Early Tumor Shrinkage and Depth of Response as Predictors of Survival for Advanced Biliary Tract Cancer: An Exploratory Analysis of JCOG1113.

BACKGROUND: Recent studies suggest that early tumor shrinkage (ETS) and depth of response (DpR) reflect outcomes of chemotherapy in various cancers. This study evaluated the association of ETS and DpR with clinical outcomes using data from JCOG1113, which demonstrated the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for chemotherapy-naïve advanced biliary tract cancer. MATERIAL AND METHODS: In total, 354 (289 with measurable target lesions) patients enrolled in JCOG1113 were divided into ETS-unachieved and ETS-achieved groups (≥20% tumor reduction at week 6) and DpR-low and DpR-high groups (≥40% maximum shrinkage) until 12 weeks after enrollment. The impact of ETS and DpR on survival outcome was evaluated using the multivariable Cox proportional hazard model. RESULTS: The proportions of patients in the ETS-achieved and DpR-high groups were similar between the 2 treatment arms. The hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for the ETS-achieved group were 0.70 (95% confidence interval (CI), 0.52-0.93) and 0.60 (95%CI, 0.44-0.81), respectively. The HRs of PFS and OS for the DpR-high group were 0.67 (95%CI, 0.48-0.94) and 0.64 (95%CI, 0.46-0.90), respectively. In the subpopulation treatment effect pattern plot analysis, most patients in the ETS-achieved group in the GC arm did not experience disease progression after 12 weeks from the landmark. CONCLUSION: As on-treatment markers, ETS and DpR were effective tools. ETS was clinically useful, because it can be used to evaluate the outcomes of treatment early at a specific time.

Development of a nomogram to predict survival in advanced biliary tract cancer.

The prognosis of advanced biliary tract cancer (BTC) patients remains poor due to limited efficacy of chemotherapy and difficulties in management. Thus, prediction of survival is crucial for the clinical management of advanced BTC. The aim was to develop and validate a nomogram to predict 6-month and 12-month survival in advanced BTC patients treated with chemotherapy. A multivariable Cox regression model was used to construct a nomogram in a training set (JCOG1113, a phase III trial comparing gemcitabine plus S-1 [GS] and gemcitabine plus cisplatin, n = 351). External validity of the nomogram was assessed using a test set (JCOG0805, a randomized, phase II trial comparing GS and S-1 alone, n = 100). Predictive performance was assessed in terms of discrimination and calibration. The constructed nomogram included lymph node metastasis, liver metastasis, carbohydrate antigen 19-9, carcinoembryonic antigen, albumin, and C-reactive protein. Uno's concordance index was 0.661 (95% confidence interval [CI] 0.629-0.696) in the training set and 0.640 (95% CI 0.566-0.715) in the test set. The calibration plots for 6-month and 12-month survival showed good agreement in the two analysis sets. The present nomogram can facilitate prediction of the prognosis of advanced BTC patients treated with chemotherapy and help clinicians' prognosis-based decision-making.

Successful endovascular embolization of the common hepatic artery for pseudoaneurysm associated with pancreatic fistula after liver transplantation: a case report.

BACKGROUND: After orthotopic liver transplantation (OLT), complications such as hepatic artery stenosis, thrombosis, and bleeding are possible. Hepatic artery pseudoaneurysms (HAP) are prone to rupture, rupture hemorrhage, and increased mortality risk. Endovascular treatment of HAP may result in recurrence, even after successful embolization with thrombin. Formation of a HAP in the common hepatic artery (CHA) is challenging because the CHA is the only artery in the liver graft after OLT. Therefore, CHA embolization in HAP is not an initial option. We report a case of HAP at the CHA after OLT that was treated with endovascular therapy, resulting in the occlusion of the CHA with coil embolization, achieving a radical cure. CASE PRESENTATION: A 59-year-old man with decompensated hepatitis C virus cirrhosis underwent deceased donor whole-liver transplantation after graft failure of a living donor liver transplantation. After the second transplantation, the patient developed infectious narrow-necked HAP at the CHA associated with postoperative pancreatic fistula. Repeated transcatheter arterial embolization with thrombin and n-butyl-2-cyanoacrylate was unsuccessful, as confirmed by postprocedure angiography, which revealed recanalization and regrowth of the HAP. Eight months after the first transcatheter arterial embolization, the patient presented with a chief complaint of abdominal pain due to an enlarged HAP. Angiography of the superior mesenteric artery (SMA) revealed a collateral bypass around the bile duct from the SMA to the liver graft. Coil embolization of the HAP in the CHA completely occluded the HAP without complications. More than 2 years after coil embolization, the liver graft function test results remained within normal limits without HAP recurrence. CONCLUSIONS: HAP at the CHA after liver transplantation can be fatal if ruptured. Because the liver is a highly angiogenic organ, even if initial treatment is not successful, radical treatment to occlude the CHA with HAP is possible if sufficient collateral vessels are developed.

A Ruptured Mucinous Cystadenocarcinoma of the Pancreas Extensively Evaluated Before and After the Rupture: A Case Report.

ABSTRACT: Pancreatic mucinous cystic neoplasm (MCN) rarely ruptures because of their surrounding fibrotic capsules and has never been reported with detailed information regarding prerupture and postrupture states. We report a case of MCN rupture where performed emergency surgery was performed while waiting for elective surgery. A 54-year-old woman was referred to our department for a pancreatic cystic tumor with slight abdominal pain. A cystic tumor with a nodular lesion was found, with a contrast effect measuring 78 mm in diameter. On day 21, the patient visited our hospital complaining of increased abdominal pain, but few signs of peritonitis were observed. Tests conducted revealed moderate ascites, marginal shrinkage of the cyst diameter, and a slight elevation of inflammatory markers. We suspected an MCN rupture and immediately performed distal pancreatectomy. Brown turbid ascites and rupture of the anterior wall of the cyst were observed. In the ascites, amylase levels were not elevated, and bacterial cultures were negative. The histopathological diagnosis was noninvasive mucinous cystadenocarcinoma. At 9 months after surgery, she started chemotherapy because of a recurrence of the peritoneal dissemination. This case provided valuable insight into the rupture of MCNs using thorough imaging techniques, laboratory, and physical findings before and after rupturing.

Anti-tumor effect of avadomide in gemcitabine-resistant pancreatic ductal adenocarcinoma.

PURPOSE: Although gemcitabine-based chemotherapy is most recommended for pancreatic ductal adenocarcinoma (PDAC), its effectiveness is limited because of drug resistance. Given thalidomide's anti-tumor effects in solid tumors, we investigated the effect of avadomide, a novel thalidomide analog, on PDAC and explored its anti-tumor mechanisms. METHODS: PDAC cell lines, including gemcitabine-resistant (GR) clones derived from MiaPaCa2 cells, were used to evaluate the effects of avadomide. An annexin V assay, a cell cycle assay, and western blot analysis were performed to explain the mechanism of avadomide as an anti-tumor reagent. Moreover, we investigated the anti-tumor effect on tumor growth using a subcutaneous xenograft murine model. RESULTS: Avadomide showed anti-tumor effects in human PDAC cell lines. The proportion of apoptotic cells and G0/G1 phase cells after avadomide treatment increased, especially in the GR PDAC clones. Western blot analysis also showed the induction of the apoptotic pathway by inhibiting the NF-κB process and G1 phase cell cycle arrest. The xenograft murine model revealed that the proportion of viable cells in the avadomide-treated group was lower than that in the untreated group. CONCLUSION: Our findings suggest that avadomide could be a novel therapeutic option to overcome gemcitabine resistance in patients with PDAC.

SPARC accelerates biliary tract cancer progression through CTGF-mediated tumor-stroma interactions: SPARC as a prognostic marker of survival after neoadjuvant therapy.

PURPOSE: In biliary tract cancer (BTC), malignancy is strongest at the invasion front. To improve the BTC prognosis, the invasion front should be controlled. We evaluated tumor-stroma crosstalk at the tumor center and at the invasion front of BTC lesions. We investigated the expression of SPARC, a marker of cancer-associated fibroblasts, and determined its ability to predict BTC prognosis after neoadjuvant chemoradiotherapy (NAC-RT). METHODS: We performed immunohistochemistry to evaluate SPARC expression in resected specimens from patients that underwent BTC surgery. We established highly invasive (HI) clones in two BTC cell lines (NOZ, CCLP1), and performed mRNA microarrays to compare gene expression in parental and HI cells. RESULTS: Among 92 specimens, stromal SPARC expression was higher at the invasion front than at the lesion center (p = 0.014). Among 50 specimens from patients treated with surgery alone, high stromal SPARC expression at the invasion front was associated with a poor prognosis (recurrence-free survival: p = 0.033; overall survival: p = 0.017). Coculturing fibroblasts with NOZ-HI cells upregulated fibroblast SPARC expression. mRNA microarrays showed that connective tissue growth factor (CTGF) was upregulated in NOZ-HI and CCLP1-HI cells. A CTGF knockdown suppressed cell invasion in NOZ-HI cells. Exogeneous CTGF upregulated SPARC expression in fibroblasts. SPARC expression at the invasion front was significantly lower after NAC-RT, compared to surgery alone (p = 0.003). CONCLUSION: CTGF was associated with tumor-stroma crosstalk in BTC. CTGF activated stromal SPARC expression, which promoted tumor progression, particularly at the invasion front. SPARC expression at the invasion front after NAC-RT may serve as a prognosis predictor.

Long-Term Feasibility of Rescue Reconstruction for Isolated Bile Ducts With Using Cystic Duct in Living Donor Liver Transplantation.

BACKGROUND: The isolated bile duct is sometimes observed in the right liver graft of living donor liver transplantation (LDLT). Even though, as a rescue option, it is known to use the recipient's cystic duct (CyD) for duct-to-duct anastomosis, the long-term feasibility of rescue duct-to-CyD (D-CyD) anastomosis remains unclear. METHODS: We prospectively collected data in the right liver-LDLT cohort and compared rescue D-CyD anastomosis (n = 4) with standard duct-to-hepatic duct (D-HD, n = 45) anastomosis (D-CyD group, n = 4). RESULTS: The observation period was over 5 years (range, 68-171 mo) after LDLT. The D-CyD group included the following anastomosis procedures: anastomosis between the intrahepatic bile duct of the graft and the CyD of the recipient and anastomosis between the posterior HD and the CyD. Surgical outcomes between the 2 groups are similar, excluding the time for the biliary reconstruction (D-CyD, 116 ± 13 min vs D-HD, 57 ± 3 min). During the period, one recipient in the D-CyD group exhibited postoperative biliary stricture and biliary stone, and 6 recipients underwent those complications in the D-HD group (D-CyD, 25.0% vs D-HD, 13.3%) All recipients in the D-CyD group are presently alive and have not experienced liver dysfunction. CONCLUSIONS: Our findings suggest that rescue D-CyD anastomosis for an isolated bile duct in a right liver LDLT is acceptable as a life-saving option in terms of long-term feasibility.

Effect of systemic inflammatory response on induction chemotherapy followed by chemoradiotherapy for locally advanced pancreatic cancer: an exploratory subgroup analysis on systemic inflammatory response in JCOG1106.

OBJECTIVE: JCOG1106, a randomized phase II trial conducted to compare chemoradiotherapy (S-1 concurrent radiotherapy) with (Arm B) or without (Arm A) induction chemotherapy using gemcitabine in patients with locally advanced pancreatic cancer, showed a more favorable long-term survival in Arm A. This study was aimed at exploring whether some subgroups classified by the systemic inflammatory response might derive greater benefit from either treatment. METHODS: All subjects eligible for JCOG1106 were included in this analysis (n = 51/49 in Arm A/B). This exploratory subgroup analysis was performed by Cox regression analysis to investigate the impact of the systemic inflammatory response, as assessed based on the serum C-reactive protein, serum albumin (albumin), Glasgow Prognostic Score and derived neutrophil-lymphocyte ratio, at the baseline on overall survival. P values <0.1 for the interaction were regarded as denoting significant association. RESULTS: Glasgow prognostic score showed significant treatment interactions for overall survival. Hazard ratios of Arm B to Arm A were 1.35 (95% confidence interval, 0.82-2.23) in the Glasgow Prognostic Score 0 (C-reactive protein ≤10 mg/L and albumin ≥35 g/L) (n = 44/34 in Arm A/B) and 0.59 (95% confidence interval, 0.24-1.50) in the Glasgow Prognostic Score 1/2 (C-reactive protein >10 mg/L and/or albumin <35 g/L) (n = 7/15) (P-interaction = 0.06). C-reactive protein alone and albumin alone also showed significant treatment interactions for overall survival. CONCLUSIONS: Survival benefits of induction chemotherapy in chemoradiotherapy for locally advanced pancreatic cancer were observed in patients with elevated Glasgow Prognostic Score, high C-reactive protein and low albumin. These results suggest that systemic inflammatory response might be considered to apply induction chemotherapy preceding chemoradiotherapy.

[A Case of Sister Mary Joseph's Nodule after Radiation Therapy for Cervical Cancer].

An umbilical metastasis from an internal malignancy is called Sister Mary Joseph's nodule(SMJN)and has a poor prognosis. Herein, we report a case of umbilical metastasis of cervical cancer. A woman in her eighties underwent radiation therapy for cervical cancer(cT3bN0M0, cStage ⅢB). Primary tumor shrank after treatment, suggesting that radiation therapy induced complete response. Two years and 9 months after treatment, the patient presented with umbilical pain. A CT scan showed an umbilical mass near the umbilical hernia. PET-CT demonstrated high accumulation of FDG at the mass, which led to suspicion of umbilical metastasis(SMJN). Although she underwent radical surgery, she died from cancer 8 months after surgery.

The impact of cellular senescence and senescence­associated secretory phenotype in cancer­associated fibroblasts on the malignancy of pancreatic cancer.

Cancer­associated fibroblasts (CAFs) are implicated in the strong malignancy of pancreatic cancer (PC). Various CAF subtypes have different functions, and their heterogeneity likely influence the malignancy of PC. Meanwhile, it is known that senescent cells can create a tumor­promoting microenvironment by inducing a senescence­associated secretory phenotype (SASP). In the present study, the effects of individual differences in CAFs on PC malignancy were investigated with a focus on cellular senescence. First, primary cultures of CAFs from 8 PC patients were generated and co­cultured with PC cell lines. This co­culture assay showed that differences in CAFs induce differences in PC cell proliferation. It was further investigated which clinical factors affected the malignant potential of CAF and it was found that the difference of malignant potential of each CAF was marginally related to the age of original patients. Next, to verify the senescence of CAFs really affected the malignant potential of CAF, PCR array analysis of each CAF sample was performed and it was revealed that expression of genes about cellular senescence and SASP such as tumor protein p53, nuclear factor kappa B subunit 1, and IL6, are related to the malignant potential of CAFs impacting on PC proliferation. Finally, to elucidate the effect of p53­mediated cellular senescence of CAFs on malignant potential of PC, it was examined whether CAFs with the treatment of p53 inhibitor affected PC cell proliferation in co­culture assays. The treatment of CAFs with p53 inhibitor significantly suppressed PC cell proliferation. In addition, a comparison of the concentration of IL­6, a SASP cytokine, in the co­culture supernatant showed a significant decrease in the sample after p53 inhibitor treatment. In conclusion, the present results suggested that proliferation potential of PC may be related to p53­mediated cellular senescence and SASP of CAFs.

[A Case of Conversion Surgery after Long-Term Chemotherapy for Pancreatic Cancer with Peritoneal Metastasis].

A 66-year-old woman was referred to the gastroenterology division of our hospital due to elevation of serum CEA level. Contrast-enhanced CT showed a hypovascular tumor at the body of pancreas. She was diagnosed with pancreatic cancer by EUS-FNA. By laparotomy, we found white nodules on mesentery and abdominal wall, which were diagnosed as peritoneal metastasis. After systemic chemotherapy with 9 courses of gemcitabine(GEM)plus nab-paclitaxel(PTX)and 30 courses of mFOLFIRINOX, the tumor had shrunk and serum CA19-9 level were remarkably decreased. Distal pancreatectomy was performed as conversion surgery. Pathological analysis revealed no remnant cancer cells in the primary tumor or the lymph nodes, confirming a pCR. S-1 was started as adjuvant chemotherapy, and she remains alive without recurrence 8 months after surgery.

[A Case of Hepatocellular Carcinoma Extending into Right Atrium Was Resected Successfully Using Cardiopulmonary Bypass].

A 59-year-old male was referred to our hospital for a thorough examination of liver function abnormality in the background of chronic hepatitis C. Abdominal contrast-enhanced CT showed multiple tumors in the right lobe of the liver, and an 8 cm tumor occupying S7, a tumor thrombus extending from the right hepatic vein to the inferior vena cava, and a tumor thrombus in the right branch of the portal vein. The patient was diagnosed with hepatocellular carcinoma, cT4N0M0, cStage ⅣA. After 5 courses of hepatic arterial infusion therapy, the intrahepatic lesion was significantly reduced, but micropulmonary metastasis appeared, and the tumor thrombus in the inferior vena cava increased to the thoracic inferior vena cava and just below the tricuspid valve. The patient had difficulty blocking blood flow in the inferior vena cava in the pericardial sac. The patient underwent right hepatectomy, tumor thrombus resection of the inferior vena cava, combined resection of the inferior vena cava, and bovine pericardial patch reconstruction under artificial cardiopulmonary support. He was discharged on the 23rd day after surgery and has been under outpatient observation for 16 months while receiving molecular-targeted drugs for lung metastasis.

Rubicon can predict prognosis in patients with pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy.

BACKGROUND: Despite previous therapeutic studies on autophagy in cancer, its role in the treatment of pancreatic ductal adenocarcinoma remains controversial, especially regarding its effect on chemotherapy, radiotherapy, and both combined. We focused on RUN domain Beclin-1 interacting and cysteine-rich-containing protein (Rubicon) to reveal its contribution to pancreatic ductal adenocarcinoma after chemoradiotherapy. METHODS: To evaluate the clinical significance of Rubicon, immunohistochemistry was performed, and Rubicon expression was analyzed across 81 specimens resected from patients with pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy. A gemcitabine-resistant pancreatic ductal adenocarcinoma cell line was established followed by Rubicon expression and autophagy flux estimation. Finally, gemcitabine sensitivity, invasion ability, and cell viability were evaluated using Rubicon-targeting small interfering RNA. RESULTS: Rubicon expression in resected pancreatic ductal adenocarcinoma samples after chemoradiotherapy revealed significantly worse overall survival and recurrence-free survival in the Rubicon-high expression group than in the Rubicon-low expression group (overall survival: median [years] 2.02 vs. 3.21, p = 0.0359; recurrence-free survival: median [years] 0.90 vs. 1.90, p = 0.0146). In vitro, gemcitabine-resistant pancreatic ductal adenocarcinoma cell lines exhibited higher Rubicon expression and lower autophagy flux than the parental cell line (p < 0.01). Transduction with small interfering RNA downregulated the expression without affecting gemcitabine sensitivity, but it reduced invasion ability and cell viability (p < 0.01) in the gemcitabine-resistant pancreatic ductal adenocarcinoma cell line. CONCLUSIONS: High Rubicon expression is a significant, unfavorable prognostic factor in pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy. Downregulation of Rubicon expression improves invasion ability and cell viability in gemcitabine-resistant pancreatic ductal adenocarcinoma.

[A Case of Thoracic Esophageal Cancer Treated with COVID-19 Pneumonia during Preoperative Chemoradiotherapy(CRT)].

INTRODUCTION: There is concerned that prognosis of cancer-bearing patients is adversely affected by postponement of cancer treatment due to infection with a new type of coronavirus(COVID-19). We report a case of thoracic esophageal cancer treated with COVID-19 pneumonia during preoperative CRT. A 60-year-old female diagnosed as having Stage Ⅳ thoracic esophageal cancer(cT3N0M1LYM[104R])started receiving preoperative chemoradiotherapy. On the 12th day, she had a fever and was diagnosed with COVID-19 infection. CRT temporarily interrupted and she was treated for COVID-19 pneumonia preferentially. CRT was resumed promptly after remission. Finally, video-Assisted radical esophagectomy was performed. There were no postoperative complications. Nivolumab was started as an adjuvant therapy on the 2nd postoperative months. CONCLUSIONS: We experienced a case of thoracic esophageal cancer in which COVID-19 pneumonia was treated during preoperative CRT, and CRT and surgery were completed without complications by appropriate treatment.

Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. METHODS: This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). FINDINGS: Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). INTERPRETATION: Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. FUNDING: The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

[A Case of Pancreatic Metastasis from Renal Cell Carcinoma 16 Years after Left Nephrectomy].

A 73-year-old woman underwent left nephrectomy for renal cell carcinoma(RCC). The computed tomography(CT)and magnetic resonance imaging(MRI)revealed a 20-mm tumor in the pancreatic tale showing early enhancement in the arterial phase 16 years after surgery. Fluorodeoxyglucose positron emission tomography(FDG-PET)showed slightly uptake (maximum standard uptake value: SUVmax 2.3)and EUS-FNA showed a hyper-vascularized tumor in the pancreatic tail. A single pancreatic metastasis from RCC was diagnosed, and we performed distal pancreatectomy. The histopathological diagnosis was a metastatic pancreatic tumor from RCC. The postoperative course was uneventful and 1 month after surgery, she is alive with no recurrence.

[A Case of Radical Resection after Neoadjuvant Chemotherapy for Rectal Cancer with Pelvic Abscess].

A 66-year-old man with a history of frequent diarrhea was diagnosed with rectal cancer with obstruction and a pelvic abscess. Following a transverse colostomy, he was referred to our hospital. The initial diagnosis was rectal cancer(cT4a N1bM0, cStage Ⅲb)and a pelvic abscess due to tumor perforation. To address this condition, we performed neoadjuvant chemotherapy using a combination of 5-fluorouracil, Leucovorin, oxaliplatin, and irinotecan(FOLFOXIRI). Following 6 courses of FOLFOXIRI, the abscess disappeared and no signs of tumor progression and distant metastases were detected. Subsequently, we performed radical resection with D3LD2 lymph node dissection, leading to a pathological diagnosis of ypT3N1aM0, ypStage Ⅲb. The patient then underwent adjuvant chemotherapy with capecitabine and oxaliplatin(CAPOX). No recurrence was observed after 9 months of follow-up.

[A Case of Long-Term Survival with Multidisciplinary Treatment for Postoperative Local Recurrence of Intrahepatic Cholangiocarcinoma].

We report a case of local recurrence of intrahepatic bile duct cancer that was successfully treated using chemotherapy and radiation therapy. A man in his 80s underwent hepatic resection for intrahepatic cholangiocarcinoma, and abdominal CT 11 months after surgery revealed local recurrence around the dissected surface. He was diagnosed with a local recurrence of intrahepatic cholangiocarcinoma and started systemic chemotherapy(GEM plus CDDP plus S-1). After 11 courses of chemotherapy, stereotactic body radiation therapy(SBRT)was administered to the same site at 50 Gy/10 Fr, as the local recurrence area had increased, although no distant metastases were detected on imaging. The patient was then started on chemotherapy( GEM plus S-1), but after 2 courses, 8 courses of GEM alone were administered at the patient's request. No increase in tumor markers was observed, but an increase in the low-absorption area was observed on imaging. Thereafter, the regimen was changed to S-1. Three months later, the same area was reduced in size and obscured on imaging evaluation. The patient is still taking it 12 months later. No recurrence has been observed since 2 years and 7 months after the start of treatment for local recurrence. This case suggested that multidisciplinary therapy might be useful for local recurrence of intrahepatic cholangiocarcinoma.

Noninvasive Liver Fibrosis Staging: Comparison of MR Elastography with Extracellular Volume Fraction Analysis Using Contrast-Enhanced CT.

Purpose: To compare the accuracy of liver fibrosis staging with MR elastography and of staging with extracellular volume fraction (fECV) analysis using contrast-enhanced CT. Methods: This retrospective study included 60 patients who underwent both MR elastography and contrast-enhanced CT before liver surgery between October 2013 and July 2020. Two radiologists independently measured liver stiffness of MR elastography and fECV of CT images. Accuracy for liver fibrosis staging was assessed using receiver operating characteristic (ROC) analysis. Correlations between liver stiffness or fECV and liver fibrosis were also evaluated by means of the Spearman rank correlation coefficient. Results: The areas under the ROC curves for MR elastography for each stage differentiation of ≥F1 (0.85, 0.82 for the two radiologists), ≥F2 (0.88, 0.89), ≥F3 (0.87, 0.86), and F4 (0.84, 0.83) were greater than those for fECV analysis with CT (0.64, p = 0.06, 0.69, p = 0.2; 0.62, p < 0.005, 0.63, p < 0.005; 0.62, p < 0.005, 0.62, p < 0.01; and 0.70, p = 0.08, 0.71, p = 0.2, respectively). The correlation coefficients between liver stiffness and liver fibrosis in A0 (0.67, 0.69 for the two radiologists), A1 (0.64, 0.66) and A2 group (0.58, 0.51) were significantly higher than those between fECV and liver fibrosis (0.28, 0.30; 0.27, 0.31; and 0.23, 0.07; p < 0.05 for all comparisons). Conclusion: MR elastography allows for more accurate liver fibrosis staging compared with fECV analysis with CT. In addition, MR elastography may be less affected than fECV analysis by the inflammatory condition.

Prognostic value of functional SMAD4 localization in extrahepatic bile duct cancer.

BACKGROUND: SMAD4 is a key mediator of TGFß signaling and one of the mutated genes in extrahepatic bile duct cancer (eBDC). It has been also reported that SMAD4 has dual functions, in carcinogenesis via silencing and in tumor invasion/metastasis via signaling, depending on tumor stage. We previously visualized more nuclear transitioning functional SMAD4 at the tumor invasion front than the central lesion. So, we investigated the localization of functional SMAD4 (e.g., invasion area or metastasis lesion) and its association with chemotherapy and chemo-radiation therapy. METHODS: We performed SMAD4 immunostaining on 98 resected eBDC specimens and evaluated the presence of the functional form of nuclear SMAD4 at the central lesion, invasion front, and metastatic lymph node. We also examined the influence on chemotherapy after recurrence (n = 33) and neoadjuvant chemo-radiation therapy (NAC-RT, n = 21) and the prognostic value of using retrospective data. RESULTS: In 73 patients without NAC-RT, 8.2% had loss of SMAD4 expression and 23.3% had heterogeneous expression. Patients without SMAD4 expression at any site had significantly poorer overall survival (OS) than other patients (P = 0.014). Expression of SMAD4 at the invasion front was related to better survival (recurrence-free survival [RFS] P = 0.033; OS P = 0.047), and no SMAD4 expression at the metastatic lymph node was related to poorer OS (P = 0.011). The patients who had high SMAD4 expression had poorer prognosis after recurrence (RFS P = 0.011; OS P = 0.056). At the residual cancer in the resected specimen, SMAD4 was highly expressed after NAC-RT (P = 0.039). CONCLUSIONS: Loss of SMAD4 protein expression was a poor prognostic factor in eBDC at resectable stage. However, the intensity of functional SMAD4 in eBDC is a marker of resistance to chemo-radiotherapy and malignant potential at advanced stages.