhanced CT and PET demonstrated remarkable shrinkage of the primary tumor and lymph nodes except 2 peri-colic enlarged lymph nodes. Primary lesion turned almost undetectable, however the biopsy demonstrated residual tumor. Two months later, CT showed that the residual lymph nodes had also disappeared.

[A Case of Metastatic Liver Tumor from Colon Cancer with Preoperative Diagnosis Obtained by Immunohistochemical Analysis of Cytologic Specimen].

CASE: A woman in her 50s underwent sigmoid colectomy and D3 lymph node dissection for sigmoid cancer(pT3, N0, M0, Stage Ⅱ: Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma 9th). She received adjuvant chemotherapy with capecitabine. Seven months after surgery, contrast-enhanced computed tomography( CECT) scan revealed a small mass in the segment 2 (S2) of the liver with dilation of peripheral intrahepatic bile duct, and the size of this mass and the bile duct dilatation were gradually increased. FDG positron emission tomography(FDG-PET)/CT showed abnormal FDG uptakes in the lesion of S2, and EOB-MRI detected other small lesions in the S6 and S7. Considering the results of image examinations, multiple lesions intrahepatic cholangiocarcinoma was firstly assumed. However, immunohistochemistry of the tumor obtained by endoscopic retrograde cholangiopancreatography (ERCP) showed cytokeratin 7-negative. Based on preoperative diagnosis of liver metastasis from colon cancer rather than intrahepatic cholangiocarcinoma, we performed left lobectomy, partial hepatectomy of S6 and S7 and cholecystectomy. In the resected specimen, the tumor was macroscopically located in the intrahepatic bile ducts. Microscopically, there existed atypical epithelial cells with glandular duct-like structure, and the lesions was histopathologically diagnosed as metastasis from colon cancer. She was discharged on the 10th postoperative day, and she is alive without recurrence one year after surgery.

[Investigation of the Short-Term Outcome of Perioperative Heparinization in Laparoscopic Surgery for Colorectal Cancer].

In aging society, the number of colorectal cancer patients who take antithrombotic drugs is increasing. However, there are not established guidelines for perioperative management for antithrombotic drugs in laparoscopic surgery. Here, we investigated the clinical outcomes of antithrombotic drugs withdrawal and perioperative heparinization in laparoscopic surgery for colorectal cancer patients taking antithrombotic drugs. From January 2015 to December 2017 in our center, patients who took antithrombotic drugs and underwent laparoscopic surgery for colorectal cancer were reviewed retrospectively. The association between postoperative complications and heparinizations was analyzed. Among 79 patients taking antithrombotic drugs, heparinization was performed in 40 patients(50.6%). The total length of hospital stay in heparinization group was 21 days and significantly longer than 13 days in the non-heparinization group. There were no significant differences in the operation time, intraoperative blood loss, and postoperative complications between the 2 groups. The antithrombotic drugs withdrawal and perioperative heparinization were suggested to be safe and feasible in laparoscopic surgery for patients with colorectal cancer.

[A Case of Signet-Ring Cell Carcinoma of the Ampulla of Vater in a Young Male].

A male in his twentieth was referred to our hospital for jaundice. Computed tomography(CT)showed dilation of the intrahepatic and extrahepatic bile ducts and showed a lesion at the ampulla of Vater, which caused obstructive jaundice. Upper gastrointestinal endoscopy revealed a tumor of protruded-predominant type with raised margins at the ampulla of Vater, and biopsy from the lesion indicated malignancy. With no apparent distant metastasis, radical resection was assumed to be possible, thus we performed subtotal stomach preserved pancreatoduodenectomy. Before the operation, endoscopic retrograde biliary drainage(ERBD)was unsuccessful because of the existence of the tumor, so percutaneous transhepatic cholangio drainage(PTCD)was conducted. After the operation, although pancreatic fistula(ISGPF Grade B)occurred, it improved with conservative treatment, and he discharged at 30 postoperative days. Histopathological examination revealed signet-ring cell carcinoma among the tumor at the ampulla of Vater, which was infiltrating into the pancreas. Final diagnosis was pT3, pN0, M0, pStage ⅡA. Now he is alive without recurrence for 3 and a half years.

Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling.

The relative contribution of hepatocyte growth factor (HGF)/MET and epidermal growth factor (EGF)/EGF receptor (EGFR), two key signal transduction systems in the normal and diseased liver, to fate decisions of adult hepatic progenitor cells (HPCs) has not been resolved. Here, we developed a robust culture system that permitted expansion and genetic manipulation of cells capable of multilineage differentiation in vitro and in vivo to examine the individual roles of HGF/MET and EGF/EGFR in HPC self-renewal and binary cell fate decision. By employing loss-of-function and rescue experiments in vitro, we showed that both receptors collaborate to increase the self-renewal of HPCs through activation of the extracellular signal-regulated kinase (ERK) pathway. MET was a strong inducer of hepatocyte differentiation by activating AKT and signal transducer and activator of transcription (STAT3). Conversely, EGFR selectively induced NOTCH1 to promote cholangiocyte specification and branching morphogenesis while concomitantly suppressing hepatocyte commitment. Furthermore, unlike the deleterious effects of MET deletion, the liver-specific conditional loss of Egfr facilitated rather than suppressed progenitor-mediated liver regeneration by switching progenitor cell differentiation toward hepatocyte lineage. These data provide new insight into the mechanisms regulating the stemness properties of adult HPCs and reveal a previously unrecognized link between EGFR and NOTCH1 in directing cholangiocyte differentiation.

[A Case of Undifferentiated Carcinoma of Gallbladder with Five Year Recurrence-Free Survival after Radical Resection].

A woman in her 60s realized heart palpitations and was pointed out anemia. CT revealed a tumor measuring 7 cm, with internal necrosis, originating from the gallbladder and invading the liver, and diagnosed as gallbladder cancer. There existed no distant metastasis and we performed cholecystectomy with partial resection of segment 4a+5 of the liver and lymph node resection. Histopathological examination revealed highly atypical cells with large nuclei and polynuclear cells and poor cell junctions in the specimen, and the tumor was histologically diagnosed as an undifferentiated carcinoma. Metastases were not detected in dissected lymph nodes, and this case was diagnosed as undifferentiated carcinoma of gallbladder, T3a, N0, M0, Stage ⅢA(JSHBPS 6th). She was discharged at 13 days after the operation with no apparent postoperative complications. Postoperative adjuvant chemotherapy with administration of TS-1 was conducted for half a year. Now over 5 years have passed since the operation, and she is alive without recurrence.

[A Case of Nonalcoholic Fatty Liver Disease after Pancreatoduodenectomy Which Reduced Tolerability of Chemotherapy for Postoperative Recurrence].

A man in his 60s underwent pancreaticoduodenectomy(PD)for ampullary cancer(pT3, N1, M0, pStage ⅡB). One year after the operation, lymph node recurrence was observed, and gemcitabine/cisplatin regimen was introduced. Once the disease was controlled, but the tolerability of chemotherapy deteriorated due to severe anorexia and general fatigue around the 6th course of the regimen, thus we stopped the chemotherapy. The performance status was remarkably dropped and the oral intake was notably decreased, and subsequently he got hospitalized. Blood examination on admission showed signs of liver failure(Alb 1.9 g/dL, T-Bil 2.0 mg/dL, PT 36.2%, NH3 159µg/dL). CT scan revealed marked deterioration of fatty liver and newly recognized retention of ascites. We diagnosed this clinical state as liver dysfunction caused by aggravation of nonalcoholic fatty liver disease(NAFLD)due to pancreatic exocrine insufficiency after PD. Immediately pancreatic enzyme replacement therapy(pancrelipase)was performed, and liver function gradually improved. He was discharged 17 days after admission. One month after discharge, CT scan showed that the fatty liver was markedly improved and the ascites disappeared. Around the same time, the chemotherapy was able to be resumed with the improvement of general condition.

[Risk Factors for Recurrence in Patients with Pathological Stage â ¡ Colorectal Cancer].

BACKGROUND: The risk factors for recurrence in patients with pStage Ⅱ colorectal cancer still remains controversial. The aim of this study was to investigate the risk factors for recurrence after surgery in patients with pStage Ⅱ colorectal cancer. METHOD: We retrospectively reviewed 311 patients with primary pStage Ⅱ colorectal cancer who underwent radical resection without neoadjuvant therapy at our institute between January 2014 and December 2019. RESULTS: Of 311 patients, 32 patients(10.3%)developed recurrences after surgery at a median follow-up of 32.9(0.23-74.2)months. The 3-year and 5-year recurrence-free survival(RFS)rate was 88.4% and 87.6%, respectively. A multivariate analysis for RFS showed that only pT4 (HR: 4.06, 95%CI: 1.60-10.29, p=0.003) was an independent risk factor. CONCLUSION: This study revealed that pT4 was an independent risk factor for recurrence after surgery in patients with pStage Ⅱ colorectal cancer.

[A Case of Squamous Cell Cancer of the Anus Treated with Chemoradiotherapy].

BACKGROUND: In Japan, the standard treatment for squamous cell anal cancer(SCAC)has not been established. Herein, we report a case of SCAC that completely responded to chemoradiotherapy(CRT). CASE: A woman in her 80s presented with anal pain and bleeding. Computed tomography revealed bilateral inguinal adenopathy and a tumor in the anal canal. Histopathological examination of endoscopic biopsies showed adenocarcinoma. Thus, she was diagnosed with anal canal adenocarcinoma and lymph node metastases:cT3, cN1a(No. 292), cM0, cStage Ⅲc(Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma, 9th edition). Owing to her advanced age and refusal of a stoma, CRT(S-1, mitomycin C, and radiotherapy)was administered with the expectation that salvage surgery in the form of rectal amputation would eventually be necessary. The tumor noticeably shrank after CRT. The patient is alive to this date,14 months after the final round of CRT.