Quantitative measurements of M2BPGi depend on liver fibrosis and inflammation.

BACKGROUND: The relationship between liver fibrosis and inflammation and Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with chronic liver disease (CLD) other than hepatitis C remains uncertain, owing to the limitations of qualitative methods. Here, we evaluated the influence of liver fibrosis and inflammation on quantitative M2BPGi (M2BPGi-Qt) in CLD, considering each etiology. METHODS: We recruited 1373 patients with CLD. To evaluate the influence of liver fibrosis and inflammation on M2BPGi-Qt levels, we assessed M2BPGi-Qt levels at each fibrosis and activity stage within different etiologies of CLD based on pathological findings. Subsequently, we evaluated if the accuracy of fibrosis staging based on M2BPGi-Qt could be improved by considering the influence of liver inflammation. RESULTS: In patients with viral hepatitis, non-alcoholic fatty liver disease, and primary biliary cholangitis, the median M2BPGi-Qt levels increased liver fibrosis progression. Median M2BPGi-Qt levels were not associated with the degree of fibrosis in patients with autoimmune hepatitis (AIH). Median M2BPGi-Qt levels increased with the progression of liver activity in all etiologies. A significant difference was found at each stage in AIH. Considering the liver inflammation, we established an algorithm, M2BPGi-Qt, to determine the alanine aminotransferase-to-platelet ratio (MAP-R) in liver cirrhosis (LC). The area under the receiver operating characteristic curve (AUC) of MAP-R was higher than that of the M2BPGi-Qt for detecting LC (AUC MAP-R = 0.759 and M2BPGi-Qt = 0.700, p < 0.001). CONCLUSIONS: The quantitative measurement system for M2BPGi depends on liver fibrosis and inflammation, regardless of etiology. Liver inflammation complicates the interpretation of M2BPGi-Qt results when assessing the fibrosis stage.

Endoscopic Ultrasound-Guided Naso-gallbladder Drainage Using a Dedicated Catheter for Acute Cholecystitis After Transpapillary Metal Stent Placement for Malignant Biliary Obstruction.

BACKGROUND: Acute cholecystitis is a significant adverse event after self-expandable metal stent (SEMS) placement for malignant biliary obstruction (MBO); however, no appropriate treatment strategy has been established for its management. AIMS: This study aimed to examine the feasibility and utility of endoscopic ultrasound-guided naso-gallbladder drainage (EUS-NGBD) for the management of acute cholecystitis occurring after SEMS placement. METHODS: This retrospective study investigated consecutive patients with acute cholecystitis after SEMS placement for unresectable MBO, in whom EUS-NGBD was attempted. The study outcomes included technical success, clinical success, procedure time, adverse event, and cholecystitis recurrence, associated with the procedure. RESULTS: During the study period, EUS-NGBD was performed for SEMS-related acute cholecystitis in 30 patients with MBO. The technical and clinical success rates were 96.7% (29/30) and 96.6% (28/29), respectively. The median procedure time was 15 min, and rate of procedure-related adverse event was 3.3% (1/30). The median duration from the procedure to tube removal was 9 days. No adverse events were observed after removal. The median hospitalization duration after the procedure was 14 days, and the median duration to the (re-)start of chemotherapy from cholecystitis onset was 13 days. The median overall survival after EUS-NGBD was 123 days, and the rate of cholecystitis recurrence until death was 4.2% (1/28). CONCLUSIONS: This study demonstrated that EUS-NGBD possesses good technical and clinical feasibility with an acceptable adverse event rates and short hospitalization and chemotherapy withdrawal period. Therefore, EUS-NGBD may be a good option for the treatment of SEMS-related cholecystitis in patients with MBO.

New chemiluminescent enzyme immunoassay for quantitative measurement of Mac-2 binding protein glycosylation isomer in chronic liver disease.

BACKGROUND: This study aimed to evaluate the quantitative measurement of Mac-2 binding protein glycosylation isomer (M2BPGi) levels using the new chemiluminescent enzyme immunoassay. METHODS: The data of a total of 347 patients with hepatitis C virus (HCV) infection and 150 health volunteers from 13 locations in Japan were evaluated. The quantitative system for measuring M2BPGi-Qt levels was based on a new chemiluminescent enzyme immunoassay. We evaluated the reproducibility and quantitation range in quantitative M2BPGi-Qt measurement. We also investigated the confidence ratio of M2BPGi-Qt levels measured by the new quantitative system to M2BPGi levels measured by the current semi-quantitative system for validating the clinical utility of the new method. RESULTS: The reproducibility of M2BPGi-Qt in HCV samples with negative, positive 1+, and positive 2+ was 0.77 ± 0.02 AU/mL, 2.25 ± 0.03 AU/mL, and 6.55 ± 0.21 AU/mL, respectively, and the corresponding coefficient of variation (CV)s were 2.1%, 1.3%, and 3.2%, respectively. The range of quantification assessment resulted that all CVs showed less than 5% in investigated range. Sample stability testing found that the mean percentage difference between the pre- and post-storage values of 6 samples ranged between 96.2 and 103.9%. The correlation coefficient between M2BPGi and M2BPGi-Qt in patients with HCV and the healthy volunteers was 0.986 and 0.991, respectively. M2BPGi-Qt could be quantitatively assessed in a patient with over 20 C.O.I. CONCLUSION: Compared with qualitative methods, the M2BPGi quantitative measurement system could provide a numerical value unaffected by interpretation bias, and measurements are more precise at high M2BPGi levels.

Transperitoneal laparoscopic umbilical resection of urachal remnants: a feasible surgical method.

BACKGROUND: To date, there is no standard established laparoscopic surgical method for managing urachal remnants because of their rarity, and several questions remain unanswered. Are there any problems for considering the operative indications about patients' factors for example, body mass index and so on? This study aimed to determine the feasible surgical method for managing urachal remnants and presents the operative outcomes of our cases in relation to the findings from the existing literature. METHODS: We analyzed the data of 16 patients (7 women and 9 men; age range, 19-48 years) who underwent surgery for urachal remnants between January 2013 and March 2019 at our institution. RESULTS: In our cases, all urachal remnants were urachal sinuses, and the primary complaints were umbilical pain and pus discharge. Most of these symptoms were controlled using umbilical drainage and oral antibiotic intake; however, incisional drainage was required in two cases. In all cases, we performed a laparoscopic resection of the urachal remnants; one patient underwent an open conversion due to a very thick abdominal wall. Therefore, "peri-umbilical distanse" was proposed as an index to verify the periumbilical abdominal wall thickness. This index may clear the difficulties of the laparoscopic resection of the urachal remnunts. A postoperative complication-local infection that was treated using re-suturing-was observed in one patient. No adverse events occurred in the other cases. Our method was appropriate because it allowed for complete urachal resection with good cosmetic results, i.e., a small and natural scar appearance. Additionally, if bladder injury occurred, bladder re-suturing was easily possible because of the laparoscopic port's position. CONCLUSIONS: We present an feasible method for laparoscopic urachal resection. This method may be recommended for young patients with an peri-umbilical distanse of < 2 cm.

Double bare metal stent deployment combined with intraductal radiofrequency ablation for malignant distal biliary obstruction: a prospective pilot study.

Although uncovered self-expandable metal stents (SEMSs) possess certain advantages such as averting cystic duct obstruction and stent migration, they are susceptible to ingrowth occlusion. The combination of the double bare stent (DBS) and endobiliary radiofrequency ablation (RFA) may reduce ingrowth. Hence, this study aimed to examine the utility of this method for the treatment of unresectable malignant distal biliary obstruction (MDBO). This prospective, single-center, pilot study enrolled 51 patients who met the eligibility criteria between February 2020 and January 2022. The study outcomes included technical success, clinical success, recurrent biliary obstruction (RBO), and other adverse events (AE) besides RBO associated with DBS placement with RFA for MDBO. The technical success rate was 98.0% (50/51). Clinical success was achieved in all patients in whom technical success was achieved. The rates of early and late AEs were 5.9% (3/51) and 8.0% (4/50), respectively. The incidence rate of RBO was 38.0% (19/50). Sludge occlusion, ingrowth occlusion, and overgrowth occlusion occurred in 26.0% (13/50), 8.0% (4/50), and 2.0% (1/50) of patients, respectively (the main cause of RBO was undeterminable in 1 patient). The median time to RBO was 241 days. DBS with RFA showed good technical feasibility, good long-term outcomes, acceptable AE rates, and most importantly, a low ingrowth occlusion rate when employed for the treatment of MDBO.

Plasma progastrin-releasing peptide level shows different predictive profiles for treatment response by androgen receptor axis-targeted agents in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: The neuroendocrine (NE) pathway cannot be ignored as a mechanism for castration-resistant prostate cancer (CRPC) progression. The neuromediator, gastrin-releasing peptide (GRP) may be involved in the aberrant activation of the normal androgen receptor (AR) and increased AR variants. This study focused on plasma levels of progastrin-releasing peptide (ProGRP) and examined the treatment outcomes with androgen receptor axis-targeted (ARAT) agents. METHODS: One hundred patients with metastatic CRPC were enrolled. Enzalutamide (ENZ) or abiraterone acetate/prednisone (AA/P) were administered to 50 patients each in a nonrandomized manner as a first-line or later choice. Plasma ProGRP levels were determined using a chemiluminescent enzyme immunoassay, and data were collected prospectively. The study endpoints were prostate-specific antigen (PSA) response and survival estimates. RESULTS: In the ENZ series, ProGRP levels correlated with the maximum PSA change from baseline (high ProGRP: -34.5% vs. low ProGRP: -85.7% p = .033). PSA progression-free survival (PFS), radiographic/symptomatic (r/s) PFS, and overall survival (OS) in patients with high ProGRP were significantly worse than those in patients with low ProGRP (median PSA-PFS: 3.3 vs. 10.0 months, p = .001, r/s PFS: 5.0 vs. 15.0 months, p < 0.001, and OS 17.5 vs. 49.0 months, p < .001, respectively). In addition, ProGRP showed an independent predictive value for all survival estimates in multivariate analyses. In the AA/P series, ProGRP levels did not correlate with the PSA change or predict PSA-PFS and r/s PFS, but they maintained a significant difference in OS (19.0 vs. 48.0 months, p = .003). CONCLUSIONS: Plasma ProGRP provides a consistent predictive value for OS in metastatic CRPC patients who underwent therapy with ARAT agents. Meanwhile, ProGRP showed different predictive profiles for PSA- and r/s PFS between ENZ and AA/P. These findings clinically suggest a mechanism for CRPC progression involving the NE pathway via the GRP. The underlying mechanism of different predictive profiles by the ARAT agent should be explored in future research.

Endoscopic radiofrequency ablation for ingrowth occlusion after bilateral metal stent placement for malignant hilar biliary obstruction: a prospective pilot study.

BACKGROUND AND AIMS: Endoscopic biliary radiofrequency ablation (RFA) may be an option for the treatment of ingrowth occlusion after self-expandable metal stent (SEMS) deployment; however, its utility remains uncertain. This study aimed to examine the feasibility of RFA for the palliation of ingrowth after bilateral SEMS placement in patients with malignant hilar biliary obstruction. METHODS: This prospective, single-center, pilot study enrolled 30 patients who met the eligibility criteria between April 2020 and March 2022. Study outcomes were technical success, clinical success, recurrent biliary obstruction (RBO), and adverse events (AEs) besides RBO associated with RFA for ingrowth occlusion. Furthermore, factors predictive of clinical success were evaluated. RESULTS: Technical and clinical success rates were 93.3% (28/30) and 71.4% (20/28), respectively. The rates of early and late AEs were 6.7% (2/30) and 10.0% (2/20), respectively. The incidence rate of RBO after RFA was 45.0% (9/20), and the median time to RBO was 163 days. Multivariate analysis of the factors affecting clinical success revealed a positive association between the recanalization diameter on the ingrown part within the SEMS (odds ratio, 1.13; 95% confidence interval, 1.01-1.26; P = .038). The calculated optimal cutoff for the ratio of the recanalization diameter to the SEMS diameter for predicting clinical success was 51.1%. CONCLUSIONS: Endoscopic biliary RFA elicited promising results, with good long-term stent patency and without the requirement of any additional stent placement, for the palliation of ingrowth occlusion after bilateral SEMS placement. However, the clinical success rate was insufficient, necessitating improvements in the future. (Clinical trial registration number: UMIN000040154.).

Endoscopic Ultrasound-Guided Hepaticogastrostomy with Antegrade Stenting Without Dilation Device Application for Malignant Distal Biliary Obstruction in Pancreatic Cancer.

BACKGROUND: Endoscopic ultrasound-guided hepaticogastrostomy with antegrade stenting (EUS-HGAS) is a promising therapeutic option for malignant distal biliary obstruction (MDBO) in the event of transpapillary approach failure. Eliminating the fistula dilation step may further decrease the incidence of adverse events (AE) and simplify the procedure. AIMS: This study focused on MDBO associated with pancreatic cancer and aimed to examine the utility of EUS-HGAS without the use of any dilation devices. METHODS: This retrospective study investigated consecutive patients in whom the transpapillary approach had failed or was difficult, and who underwent EUS-HGAS without dilation device usage, using a tapered small-diameter catheter, ultrathin delivery system, and tapered dedicated plastic stent. The outcomes of this study included the technical success, clinical success, AE incidence, and recurrent biliary obstruction (RBO) associated with the procedure. RESULTS: During the study period, EUS-HGAS without dilation device usage was attempted for 57 patients with MDBO due to pancreatic cancer. The technical and clinical success rates were 91.2% (52/57) each. The median procedural time was 25 min. The rates of early and late AE besides RBO were 3.5% (2/57) and 1.9% (1/52), respectively. The incidence rate of RBO was 30.8% (16/52), and the median time to RBO was 245 days. The rate of successful endoscopic reintervention for RBO via the fistula was 100% (16/16). CONCLUSIONS: EUS-HGAS without the use of dilation devices showed good technical feasibility with a low AE rate. It may be a useful option for MDBO associated with pancreatic cancer when the transpapillary approach is difficult.

Mac-2 binding protein glycosylation isomer, the FIB-4 index, and a combination of the two as predictors of non-alcoholic steatohepatitis.

Approximately 10% non-alcoholic fatty liver disease (NAFLD) cases progress to non-alcoholic steatohepatitis (NASH). Liver biopsy, the gold standard for diagnosing NASH and associated liver fibrosis, is invasive with a risk of life-threatening complications. Therefore, reliable non-invasive biomarkers for predicting NASH are required to prevent unnecessary liver biopsies. We evaluated the performance of two non-invasive fibrosis markers, Mac-2 binding protein glycosylation isomer (M2BPGi) and the FIB-4 index for predicting the fibrosis staging, NAFLD activity scoring (NAS) index, and NASH. We also analyzed the correlation between the two markers. The sensitivities, specificities, positive predictive values (PPV), and negative predictive values of the FIB-4 index, M2BPGi, and a combination of both markers for NASH diagnosis were evaluated. The M2BPGi and FIB-4 index showed a good performance in diagnosing NASH, the fibrosis stage, and the NAS index in NAFLD patients. While both markers were well-correlated with each other in most cases, no correlation was found in some patients. Compared with the FIB-4 index or the M2BPGi alone, a combination of the two showed a higher specificity, PPV, and accuracy for NASH diagnosis. The M2BPGi and the FIB-4 index are easily accessible and reliable liver fibrosis markers. Diseases other than liver disease may cause dissociation between the two markers, causing failure to predict NASH. However, the combination of both markers can compensate for their disadvantages. Because the PPV of the combination was relatively high, patients who test positive for both markers should undergo liver biopsy for NASH diagnosis.

Endobiliary Radiofrequency Ablation Using a Short-Type Balloon Enteroscope in Patients with Surgically Altered Anatomy.

BACKGROUND: Endoscopic radiofrequency ablation (RFA) is expected to prolong stent patency for malignant biliary obstruction (MBO). However, its feasibility when used in conjunction with a balloon enteroscope (BE) in patients with surgically altered anatomy (SAA) remains unknown. AIMS: This study aimed to investigate the feasibility of RFA combined with metal stent insertion under BE guidance for MBO in patients with SAA. METHODS: Thirty-seven patients who underwent treatment between October 2016 and January 2021 and met the eligibility criteria were investigated retrospectively. Study outcomes included technical and clinical success, recurrent biliary obstruction (RBO), and other adverse events besides RBO associated with RFA with metal stent placement using BE. RESULTS: Technical and clinical success rates were 100% (37/37) each. The rates of early and late adverse events were 8.1% (3/37) and 8.1% (3/37), respectively. RBO occurred in 32.4% (12/37) of the patients, and the median time to RBO was 296 days. The cause of RBO was ingrowth in eight patients, overgrowth in three patients, and indeterminate in one patient. All reinterventions for RBO were successful using the BE approach; all ingrowths, except one, were recanalized using additional RFA without additional stent placement. The frequency of reintervention-related adverse events was 9.1% (1/11). The median time to RBO after reintervention was 166 days. CONCLUSIONS: This study demonstrated the technical safety and feasibility as well as good long-term outcomes of endobiliary RFA combined with metal stent placement under BE guidance. This approach may be a useful option for treating MBO in patients with SAA.

Safety and Efficacy of Gemcitabine Plus Nab-Paclitaxel for Metastatic Pancreatic Cancer Patients Undergoing Biliary Stent Placement.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) is the first-line chemotherapeutic regimen for metastatic pancreatic cancer (MPC); however, there are concerns regarding its safety in patients undergoing biliary stent placement. This study aimed to examine the tolerability and efficacy of GnP in MPC patients who underwent biliary stent placement. METHODS: A total of 105 MPC patients who had received GnP treatment between 2015 and 2020 were included and investigated. The patients were divided into two groups: those undergoing biliary stent placement for symptomatic biliary obstruction (BO) (With-BO group) and those without biliary stent placement (Without-BO group). The best tumor response, overall survival (OS), and adverse events in each group were compared. RESULTS: The partial response, stable disease, and progressive disease rates were 22%, 61%, and 14.6% in the With-BO group, and 26.6%, 46.9%, and 21.9% in the Without-BO group, respectively, with no significant differences. The median OS was 12.2 months and 14.6 months in the With-BO and Without-BO groups, respectively (P = 0.483). Grade 3 or higher biliary tract-related events were significantly more common in the With-BO group (41.5%) than in the Without-BO group (1.6%) (P < 0.001), but all events were managed successfully by urgent intervention. The rates of any treatment-related toxicities, including febrile neutropenia, were not significantly different, and there were no chemotherapy-related deaths in either group. CONCLUSIONS: GnP can be as tolerable and effective in MPC patients with biliary stents as in those without biliary stents. However, careful management and appropriate reintervention to treat biliary tract-related adverse events are required.

A case of clear cell renal cell carcinoma with vena cava thrombus responding to presurgical avelumab, and axitinib.

INTRODUCTION: We report a case of renal cell carcinoma with vena cava thrombus showing a marked reduction with presurgical avelumab plus axitinib, facilitating nephrectomy with thrombectomy. CASE PRESENTATION: A 50-year-old man was taken to emergent care unit due to spontaneous renal rupture and was diagnosed to have left-sided renal cell carcinoma with level IV tumor thrombus. After hemostasis was obtained via transcatheter arterial embolization, avelumab plus axitinib was introduced because upfront surgery was deemed unfeasible due to poor performance status and possible retroperitoneal tumor dissemination. After four treatment cycles, thrombus was reduced to level II, and nephrectomy with thrombectomy was performed. Histological analyses revealed massive CD8+ T cell infiltration in the thrombus, suggesting immunotherapy efficacy. He has remained recurrence-free without any additional treatment for eight months. CONCLUSION: For locally advanced renal cell carcinoma with vena cava thrombus, presurgical combination therapy with avelumab plus axitinib could be an option to facilitate curative surgery.

A case of estrogen-secreting adrenocortical carcinoma: Comprehensive immunohistochemical analysis of disorganized steroid genesis.

INTRODUCTION: Adrenocortical carcinoma rarely secretes estrogens, and little is known regarding the mechanism of intra-tumor estrogen production. We report an estrogen-secreting adrenocortical carcinoma in a postmenopausal woman, where comprehensive immunohistochemical analyses of the resected tumor revealed disorganized steroidogenesis. CASE PRESENTATION: A 68-year-old woman presented with postmenopausal vaginal bleeding and was found to have a left adrenal tumor. Serum estradiol and testosterone were elevated but they normalized after resection of the tumor, suggestive of adrenocortical carcinoma with disorganized steroidogenesis. Immunohistochemical analyses revealed that the tumor expressed aromatase which converts androgens into estrogens. Furthermore, the tumor lacked 17ßHSD2, which converts estradiol to estrone, suggesting that estradiol accumulated as the final product of the tumor's steroidogenic pathway. CONCLUSION: The capability of adrenocortical carcinoma to produce estrogen can be demonstrated by comprehensive immunohistochemical analyses of steroidogenic enzymes, such as those reported here.

Novel anatomical apical dissection utilizing puboprostatic "open-collar" technique: Impact on apical surgical margin and early continence recovery.

PURPOSE: To evaluate the impact of modifications to anatomical apical dissection including a puboprostatic open-collar technique, which visualizes the lateral aspect of the apex and dorsal vein complex (DVC) covering the rhabdosphincter while preserving the puboprostatic collar, on positive surgical margin (PSM) and continence recovery. METHODS: One-hundred-and-sixty-seven patients underwent gasless single-port retroperitoneoscopic radical prostatectomy using a three-dimensional head-mounted display system. Sequentially modified surgical techniques comprised puboprostatic open-collar technique, sutureless transection of the DVC, retrograde urethral dissection, and anterior reconstruction. The associations of these modifications with PSM and continence recovery were assessed. RESULTS: The puboprostatic open-collar technique, sutureless DVC transection, and retrograde urethral dissection were significantly associated with lower apical PSM (P = 0.003, 0.003, and 0.010, respectively). The former two also showed similar associations in 84 patients with anterior apical tumor (P = 0.021 and 0.030, respectively). Among 92 patients undergoing all of these three procedures, overall and apical PSM rates were 13.0% and 3.3%, respectively. Retrograde urethral dissection (odds ratio [OR] 2.73, P = 0.004) together with nerve sparing (OR 2.77, P = 0.003) and anterior apical tumor (OR 0.45, P = 0.017) were independently associated with immediate continence recovery. A multivariable model for 3-month continence recovery included anterior apical tumor (OR 0.28, P = 0.003) and puboprostatic open-collar technique (OR 3.42, P = 0.062). Immediate and 3-month continence recovery rates were 56.3% and 85.4%, respectively, in 103 patients undergoing both the puboprostatic open-collar technique and retrograde urethral dissection. CONCLUSION: Novel anatomical apical dissection utilizing a puboprostatic open-collar technique may favorably impact on both apical surgical margin and continence recovery.

Utility of whole-body diffusion-weighted magnetic resonance imaging in the management of treatment-related neuroendocrine prostate cancer.

INTRODUCTION: Treatment-related neuroendocrine prostate cancer, a rare and aggressive malignancy that emerges during androgen deprivation therapy characterized by low serum prostate-specific antigen concentrations, is challenging to monitor because it is associated with predominantly visceral and lytic bone metastases. CASE PRESENTATION: We describe the case of a 69-year-old man with treatment-related neuroendocrine prostate cancer in whom the treatment response could be monitored using whole-body diffusion-weighted magnetic resonance imaging in addition to serum concentrations of neuroendocrine markers. The patient responded well to platinum-based chemotherapy and achieved a complete response, as evidenced by these diagnostic modalities. CONCLUSION: Our case suggests that whole-body diffusion-weighted magnetic resonance imaging is useful in disease management for treatment-related neuroendocrine prostate cancer as well as the potential evaluation of mixed responses and treatment resistance.

Spontaneous regression of multiple pulmonary metastases accompanied by normalization of serum immune markers following cytoreductive nephrectomy in a patient with clear-cell renal cell carcinoma.

INTRODUCTION: The spontaneous regression of metastases, which mostly occurs after surgical resection of the primary tumor, has been described in various malignancies, including renal cell carcinoma. The involvement of the host immune system is currently postulated as the underlying mechanism. CASE PRESENTATION: We present a case of metastatic clear-cell renal cell carcinoma that achieved complete spontaneous regression of multiple pulmonary metastases preceded by normalization of serum immune markers after cytoreductive nephrectomy. The patient remained disease free for 3 years without any systemic therapy, suggesting that postoperative normalization of serum immune markers may indicate recovery of the host immune system, which prevents tumor recurrence. CONCLUSION: Monitoring of serum immune markers may be useful to identify patients with recovered immune function and, therefore, may not require systemic therapy. Similarly, the case suggests a potential role of cytoreductive nephrectomy in the contemporary management of metastatic renal cell carcinoma.

Dual Agonist of Farnesoid X Receptor and Takeda G Protein-Coupled Receptor 5 Inhibits Hepatitis B Virus Infection In Vitro and In Vivo.

BACKGROUND AND AIMS: Chronic HBV infection is a major health problem worldwide. Currently, the first-line treatment for HBV is nucleos(t)ide analogs or interferons; however, efficient therapeutic approaches that enable cure are lacking. Therefore, anti-HBV agents with mechanisms distinct from those of current drugs are needed. Sodium taurocholate cotransporting polypeptide (NTCP) was previously identified as an HBV receptor that is inhibited by several compounds. Farnesoid X receptor (FXR) activation also inhibits NTCP function. APPROACH AND RESULTS: In this study, we investigated the inhibitory effect of bile acid (BA) derivatives-namely obeticholic acid (OCA), 6α-ethyl-24-nor-5ß-cholane-3α,7α,23-triol-23 sulfate sodium salt (INT-767; a dual agonist of FXR and Takeda G protein-coupled receptor [TGR5]), and 6α-ethyl-23(S)-methyl-cholic acid (INT-777; a TGR5 agonist)-3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064; a FXR agonist), cyclosporin A, and irbesartan. OCA and INT-777 suppressed HBV infection in HepG2-human NTCP-C4 cells. Interestingly, INT-767 showed potent inhibition by attaching to HBV particles rather than binding to NTCP. As an entry inhibitor, INT-767 was stronger than various natural BAs. Furthermore, in chimeric mice with humanized liver, INT-767 markedly delayed the initial rise of HBsAg, HBeAg, and HBV DNA and reduced covalently closed circular DNA. The strong inhibitory effect of INT-767 may be due to the cumulative effect of its ability to inhibit the entry of HBV and to stimulate FXR downstream signaling, which affects the postentry step. CONCLUSIONS: Our results suggest that BA derivatives, particularly INT-767, are prospective candidate anti-HBV agents. Clarifying the underlying mechanisms of BA derivatives would facilitate the development of anti-HBV agents.

Who Can Avoid Biopsy of Magnetic Resonance Imaging-Negative Lobes without Compromising Significant Cancer Detection among Men with Unilateral Magnetic Resonance Imaging-Positive Lobes?

OBJECTIVES: To assess whether biopsy of multiparametric magnetic resonance imaging (MRI)-negative lobes can be avoided without compromising significant cancer (SC) detection among men with unilateral MRI-positive lobes. METHODS: From April 2013 to April 2019, 322 men with elevated prostate-specific antigen (PSA <20 ng/mL) and unilateral MRI-positive lobes underwent targeted 4-core and systematic 14-core biopsy. MRI findings were prospectively collected and evaluated according to the Prostate Imaging-Reporting and Data System (PI-RADS) version 2, and scores ≥3 were considered positive. SC was defined as Gleason score ≥3 + 4 or maximal cancer length ≥5 mm. We developed predictive models of overall cancer and SC in MRI-negative lobes and evaluated the performance of these models. RESULTS: Detection rates of overall cancer/SC were 69%/61% for the overall cohort, 58%/48% for MRI-positive lobes, and 36%/20% for MRI-negative lobes. Age ≥75 years, PSA density ≥0.3, and PI-RADS ≥4 were independently predictive of both overall cancer and SC in MRI-negative lobes; 1 point was assigned for each risk factor, and the predictive score was defined as the sum of points (0-3) for both overall cancer and SC. Areas under the curve of the model for overall cancer/SC were 0.67/0.71. In the decision curve analysis, the model was of value above the threshold probability of 13%/6% for detecting overall cancer/SC in MRI-negative lobes. Of 40 men with score 0, overall cancer/SC was detected in the MRI-negative lobe in 4 (10%)/1 (2.5%). CONCLUSION: Biopsies of MRI-negative lobes may be avoided without compromising SC detection using our predictive model.

Gemcitabine plus nab-paclitaxel with initial dose reduction for older patients with advanced pancreatic cancer.

OBJECTIVES: For older patients with pancreatic cancer (PC), the benefits of gemcitabine plus nab-paclitaxel (GnP) are still uncertain, and the toxicity may be excessive. We aimed to examine the efficacy and safety of modified GnP (m-GnP), which is a nab-paclitaxel reduced regimen, for older patients (≥75 years) with advanced PC. MATERIALS AND METHODS: In total, 34 patients met the eligibility criteria for study inclusion between 2015 and 2020. We evaluated the overall survival (OS), progression-free survival (PFS), best response, and adverse events associated with m-GnP treatment. RESULTS: The median OS and PFS were 15.4 months and 5.9 months, respectively. The best response was partial response in 29% (10/34), stable disease in 53% (18/34), and progressive disease in 15% of patients (5/34); one patient was not evaluated. Among the grade 3 or higher hematological adverse events, neutropenia was the most frequent, occurring in 38% of patients (13/34), whereas febrile neutropenia occurred in 3% (1/34). Grade 3 or higher non-hematological adverse events occurred in 12% of patients (4/34). Early discontinuation owing to intolerable adverse events occurred in one patient, and there were no chemotherapy-related deaths. CONCLUSIONS: The present study demonstrated that m-GnP exhibited good efficacy with acceptable toxicity. To avoid early discontinuation and maintain dose intensities, initial dose reduction may be a good option for older patients with PC when receiving GnP.