A Patient-Derived Organoid-Based Radiosensitivity Model for the Prediction of Radiation Responses in Patients with Rectal Cancer.

Patient-derived tumor organoids closely resemble original patient tumors. We conducted this co-clinical trial with treatment-naive rectal cancer patients and matched patient-derived tumor organoids to determine whether a correlation exists between experimental results obtained after irradiation in patients and organoids. Between November 2017 and March 2020, we prospectively enrolled 33 patients who were diagnosed with mid-to-lower rectal adenocarcinoma based on endoscopic biopsy findings. We constructed a prediction model through a machine learning algorithm using clinical and experimental radioresponse data. Our data confirmed that patient-derived tumor organoids closely recapitulated original tumors, both pathophysiologically and genetically. Radiation responses in patients were positively correlated with those in patient-derived tumor organoids. Our machine learning-based prediction model showed excellent performance. In the prediction model for good responders trained using the random forest algorithm, the area under the curve, accuracy, and kappa value were 0.918, 81.5%, and 0.51, respectively. In the prediction model for poor responders, the area under the curve, accuracy, and kappa value were 0.971, 92.1%, and 0.75, respectively. Our patient-derived tumor organoid-based radiosensitivity model could lead to more advanced precision medicine for treating patients with rectal cancer.

Implication of FDG-PET/CT without synchronous colonic lesion in patients with stenotic left-sided colorectal cancer.

Although 18-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is useful for detecting synchronous colorectal cancer (CRC) in stenotic CRC, long-term outcomes of patients without synchronous FDG-avid lesions are not well reported. We investigated postoperative colonoscopy results in patients with left-sided stenosing CRC without synchronous FDG-avid lesions. In this retrospective review, 754 patients with left-sided CRC without synchronous FDG-avid lesions on preoperative 18F-FDG PET/CT were divided into two groups based on the completeness of preoperative colonoscopy. Propensity score matching was performed to balance baseline characteristics. Results of postoperative colonoscopy were compared in both the unmatched and matched cohorts. At 1 and 5 years after surgery, the cumulative risk of advanced adenoma (AA) or carcinoma (CA) in all patients, risk of CA, and additional surgical risk were 1.8% and 10.1%, 0.1% and 0.4%, and 0% and 0.5%, respectively. In both cohorts, the AA risk was significantly higher in the incomplete colonoscopy group. However, the risk of CA showed no between-group difference in the matched cohort. Additional surgical risk did not differ between the two groups. Thus, the finding of negative FDG-avid lesions in the proximal colon in addition to the target CRC ensures the absence of additional lesions warranting surgical plan changes.

Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells.

BACKGROUND/AIMS: Silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells. METHODS: Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis. RESULTS: Gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin. CONCLUSIONS: Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future.

Clinical outcomes of early gastric cancer with lymphovascular invasion or positive vertical resection margin after endoscopic submucosal dissection.

BACKGROUND: In early gastric cancer (EGC) cases with lymphovascular invasion or positive vertical margins after endoscopic submucosal dissection (ESD), additional radical gastrectomy is performed on principle. However, an additional surgery is often difficult to consider if the surgical approach itself is challenging or the patient refuses surgery. In such cases, only close surveillance is performed without additional surgical procedures. This study aimed to examine the difference in clinical prognosis of EGC cases with lymphovascular invasion or positive vertical margins after ESD either with or without surgery. METHODS: We retrospectively studied 83 patients with lymphovascular invasion or positive vertical margins after ESD from July 2005 to November 2013. RESULTS: Of the 83 patients, 45 (54.2%) underwent radical additional gastrectomy (surgical group) and 38 (45.8%) were under close surveillance without surgical or endoscopic treatments (close surveillance group.) The cancer-free survival period was 78.3 ± 3.4 months in the surgical group and 64.5 ± 4.6 months in the close surveillance group. The recurrence rates did not significantly differ between the 2 groups, at 7.9% in the surgical group and 6.7% in the non-surgical group. CONCLUSIONS: Close surveillance may be suggested as an option for EGC patients for whom a surgical approach is difficult, who exhibit a positive vertical margin after ESD, and who have no lymphovascular or deep submucosa invasion after ESD.

Allopurinol-induced DRESS syndrome mimicking biliary obstruction.

An 84-year-old man was admitted to our hospital with fever, jaundice, and itching. He had been diagnosed previously with chronic renal failure and diabetes, and had been taking allopurinol medication for 2 months. A physical examination revealed that he had a fever (38.8℃), jaundice, and a generalized maculopapular rash. Azotemia, eosinophilia, atypical lymphocytosis, elevation of liver enzymes, and hyperbilirubinemia were detected by blood analysis. Magnetic resonance cholangiography revealed multiple cysts similar to choledochal cysts in the liver along the biliary tree. Obstructive jaundice was suspected clinically, and so an endoscopic ultrasound examination was performed, which ruled out a diagnosis of obstructive jaundice. The patient was diagnosed with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome due to allopurinol. Allopurinol treatment was stopped and steroid treatment was started. The patient died from cardiac arrest on day 15 following admission.

A Multicenter Phase II Trial of Gemcitabine Plus Oxaliplatin in Unresectable Gallbladder Cancer.

BACKGROUND/AIMS: No standard chemotherapy has been established for advanced gallbladder cancer. The authors studied the activity and tolerability of a gemcitabine and oxaliplatin (GEMOX) combination in unresectable gallbladder cancer (GBC). METHODS: Adult patients with pathologically confirmed unresectable GBC were prospectively recruited at three centers. No patient had received prior chemotherapy or radiotherapy. Patients received cycles of gemcitabine at 1,000 mg/m(2) on day 1, followed by oxaliplatin at 100 mg/m(2) on day 2, every 2 weeks. The primary study endpoint was time to progression. RESULTS: Forty patients with unresectable GBC were enrolled. The median age was 60 years (range, 38 to 79 years). All patients showed good performance status. Of the 33 analyzable patients, 12 achieved partial response (36%), 17 stable disease (52%), and four progressive disease (12%). No patient achieved a complete response. The tumor control rate was 88%. At a median follow-up of 6.8 months, the median time to progression was 5.3 months (95% confidence interval [CI], 3.7 to 6.9), and median overall survival was 6.8 months (95% CI, 6.1 to 7.5). Nine of the 40 patients (23%) experienced at least a grade-3 adverse event, but no patient experienced a grade-4 adverse event. CONCLUSIONS: GEMOX combination therapy is a feasible option and is well tolerated in unresectable GBC.

Severe intestinal toxicity after stereotactic ablative radiotherapy for abdominopelvic malignancies.

PURPOSE: The purpose of this study is to identify the predictors for severe intestinal toxicity (IT) in patients with abdominopelvic malignancies treated with three fractions of stereotactic ablative radiotherapy (SABR). METHODS: From 2001 to 2011, 202 patients with abdominopelvic malignancies were treated with curative-intent SABR. Among these, we retrospectively reviewed the clinical records of 55 patients with the presence of the intestine that received a dose ≥20 % of the prescribed dose. The total dose ranged from 33 to 60 Gy in three fractionations (median dose, 45 Gy). We analyzed the clinical and dosimetric parameters for severe IT ≥ grade 3 according to the National Cancer Institute Common Toxicity Criteria v4.0: V(20-35) (volume of the intestine that received xGy) and D(max) (maximum point dose). RESULTS: Severe IT was found in six patients (the median time, 3 months). V(25) was the best dosimetric predictor for severe IT (P = 0.004). With V(25) ≤ 20 ml, severe IT decreased from 50 to 4 %. SABR duration was the best clinical predictor. Severe IT decreased in patients who received SABR at 4-8 days than on three consecutive days (0 vs. 18 %, P = 0.037). CONCLUSIONS: Following three fractions of SABR, V(25) is a valuable predictor of severe IT. And SABR would be conducted with a treatment interval of at least 48 h if possible.

Predictor of severe gastroduodenal toxicity after stereotactic body radiotherapy for abdominopelvic malignancies.

PURPOSE: To identify the predictors for the development of severe gastroduodenal toxicity (GDT) in patients treated with stereotactic body radiotherapy (SBRT) using 3 fractionations for abdominopelvic malignancies. METHODS AND MATERIALS: From 2001 to 2011, 202 patients with abdominopelvic malignancies were treated with curative-intent SBRT. Among these patients, we retrospectively reviewed the clinical records of 40 patients with the eligibility criteria as follows: 3 fractionations, follow-up period≥1 year, absence of previous radiation therapy (RT) history or combination of external-beam RT and the presence of gastroduodenum (GD) that received a dose higher than 20% of prescribed dose. The median SBRT dose was 45 Gy (range, 33-60 Gy) with 3 fractions. We analyzed the clinical and dosimetric parameters, including multiple dose-volume histogram endpoints: V20 (volume of GD that received 20 Gy), V25, V30, V35, and Dmax (the maximum point dose). The grade of GDT was defined by the National Cancer Institute Common Toxicity Criteria version 4.0, and GDT≥grade 3 was defined as severe GDT. RESULTS: The median time to the development of severe GDT was 6 months (range, 3-12 months). Severe GDT was found in 6 patients (15%). Dmax was the best dosimetric predictor for severe GDT. Dmax of 35 Gy and 38 Gy were respectively associated with a 5% and 10% probability of the development of severe GDT. A history of ulcer before SBRT was the best clinical predictor on univariate analysis (P=.0001). CONCLUSIONS: We suggest that Dmax is a valuable predictor of severe GDT after SBRT using 3 fractionations for abdominopelvic malignancies. A history of ulcer before SBRT should be carefully considered as a clinical predictor, especially in patients who receive a high dose to GD.

Effects and mechanisms of the combination of suberoylanilide hydroxamic acid and bortezomib on the anticancer property of gemcitabine in pancreatic cancer.

OBJECTIVES: Earlier studies that dealt with the combination therapy of gemcitabine and histone deacetylation inhibitors for pancreatic cancer revealed unsatisfactory results. The activation of nuclear factor κB (NF-κB) was referred as one of the attributable causes, and we attempted to overcome this resistance by the addition of a proteasome inhibitor. METHODS: The influences of suberoylanilide hydroxamic acid (vorinostat, SAHA), a histone deacetylase inhibitor, and bortezomib, a novel selective antagonist of 26S proteasome, with or without gemcitabine on cell growth and apoptosis and the expressions of related proteins were observed in pancreatic cancer cell lines (MiaPaCa-2 and ASPC-1). The xenograft model of pancreatic cancer was used to notice effects in vivo. RESULTS: Vorinostat and bortezomib had independent inhibitory effects and potentiated the antitumor property of gemcitabine in vitro. In the xenograft model, more augmented effects were achieved when bortezomib was combined with gemcitabine than gemcitabine alone. The down-regulation of pAkt and suppression of NF-κB activity was induced by the triple combination. CONCLUSIONS: The triple combination of vorinostat, bortezomib, and gemcitabine resulted in the strongest antitumor effects both in vitro and in vivo and pAkt and NF-κB seems to be involved in this process.

A comparison of metal and plastic stents for the relief of jaundice in unresectable malignant biliary obstruction in Korea: an emphasis on cost-effectiveness in a country with a low ERCP cost.

BACKGROUND: In countries where ERCP costs are low relative to those of metal stents (eg, Korea), initial endoscopic retrograde biliary drainage (ERBD) with a plastic stent is thought to be more economical. OBJECTIVE: We conducted this study to compare metal and plastic stent-based ERBD in efficacy, complications, and total cost of biliary drainage. DESIGN: Retrospective study. SETTING: Tertiary referral center. PATIENTS: A total of 112 patients who had not undergone previous biliary drainage procedures and who underwent ERBD for unresectable malignant biliary obstruction. INTERVENTIONS: Endoscopic sphincterotomy was performed, and covered or uncovered Wallstents were used in 56 patients and plastic stents in 56 patients. RESULTS: Stent occlusion occurred in 31 patients after a mean of 278 days in the metal stent group and in 39 patients after a mean of 133 days in the plastic stent group (P = .0004). The incidence of and length of hospitalization for cholangitis were significantly lower in the metal stent group. There was no difference in the total number of drainage procedures between the 2 groups. There was no statistical difference in the mean cost of the relief of jaundice between the 2 groups ($1488.77 in the metal stent group vs $1319.26 in the plastic stent group, P = .422). LIMITATIONS: Nonrandomized, retrospective study. CONCLUSION: Even in countries where ERCP costs are lower than those of metal stents, ERBD with metal biliary stents as the first-line treatment may offer better palliation without a significant increased cost in patients with unresectable malignant biliary obstruction.

A comparison of the Niti-D biliary uncovered stent and the uncovered Wallstent in malignant biliary obstruction.

BACKGROUND: The conformability of uncovered self-expandable metal stents (SEMSs) plays an important role in maintaining stent patency. However, whether increased conformability can prolong the duration of SEMS patency remains to be proved. OBJECTIVE: The aim of this study was to examine the efficacy and complication rates of the Niti-D biliary uncovered metal stent (NDS), which is more conformable than the uncovered Wallstent. DESIGN: Nonrandomized, retrospective study. SETTING: Tertiary-care academic medical center. PATIENTS: From March 2005 to July 2007, 101 patients received an NDS (41 cases) or a Wallstent (60 cases) for malignant biliary obstruction. INTERVENTIONS: SEMS placement. RESULTS: Stent occlusion occurred in 11 patients (26.8%) with the NDS and 17 patients (28.3%) with the Wallstent. The median duration of stent patency tended to be longer for the NDS group (153 days) than for the Wallstent group (124 days); however, the difference was not statistically significant (P = .204). The median duration of overall survival of patients was 160 days for the NDS and 148 days for the Wallstent. The subgroup analysis showed that 27 patients had hilar obstruction (NDS 13, Wallstent 14). The median duration of stent patency was 249 days for the NDS group and 76 days for the Wallstent group; this difference was statistically significant (P = .006). The complications included pancreatitis in 3 NDS cases and 5 Wallstent cases. LIMITATION: The absence of prospective randomized recruitment. CONCLUSION: The results of this study showed no significant differences between the NDS and the Wallstent for the palliative endoscopic management of malignant biliary obstruction. There were no significant differences in patency, complication rates, and patient survival between the more conformable NDS and the conventional Wallstent. However, the NDS, which has good conformability, may be preferred for hilar obstruction.

Endoscopic treatment for biliary stricture after adult living donor liver transplantation.

Endoscopic intervention is considered to be the primary treatment for biliary stricture after adult living donor liver transplantation (LDLT) with duct-to-duct biliary reconstruction. The aim of this study was to investigate the risk factors of biliary stricture and the clinical outcomes and predictors of failure after endoscopic retrograde cholangiography with balloon dilation (ERC-D). We enrolled 239 adult patients who underwent LDLT between 2000 and 2006. Sixty-eight patients (28.4%) developed biliary stricture. Twenty-nine patients with anastomotic biliary stricture were treated with ERC-D and stenting. We retrospectively analyzed the risk factors of biliary stricture and the clinical outcomes of ERC-D. The median follow-up period was 31 months. The risk factors of biliary stricture on multiple logistic regression analysis were a graft with multiple bile ducts, a previous history of bile leakage, and hepatic artery stenosis. The overall success rate of ERC-D was 64.5%. On simple logistic regression, the failure of primary ERC-D was associated with late biliary stricture over 24 weeks and more than 8 weeks between a 2-fold increase of serum alkaline phosphatase from the stable level and ERC-D, even though these were not statistically significant on multiple logistic regression. The relapse rate of stricture after successful ERC-D was 30%. The duration of stenting in the recurrence group was shorter than that in the nonrecurrence group (11.8 +/- 5.03 versus 29.0 +/- 11.6 weeks, P = 0.004). ERC-D is effective for the management of anastomotic biliary stricture. However, the failure rate of primary ERC-D may be high in patients with late onset and delayed diagnosis of biliary stricture. The recurrence seems to occur frequently in patients with a short duration of stenting.

[Pancreatic endocrine tumors: clinical manifestations and predictive factors associated with survival].

BACKGROUND/AIMS: Since pancreatic endocrine tumors (PET) are rare and heterogeneous diseases, their survival and prognosis are not well known. Due to recent advances in CT/MRI technology, incidentalomas of the pancreas are detected with increasing frequency. This study presents results of clinical manifestations of PET and predictive factors associated with survival. METHODS: From year 1990 through 2006, medical records of 98 patients (56 men, 42 women) who were diagnosed as PET pathologically at Seoul National University Hospital were reviewed retrospectively. RESULTS: Ages ranged from 17 to 76 years (mean 51.6+/-1.3 years) with a mean follow-up of 3.6+/-0.4 years (range 0-10.1 years). Overall 5-year survival rate was 68.1%, and 5-year survival rate of the patients who had distant metastases at initial diagnosis was 43.9%. Functioning tumors [hazard ratio (HR) 0.229, 95% confidence interval (CI) 0.056-0.943, p=0.041] and lymph node or liver metastases (HR 5.537, 95% CI 2.106-14.555, p<0.001) were the significant prognostic factors associated with survival rate. However, tumor size and pathology showed no significant association with survival. CONCLUSIONS: Because small and pathologically benign nature do not predict good prognosis in PET, aggressive treatment such as curative resection would be considered initially even in the case of incidental PET.

Does endoscopic sphincterotomy reduce the recurrence rate of cholangitis in patients with cholangitis and suspected of a common bile duct stone not detected by ERCP?

BACKGROUND: It has not been established whether endoscopic sphincterotomy (ES) prevents subsequent cholangitis in patients with cholangitis and with a common bile duct (CBD) stone not documented by ERCP. OBJECTIVE: The aim of this study was to investigate the role of ES on the recurrence of cholangitis in patients with a high probability of having a CBD stone, not demonstrated by ERCP. DESIGN AND PATIENTS: A total of 117 patients who were diagnosed as having cholangitis and a high probability of a CBD stone, not detected by ERCP, were retrospectively reviewed. Cumulative recurrence rates of cholangitis were compared for treatments with and without ES. SETTING: Multicenter, retrospective study. INTERVENTIONS: ES. MAIN OUTCOME MEASUREMENTS: Cumulative recurrence of cholangitis after ERCP. RESULTS: Eighty-three patients underwent ES (ES group) and 34 patients did not (non-ES group). No statistically significant differences between the 2 groups were evident in terms of demographic factors or laboratory findings. The mean (standard deviation) follow-up was 22.1 +/- 17.2 months (range 3-66 months) in the ES group and 23.3 +/- 14.9 months (range 6-84 months) in the non-ES group (P = .72). The cumulative rates of cholangitis were 6.3% (4.8% vs 9.9%) at 1 year, 15.6% (9.2% vs 29.3%) at 3 years, and 19.5% (9.2% vs 52.9%) at 5 years for ES vs non-ES groups, respectively (P = .04). By multivariate analysis, ES reduced cholangitis recurrence, with a hazard ratio of 0.305 (95% CI 0.095-0.975, P = .045). LIMITATIONS: Retrospective study. CONCLUSIONS: ES reduced further episodes of cholangitis in patients with an episode of cholangitis and a high probability of choledocholithiasis, despite the lack of a CBD stone seen on ERCP.

Overexpression of PRE1 and its homologous genes activates Gibberellin-dependent responses in Arabidopsis thaliana.

Gibberellins control various aspects of growth and development. Here, we identified a gene, designated paclobutrazol resistance1 (PRE1), by screening Arabidopsis activation-tagged lines. PRE1 encodes a helix-loop-helix protein and belongs to a small gene family. Physiological and genetic analysis indicated that overexpression of PRE1 altered various aspects of gibberellin-dependent responses such as germination, elongation of hypocotyl/petiole, floral induction and fruit development, and suppressed gibberellin-deficient phenotypes of the ga2 mutant. Expression of some gibberellin-responsive genes was also affected by PRE1. Expression of PRE1 was shown to be early gibberellin inducible in the wild-type plants and under control of SPY and GAI, upstream negative regulators of gibberellin signaling. The shortened hypocotyl length phenotype of the gai-1 mutant was suppressed by PRE1 overexpression. Ectopic overexpression of each of the four PRE1-related genes conferred pleiotropic phenotypes similar to PRE1 overexpression, indicative of overlapping functions among the PRE gene family. Our results of gain-of-function studies suggest that PRE genes may have a regulatory role in gibberellin-dependent development in Arabidopsis thaliana.

Overexpression of a mutant basic helix-loop-helix protein HFR1, HFR1-deltaN105, activates a branch pathway of light signaling in Arabidopsis.

The HFR1, a basic helix-loop-helix protein, is required for a subset of phytochrome A-mediated photoresponses in Arabidopsis. Here, we show that overexpression of the HFR1-deltaN105 mutant, which lacks the N-terminal 105 amino acids, confers exaggerated photoresponses even in darkness. Physiological analysis implied that overexpression of HFR1-deltaN105 activated constitutively a branch pathway of light signaling that mediates a subset of photomorphogenic responses, including germination, de-etiolation, gravitropic hypocotyl growth, blocking of greening, and expression of some light-regulated genes such as CAB, DRT112, PSAE, PSBL, PORA, and XTR7, without affecting the light-responsiveness of anthocyanin accumulation and expression of other light-regulated genes such as CHS and PSBS. Although the end-of-day far-red light response and petiole elongation were suppressed in the HFR1-deltaN105-overexpressing plants, flowering time was not affected by HFR1-deltaN105. In addition, the HFR1-deltaN105-overexpressing plants showed hypersensitive photoresponses in the inhibition of hypocotyl elongation, dependently on phytochrome A, FHY1, and FHY3 under FR light or phyB under R light, respectively. Moreover, our double mutant analysis suggested that the hypersensitive photoresponse is due to functional cooperation between HFR1-deltaN105 and other light-signaling components including HY5, a basic leucine zipper protein. Taken together, our results of gain-of-function approach with HFR1-deltaN105 suggest the existence of a complex and important basic helix-loop-helix protein-mediated transcriptional network controlling a branch pathway of light signaling and provide a useful framework for further genetic dissection of light-signaling network in Arabidopsis.