New Function Annotation of PROSER2 in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis due to the absence of diagnostic markers and molecular targets. Here, we took an unconventional approach to identify new molecular targets for pancreatic cancer. We chose uncharacterized protein evidence level 1 without function annotation from extensive proteomic research on pancreatic cancer and focused on proline and serine-rich 2 (PROSER2), which ranked high in the cell membrane and cytoplasm. In our study using cell lines and patient-derived orthotopic xenograft cells, PROSER2 exhibited a higher expression in cells derived from primary tumors than in those from metastatic tissues. PROSER2 was localized in the cell membrane and cytosol by immunocytochemistry. PROSER2 overexpression significantly reduced the metastatic ability of cancer cells, whereas its suppression had the opposite effect. Proteomic analysis revealed that PROSER2 interacts with STK25 and PDCD10, and their binding was confirmed by immunoprecipitation and immunocytochemistry. STK25 knockdown enhanced metastasis by decreasing p-AMPK levels, whereas PROSER2-overexpressing cells increased the level of p-AMPK, indicating that PROSER2 suppresses invasion via the AMPK pathway by interacting with STK25. This is the first demonstration of the novel role of PROSER2 in antagonizing tumor progression via the STK25-AMPK pathway in PDAC. LC-MS/MS data are available at MassIVE (MSV000092953) and ProteomeXchange (PXD045646).

Application of plasma circulating KRAS mutations as a predictive biomarker for targeted treatment of pancreatic cancer.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in circulating tumor deoxyribonucleic acid (ctDNA) have been reported as representative noninvasive prognostic markers for pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to evaluate single KRAS mutations as prognostic and predictive biomarkers, with an emphasis on potential therapeutic approaches to PDAC. A total of 128 patients were analyzed for multiple or single KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, and G13D) in their tumors and plasma using droplet digital polymerase chain reaction (ddPCR). Overall, KRAS mutations were detected by multiplex ddPCR in 119 (93%) of tumor DNA and 68 (53.1%) of ctDNA, with a concordance rate of 80% between plasma ctDNA and tumor DNA in the metastatic stage, which was higher than the 44% in the resectable stage. Moreover, the prognostic prediction of both overall survival (OS) and progression-free survival (PFS) was more relevant using plasma ctDNA than tumor DNA. Further, we evaluated the selective tumor-suppressive efficacy of the KRAS G12C inhibitor sotorasib in a patient-derived organoid (PDO) from a KRAS G12C-mutated patient using a patient-derived xenograft (PDX) model. Sotorasib showed selective inhibition in vitro and in vivo with altered tumor microenvironment, including fibroblasts and macrophages. Collectively, screening for KRAS single mutations in plasma ctDNA and the use of preclinical models of PDO and PDX with genetic mutations would impact precision medicine in the context of PDAC.

Refining Classification of Cholangiocarcinoma Subtypes via Proteogenomic Integration Reveals New Therapeutic Prospects.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinomas (iCCs) are characterized by their rarity, difficult diagnosis, and overall poor prognosis. The iCC molecular classification for developing precision medicine strategies was investigated. METHODS: Comprehensive genomic, transcriptomic, proteomic, and phosphoproteomic analyses were performed on treatment-naïve tumor samples from 102 patients with iCC who underwent surgical resection with curative intent. An organoid model was constructed for testing therapeutic potential. RESULTS: Three clinically supported subtypes (stem-like, poorly immunogenic, and metabolism) were identified. NCT-501 (aldehyde dehydrogenase 1 family member A1 [ALDH1A1] inhibitor) exhibited synergism with nanoparticle albumin-bound-paclitaxel in the organoid model for the stem-like subtype. The oncometabolite dysregulations were associated with different clinical outcomes in the stem-like and metabolism subtypes. The poorly immunogenic subtype harbors the non-T-cell tumor infiltration. Integrated multiomics analysis not only reproduced the 3 subtypes but also showed heterogeneity in iCC. CONCLUSIONS: This large-scale proteogenomic analysis provides information beyond that obtained with genomic analysis, allowing the functional impact of genomic alterations to be discerned. These findings may assist in the stratification of patients with iCC and in developing rational therapeutic strategies.

Cancer depends on fatty acids for ATP production: A possible link between cancer and obesity.

Several metabolic pathways for the supply of adenosine triphosphate (ATP) have been proposed; however, the major source of reducing power for ADP in cancer remains unclear. Although glycolysis is the source of ATP in tumors according to the Warburg effect, ATP levels do not differ between cancer cells grown in the presence and absence of glucose. Several theories have been proposed to explain the supply of ATP in cancer, including metabolic reprograming in the tumor microenvironment. However, these theories are based on the production of ATP by the TCA-OxPhos pathway, which is inconsistent with the Warburg effect. We found that blocking fatty acid oxidation (FAO) in the presence of glucose significantly decreased ATP production in various cancer cells. This suggests that cancer cells depend on fatty acids to produce ATP through FAO instead of glycolysis. We observed that cancer cell growth mainly relies on metabolic nutrients and oxygen systemically supplied through the bloodstream instead of metabolic reprogramming. In a spontaneous mouse tumor model (KrasG12D; Pdx1-cre), tumor growth was 2-fold higher in mice fed a high-fat diet (low-carbo diet) that caused obesity, whereas a calorie-balanced, low-fat diet (high-carbo diet) inhibited tumor growth by 3-fold compared with that in mice fed a control/normal diet. This 5-fold difference in tumor growth between mice fed low-fat and high-fat diets suggests that fat-induced obesity promotes cancer growth, and tumor growth depends on fatty acids as the primary source of energy.

Phase 1 trial of 4-1BB-based adoptive T-cell therapy targeting human telomerase reverse transcriptase in patients with advanced refractory solid tumors.

BACKGROUND AIMS: Human telomerase reverse transcriptase (hTERT) is an attractive target for anti-cancer therapies. We developed an effective method for generating hTERT-specific CD8+ T cells (hTERT-induced natural T cells [TERTiNTs]) using peripheral blood mononuclear cells (PBMCs) from patients with solid cancers and investigated their feasibility and safety. METHODS: This was a single-center phase 1 trial using a 3 + 3 dose escalation design to evaluate six dose levels of TERTiNTs. PBMCs from each patient were screened using an hTERT peptide panel to select those that stimulated CD8+ T cells. The four most stimulatory peptides were used to produce autologous CD8+ T cells from patients refractory or intolerant to standard therapies. Eligible patients received a single intravenous infusion of TERTiNTs at different dose levels (4 × 108 cells/m2, 8 × 108 cells/m2 and 16 × 108 cells/m2). Pre-conditioning chemotherapy, including cyclophosphamide alone or in combination with fludarabine, was administered to induce lymphodepletion. RESULTS: From January 2014 to October 2019, a total of 24 patients with a median of three prior lines of therapy were enrolled. The most common adverse events were lymphopenia (79.2%), nausea (58.3%) and neutropenia (54.2%), mostly caused by pre-conditioning chemotherapy. The TERTiNT infusion was well tolerated, and dose-limiting toxicities were not observed. None of the patients showed objective responses. Seven patients (30.4%) achieved stable disease with a median progression-free survival of 3.9 months (range, 3.2-11.3). At the highest dose level (16 × 108 cells/m2), four of five patients showed disease stabilization. CONCLUSIONS: The generation of TERTiNTs was feasible and safe and provided an interesting disease control rate in heavily pre-treated cancer patients.

Prolonged patency of fully covered self-expandable metal stents with an externally anchored plastic stent in distal malignant biliary obstruction.

BACKGROUND : Fully covered self-expandable metal stents (FCSEMSs) are widely used for endoscopic treatment of distal malignant biliary obstruction (dMBO). We aimed to assess the efficacy of anchoring an external plastic stent to an FCSEMS in dMBO. METHODS : A multicenter retrospective cohort study was performed in patients with dMBO to compare stent patency between FCSEMSs and FCSEMSs with an externally anchored plastic stent (EPS). For external anchoring, a 7-Fr double-pigtail plastic stent (DPPS) was placed first in the bile duct, then an FCSEMS was deployed side-by-side. RESULTS : Among a total of 185 patients, 65 had an FCSEMS alone and 120 had an FCSEMS with an EPS. The median stent patency was significantly longer in the FCSEMS with an EPS group than in the FCSEMS only group (342 vs. 240 days; P = 0.04). The rate of stent migration was significantly lower in the FCSEMS with an EPS group than in the FCSEMS only group (10.8 % vs. 27.7 %; P = 0.01). There were no significant differences in the rates of stent occlusion and adverse events between the two groups. CONCLUSIONS : A novel and simple technique of anchoring an external plastic stent may decrease the risk of FCSEMS migration and prolong stent patency, without significantly increasing the adverse events rate in dMBO.

Percutaneous transhepatic treatment for biliary stricture after duct-to-duct biliary anastomosis in living donor liver transplantation: a 9-year single-center experience.

OBJECTIVES: To investigate clinical outcomes of percutaneous transhepatic treatment for biliary stricture after duct-to-duct biliary anastomosis in living donor liver transplantation (LDLT). METHODS: This retrospective study examined baseline characteristics, procedural details, clinical outcomes, drainage catheter removal rate within 8 months, and recurrence after catheter removal using patients' medical records and images. Risk factors for failure of drainage catheter removal within 8 months and recurrence of biliary stricture after drainage catheter removal were assessed via univariable and multivariable analyses. RESULTS: A total of 112 patients (53.4 ± 8.79 years, 91 men) were evaluated. Multiple drainage catheters were placed in 75 patients (70.0%). Drainage catheters were successfully removed in 107 patients (95.5%). Failure of drainage catheter removal within 8 months was associated with hepatic artery complications (p = 0.034) and strictures requiring alternative passage techniques (p = 0.034). The cumulative primary patency rates after drainage catheter removal at 1, 2, 3, and 5 years were 85.4%, 79.8%, 75.8%, and 68.4%, respectively. Recurrence of biliary stricture was associated with the presence of an untreated isolated sectoral duct (aHR, 3.632; 95% CI, 1.086-12.150, p = 0.037) and with concurrent bile leaks (aHR, 2.475; 95% CI, 1.090-5.621, p = 0.031). CONCLUSION: Percutaneous transhepatic treatment was effective for the treatment of biliary strictures after duct-to-duct biliary anastomosis in LDLT. Multiple drainage catheter maintenance was needed because multiple strictures often occurred in these patients. KEY POINTS: • Percutaneous transhepatic treatments are useful and effective for the treatment of biliary stricture after duct-to-duct biliary anastomosis in living donor liver transplantation (LDLT), although an endoscopic approach is available for this type of reconstruction. • Multiple drainage catheters were frequently placed in these patients because of multiple complex strictures. • We found that recurrence after drainage catheter removal was associated with isolation of the sectoral duct and with concurrent bile leaks.

Malignant potential of small pancreatic neuroendocrine neoplasm and its risk factors: A multicenter nationwide study.

BACKGROUND: Pancreatic neuroendocrine neoplasms (PNENs) show heterogeneous biological behavior, and most small PNENs show indolent features. Consequently, selected cases can be considered for observation only, according to the National Comprehensive Cancer Network guideline, however, supporting clinical evidence is lacking. We investigated the clinical course of small PNENs and their risk factors for malignant potential. METHODS: A total of 158 patients with small pathologically confirmed PNENs ≤2 cm in initial imaging were retrospectively enrolled from 14 institutions. The primary outcome was any metastasis or recurrence event during follow-up. RESULTS: The median age was 57 years (range, 22-82 years), and 86 patients (54%) were female. The median tumor size at initial diagnosis was 13 mm (range, 7-20 mm). PNENs were pathologically confirmed by surgery in 137 patients and by EUS-guided fine needle aspiration biopsy (EUS-FNAB) in 21 patients. Eight patients underwent EUS-FNAB followed by surgical resection. The results of WHO grade were available in 150 patients, and revealed 123 grade 1, 25 grade 2, and 2 neuroendocrine carcinomas. A total of 145 patients (92%) underwent surgical resection, and three patients had regional lymph node metastasis. During the entire follow-up of median 45.6 months, 11 metastases or recurrences (7%) occurred. WHO grade 2 (HR 13.97, 95% CI 2.60-75.03, p = 0.002) was the only predictive factor for malignant potential in multivariable analysis. CONCLUSIONS: WHO grade is responsible for the malignant potential of small PNENs ≤2 cm. Thus, EUS-FNAB could be recommended in order to provide early treatment strategies of small PNENs.

Efficacy of an internal anchoring plastic stent to prevent migration of a fully covered metal stent in malignant distal biliary strictures: a randomized controlled study.

BACKGROUND: Two types of self-expandable metal stents (SEMS) are available for malignant distal biliary obstruction: fully covered SEMS (FCSEMS) and uncovered SEMS. FCSEMS can prevent stent ingrowth, but a major concern is spontaneous migration. This study aimed to determine whether the additional insertion of a double-pigtail plastic stent to anchor the FCSEMS can prevent migration. METHODS: 68 patients with unresectable, malignant, distal, biliary obstruction were included in this multicenter, randomized, superiority trial. The patients were randomly assigned to receive either the FCSEMS plus an anchoring plastic stent (n = 33) or an FCSEMS alone (n = 35). After placement of the FCSEMS, the anchoring stent was inserted inside the FCSEMS. The primary outcome was the rate of stent migration during the 6-month follow-up. The secondary outcomes were stent-related adverse events, stent patency, and survival rates. RESULTS: The baseline characteristics were similar between the two groups. The rate of stent migration at 6 months was significantly lower in patients with the FCSEMS plus anchoring stent (15 % vs. 40 %; P = 0.02). The mean stent patency was significantly longer in the FCSEMS plus anchoring group (237 days [95 % confidence interval [CI] 199 to 275] vs. 173 days [95 %CI 130 to 217]; P = 0.048). There were no significant differences in stent-related adverse events and overall survival rates at 6 months between the two groups. CONCLUSIONS: Our data suggest that the additional double-pigtail plastic stent anchored the FCSEMS to prevent migration and prolonged patency without any serious adverse events.

Use of Gadoxetic Acid-enhanced Liver MRI and Mortality in More than 30 000 Patients with Hepatocellular Carcinoma: A Nationwide Analysis.

Background The impact on survival of gadoxetic acid-enhanced MRI in addition to multiphase contrast material-enhanced CT for initial staging in patients with hepatocellular carcinoma (HCC) is unknown. Purpose To compare all-cause mortality in patients with HCC who underwent CT only, CT plus non-gadoxetic acid-enhanced MRI, or CT plus gadoxetic acid-enhanced MRI as part of their initial diagnostic work-up. Materials and Methods The authors performed a nationwide retrospective cohort study of patients diagnosed with HCC in South Korea between January 2008 and December 2010. Follow-up extended through December 2014. The primary outcome was all-cause mortality. Cox proportional hazards regression model with adjustment of confounding factors was used to estimate hazard ratios (HRs) for all-cause mortality. Results Among 30 023 patients with HCC (mean age ± standard deviation, 58.5 years ± 10.7, 23 978 men), the proportions of patients in whom HCC was diagnosed using CT only, CT plus non-gadoxetic acid-enhanced MRI, and CT plus gadoxetic acid-enhanced MRI were 56.1%, 12.9%, and 31.0%, respectively. In adjusted analysis using CT only as the reference category, the HR for mortality for CT plus gadoxetic acid-enhanced MRI was 0.64 (95% confidence interval [CI]: 0.62, 0.67; P < .001), and the HR for CT plus non-gadoxetic acid-enhanced MRI was 0.71 (95% CI: 0.68, 0.75; P < .001). Use of CT plus gadoxetic acid-enhanced MRI was associated with lower mortality compared with CT plus non-gadoxetic acid-enhanced MRI (adjusted HR, 0.90; 95% CI: 0.85, 0.95; P < .001), but this survival advantage was restricted to patients with localized disease. Conclusion In patients with hepatocellular carcinoma, additional use of contrast-enhanced MRI was associated with lower mortality. Furthermore, CT plus gadoxetic acid-enhanced MRI was associated with better survival than CT plus non-gadoxetic acid-enhanced MRI but only in patients with localized disease. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kim in this issue.

Intraductal placement of non-flared fully covered metallic stent for refractory anastomotic biliary strictures after living donor liver transplantation: Long-term results of prospective multicenter trial.

BACKGROUND AND AIM: Fully covered self-expandable metallic stent (FCSEMS) may be an effective modality for managing anastomotic biliary stricture (ABS) after liver transplantation. However, stent migration and stent-induced ductal injury are the main limitations. The objective of this study was to evaluate the usefulness of an unflared, intraductal FCSEMS that was designed to minimize migration and ductal injury for refractory ABS after living donor liver transplantation (LDLT). METHODS: A total of 32 consecutive patients with symptomatic ABS after LDLT unresolved by plastic stents with or without balloon dilation at four tertiary medical centers were prospectively enrolled. A short (3 or 5 cm) FCSEMS having long lasso (10 cm) used in this study had unflared convex ends to minimize tissue hyperplasia and smaller center portion to prevent migration. The FCSEMS was placed above the papilla and removed at 3-4 months after stenting. RESULTS: Technical and clinical success rates of intraductal placement with FCSEMS were 100% (32/32) and 81.2% (26/32), respectively. Early stent migration was observed in five (15.6%) patients. However, three patients with early stent migration had stricture resolution without needing additional intervention. Intended stent removal was successful in 27 (100%) patients (median, 101 days; range, 23-118 days). No stent-induced ductal change was observed in all patients. Stricture recurrence was observed in 11.5% (3/26) of patients during 639 days of median duration of follow-up (range, 366-2079 days). CONCLUSIONS: Intraductal placement of an unflared short FCSEMS may be a promising option for refractory ABS after LDLT with minimal stent-induced ductal injury and stent migration.

Cytopathological results of initial endoscopic ultrasound-guided fine needle aspiration for primary mass and prognosis in pancreatic cancer patients.

OBJECTIVES: Clinical outcomes remain unclear in patients suspected of having pancreatic cancer with indeterminate endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) results. This work aimed to investigate the prognosis of pancreatic cancer patients with indeterminate findings at initial EUS-FNA. METHODS: Findings in all patients who underwent EUS-FNA for suspected pancreatic cancer between 2008 and 2015 at the National Cancer Center, Korea, were retrospectively reviewed. A final diagnosis of pancreatic ductal adenocarcinoma was based on pathology reports. RESULTS: Of the 144 patients evaluated, 113 (78%) were diagnosed as being positive/suspicious for malignancy on cytological evaluation and 31 (22%) as having atypia/negative/non-diagnostic findings at initial EUS-FNA but subsequently diagnosed with pancreatic ductal adenocarcinoma. Tumour size, clinical stage and treatment modalities did not differ significantly between these two groups. Median overall survival was significantly shorter in patients diagnosed (11.3 ± 0.74 months; 95% confidence interval [CI], 9.4-12.8 months) than non-diagnosed (16.9 ± 2.34 months; 95% CI, 12.0-17.4 months) on initial EUS-FNA (P = .024). Multivariate Cox regression analysis showed that a non-diagnosis on initial EUS-FNA was independently associated with better overall survival (hazard ratio, 0.58; 95% CI, 0.38-0.88; P = .011). CONCLUSIONS: Non-diagnostic results on initial EUS-FNA of a primary mass may be associated with better prognosis in patients with pancreatic cancer.

Prognostic Implications of Multiplex Detection of KRAS Mutations in Cell-Free DNA from Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Cell-free DNA (cfDNA) is known to provide potential biomarkers for predicting clinical outcome, but its value in pancreatic ductal adenocarcinoma (PDAC) has not been fully evaluated. The aim of this study was to evaluate the clinical applicability of quantitative analysis of multiplex KRAS mutations in cell-free DNA from patients with PDAC. METHODS: A total of 106 patients with PDAC were enrolled in this prospective study. The concentration and fraction of KRAS mutations were determined through multiplex detection of KRAS mutations in plasma samples by use of a droplet digital PCR kit (Bio-Rad). RESULTS: KRAS mutations were detected in 96.1% of tissue samples. Eighty patients (80.5%) harbored KRAS mutations in cfDNA, with a median KRAS mutation concentration of 0.165 copies/µL and a median fractional abundance of 0.415%. Multivariable analyses demonstrated that the KRAS mutation concentration [hazard ratio (HR), 2.08; 95% CI, 1.20-3.63] and KRAS fraction (HR, 1.73; 95% CI, 1.02-2.95) were significant factors for progression-free survival. KRAS mutation concentration (HR, 1.97; 95% CI, 1.05-3.67) also had prognostic implications for overall survival. Subgroup analyses showed that KRAS mutation concentration and fractional abundance significantly affected progression-free survival in resectable PDAC (P = 0.016). Moreover, when combined with the cancer biomarker CA19-9, the KRAS mutation concentration in cfDNA showed additive benefits for the prediction of overall survival. CONCLUSIONS: This study demonstrates that multiplex detection of KRAS mutations in plasma cfDNA is clinically relevant, providing a potential candidate biomarker for prognosis of PDAC.

Clinicopathological characteristics of biliary neuroendocrine neoplasms: a multicenter study.

OBJECTIVES: This study assessed the clinicopathological features, therapeutic approaches, and prognosis of patients with biliary neuroendocrine neoplasm (NENs). MATERIALS AND METHODS: Multicenter retrospective study of patients with biliary tract NENs in the gallbladder, the extrahepatic bile duct, or the ampulla of Vater between 2005 and 2014. RESULTS: Total of 43 patients were included in the study. The median age was 62 years (range: 29-84 years) and 58.1% of the patients were male. The tumors occurred in the gallbladder (n = 11), the extrahepatic bile duct (n = 5) or the ampulla of Vater (n = 27). The liver was the most common metastatic site. Based on the 2010 World Health Organization classification, more patients with gallbladder NENs (11/11 (100%)) had neuroendocrine carcinoma G3 than those with NENs in the ampulla of Vater (10/27 (37.1%)). The median progression free survival time (39.3 vs 5.1 months, p = 0.001) and median overall survival time (46.9 vs 7.9 months, p < 0.001) were significantly longer in patients with ampulla of Vater NENs than gallbladder NENs. A 2010 World Health Organization classification of neuroendocrine carcinoma G3 was independently related to poor overall survival (hazard ratio (HR), 27.1; 95% confidence intervals (CI), 2.81-260.68; p = 0.004). CONCLUSION: The 2010 World Health Organization classification of neuroendocrine carcinoma G3 was the only factor related to poor prognosis in patients with biliary neuroendocrine neoplasms.

Efficacy of pancreatic exocrine replacement therapy for patients with unresectable pancreatic cancer in a randomized trial.

BACKGROUND: Weight loss in pancreatic cancer is associated with maldigestion due to pancreatic duct obstruction. Pancreatic exocrine replacement therapy (PERT) may significantly improve fat and protein absorption. OBJECTIVES: This prospective, double-blind, randomized, placebo-controlled phase II trial assessed whether PERT could reduce or prevent weight loss in patients with unresectable pancreatic cancer. METHODS: Sixty seven patients with unresectable pancreatic cancer were randomized to receive enteric coated PERT, consisting of 6-9 capsules of pancreatin (457.7 mg/capsule), or placebo. Patients took two capsules each three times daily during main meals and one capsule each up to three times daily when having between-meal snacks. The primary endpoint was the percentage change in body weight at eight weeks. RESULTS: The mean percentage change in body weight (1.49% [1.12 kg] vs. 2.99% [1.63 kg], P = 0.381) and the mean percent change in Patient-Generated Subjective Global Assessment (PG-SGA) score (8.85% vs. 15.69%, p = 0.18) did not differ significantly between the PERT and placebo groups. There was no improvement in quality of life and overall survival did not differ significantly between the PERT and placebo groups (5.84 months vs 8.13 months, p = 0.744). CONCLUSIONS: PERT did not reduce weight loss in patients with unresectable pancreatic cancer. Larger randomized trials are needed to identify those patients who may benefit from PERT. TRIAL REGISTRATION: ClinicalTrials.gov Number NCT01587534.

Reintervention for occluded metal stent in malignant bile duct obstruction: A prospective randomized trial comparing covered and uncovered metal stent.

BACKGROUND AND AIM: No prospective data are available on comparing covered and uncovered self-expandable metal stent (SEMS) for reintervention of occluded uncovered metal stents during endoscopic retrograde cholangiopancreatography in patients with malignant distal biliary obstruction. METHODS: From June 2010 to November 2014, 43 patients with inoperable distal biliary obstruction of a previously placed uncovered SEMS were enrolled from three centers in Korea and randomly assigned to covered (n = 22) or uncovered SEMS group (n = 21). The primary outcome was overall stent patency. Secondary outcome was time-to-stent occlusion, patient survival, cause of stent occlusion, and adverse events. RESULTS: Overall median patency of secondary stent was 112.0 days. Median stent patency of covered and uncovered SEMS was 112.0 and 181.0 days, respectively, (P = 0.373). There was a tendency towards a longer time-to-stent occlusion in uncovered SEMS group (median: 112.0 vs 181.0 days). However, it did not reach statistical significance (P = 0.214). Most common causes of occlusion were stent clogging (36.4%) and tumor ingrowth (33.3%) in covered and uncovered SEMS groups, respectively. There was no significant difference in median survival between the groups (median: 308 vs 300 days; P = 0.325). Acute cholangitis occurred in four patients (three in covered vs one in uncovered SEMS group, P = 0.607). CONCLUSIONS: In this exploratory trial, there were no statistically significant differences in stent patency, time-to-stent occlusion, patient survival, and complication rates between covered and uncovered SEMS groups. Larger confirmatory multicenter trial is needed for the clear conclusion (ClinicalTrials.gov: NCT01315522).

Prognostic indicators for radiotherapy of abdominal lymph node metastases from hepatocellular carcinoma.

PURPOSE: To identify prognostic indicators in patients treated with radiotherapy (RT) for metastases from hepatocellular carcinoma (HCC) in abdominal lymph nodes (LNs). PATIENTS AND METHODS: RT was used to treat 65 patients for metastases from HCC in abdominal LNs. Total radiation dose was 30-60 Gy (median 52.8 Gy), with fraction size 1.8-3 Gy. RT was administered five times per week to an equivalent dose in 2-Gy fractions (EQD2; Gy10) of 32.5-65 Gy10 (median 54 Gy10) and an α/ßratio for tumor and acute effects of normal tissue of 10. RESULTS: Median overall survival (OS) in all patients was 8.1 months. LN responders had significantly higher median OS than nonresponders (14.5 vs. 3.7 months, p < 0.05). Multivariate analysis showed that Child-Pugh classification, status of intrahepatic tumor, number of metastatic LNs, and LN response were independently predictive of OS (p < 0.05 each). Based on results of multivariate analysis, patients were prognostically stratified according to pretreatment risk factors, including Child-Pugh classification, intrahepatic tumor status, and number of metastatic LNs; with the expected median OS in patients with ≥ 2, 1, and 0 risk factors being 2.9, 9.8, and 27.6 months, respectively (p < 0.05). CONCLUSION: Our data showed that LN response to RT was an independent prognostic factor for OS in advanced HCC patients with abdominal LN metastases, and suggested that RT for metastatic LNs might improve OS in these patients. In addition, our data suggest that Child-Pugh classification, intrahepatic tumor status, and number of metastatic LNs may be useful prognostic and therapeutic indicators for selecting treatment strategies.

Cytidine Deaminase as a Molecular Predictor of Gemcitabine Response in Patients with Biliary Tract Cancer.

OBJECTIVE: Gemcitabine-based chemotherapy is regarded as the standard treatment for biliary tract cancer (BTC). Potential biomarkers for gemcitabine response include the activities of cytidine deaminase (CDA), human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (DCK), and ribonucleotide reductase M1 (RRM1). Here, we investigated whether single nucleotide polymorphisms (SNPs) in their encoding genes were associated with the efficacy of gemcitabine chemotherapy in treating BTC. METHODS: We retrospectively evaluated 11 SNPs in the CDA, hENT1, DCK, human concentrative nucleoside transporter 3 (hCNT3), and RRM1 genes in 80 patients with unresectable, metastatic, or recurrent BTC who were treated with gemcitabine plus cisplatin. RESULTS: After the results were adjusted for clinical predictors, the variant allele of rs1048977 in the CDA gene was associated with tumor response in a dominant model (OR, 0.23; 95% CI, 0.06-0.93; p = 0.039). No significant association was detected between the 11 SNPs and grade 3/4 toxicity. CONCLUSIONS: Our findings suggest that the polymorphism of CDA may be a potential predictive marker for the efficacy of gemcitabine-based chemotherapy in patients with BTC.

Small cell- versus large cell-sized metal stent in endoscopic bilateral stent-in-stent placement for malignant hilar biliary obstruction.

BACKGROUND AND AIM: Although the large cell-sized biliary stent facilitates contralateral stent deployment through the mesh of the first metallic stent for stent-in-stent (SIS) technique, there are concerns about its vulnerability to tumor ingrowth. The aim of the present study was to compare the clinical outcomes of endoscopic bilateral SIS placement according to the cell size of a self-expandable metallic stent (SEMS). METHODS: A total of 58 patients were enrolled who underwent endoscopic bilateral SIS placement of SEMS for malignant hilar biliary obstruction as a result of cholangiocarcinoma or gallbladder cancer. Finally, 43 patients who underwent successful stent insertion were included in the analysis and divided into the small cell-sized stent (SCS; n = 21) and the large cell-sized stent (LCS; n = 22) groups. We retrospectively compared comprehensive clinical and laboratory data in both groups. RESULTS: There were no significant differences between the two groups in successful drainage (SCS vs LCS, 100% vs 100%, respectively), early complications (38.1% vs 18.2%), late complications (14.3% vs 22.7%), stent occlusion (42.9% vs 45.5%), tumor ingrowth (33.3% vs 45.5%) or overgrowth (9.5% vs 0%). Duration of stent patency and overall survival were not significantly different between the two groups (P = 0.086 and P = 0.320, respectively). CONCLUSIONS: Endoscopic bilateral SIS placement for malignant hilar biliary obstruction shows no differences in stent patency, survival, complications and clinical course according to the cell size of SEMS.

Effectiveness and safety of proton beam therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis.

PURPOSE: To evaluate the clinical effectiveness and safety of proton beam therapy (PBT) in advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). PATIENTS AND METHODS: Twenty-seven HCC patients with PVTT underwent PBT, including 22 patients with modified International Union Against Cancer (mUICC) stage IVA,five patients with stage IVB primary tumors, and 16 with main PVTT. A median dose of 55 GyE (range, 50-66 GyE) in 20-22 fractions was delivered to a target volume encompassing both the PVTT and primary tumor. RESULTS: Overall, treatment was well tolerated, with no toxicity of grade ≥ 3. Median overall survival (OS) times in all patients and in stage IVA patients were 13.2 months and 16 months, respectively. Assessments of PVTT response showed complete response in 0 of 27 (0%) patients, partial response in 15 (55.6%), stable disease in 10 (37%), and progressive disease in 2 (7.4%) patients, with an objective response rate of 55.6%. PVTT responders showed significantly higher actuarial 1-year local progression-free survival (LPFS; 85.6% vs. 51.3%), relapse-free survival (RFS; 20% vs. 0%) and OS (80% vs. 25%) rates than nonresponders (p<0.05 each). Multivariate analysis showed that PVTT response and mUICC stage were independent prognostic factors for OS. CONCLUSION: Our data suggest that PBT could improve LPFS, RFS, and OS in advanced HCC patients with PVTT and it is feasible and safe for these patients.