Comparison of mirabegron and vibegron for clinical efficacy and safety in female patients with overactive bladder: a multicenter prospective randomized crossover trial.

PURPOSE: To compare the efficacy and safety of mirabegron and vibegron in female OAB patients. METHODS: We conducted a multicenter, prospective, randomized crossover study of female patients with OAB. The patients were assigned to Group MV (mirabegron for 8 weeks, followed by vibegron for 8 weeks) or group VM (vibegron for 8 weeks, followed by mirabegron for 8 weeks). The primary endpoint was the change in OABSS from baseline, and the secondary endpoint was the change in FVC parameters. After completion of the study, each patient was asked which drug was preferable. RESULTS: A total of 83 patients were enrolled (40 and 43 in groups MV and VM, respectively). At 8th and 16th week, 33 and 29 in Group MV and 34 and 27 in Group VM continued to receive the treatment. The change in PVR was not significantly different between treatment with mirabegron and vibegron. The changes in OABSS, nighttime frequency, mean, and maximum voided volume were similar between mirabegron and vibegron. The mean change in the daytime frequency was greater in the vibegron than in the mirabegron. Of the 56 patients, 15 (27%) and 30 (53%) preferred mirabegron and vibegron, respectively. The remaining 11 patients (20%) showed no preference. The change in the urgency incontinence score during vibegron was better in patients who preferred vibegron to mirabegron. CONCLUSION: The efficacies of mirabegron and vibegron in female patients was similar. The patients' preference for vibegron could depend on the efficacy of vibegron for urgency incontinence.

Intraoperative artificial intelligence system identifying liver vessels in laparoscopic liver resection: a retrospective experimental study.

BACKGROUND: The precise recognition of liver vessels during liver parenchymal dissection is the crucial technique for laparoscopic liver resection (LLR). This retrospective feasibility study aimed to develop artificial intelligence (AI) models to recognize liver vessels in LLR, and to evaluate their accuracy and real-time performance. METHODS: Images from LLR videos were extracted, and the hepatic veins and Glissonean pedicles were labeled separately. Two AI models were developed to recognize liver vessels: the "2-class model" which recognized both hepatic veins and Glissonean pedicles as equivalent vessels and distinguished them from the background class, and the "3-class model" which recognized them all separately. The Feature Pyramid Network was used as a neural network architecture for both models in their semantic segmentation tasks. The models were evaluated using fivefold cross-validation tests, and the Dice coefficient (DC) was used as an evaluation metric. Ten gastroenterological surgeons also evaluated the models qualitatively through rubric. RESULTS: In total, 2421 frames from 48 video clips were extracted. The mean DC value of the 2-class model was 0.789, with a processing speed of 0.094 s. The mean DC values for the hepatic vein and the Glissonean pedicle in the 3-class model were 0.631 and 0.482, respectively. The average processing time for the 3-class model was 0.097 s. Qualitative evaluation by surgeons revealed that false-negative and false-positive ratings in the 2-class model averaged 4.40 and 3.46, respectively, on a five-point scale, while the false-negative, false-positive, and vessel differentiation ratings in the 3-class model averaged 4.36, 3.44, and 3.28, respectively, on a five-point scale. CONCLUSION: We successfully developed deep-learning models that recognize liver vessels in LLR with high accuracy and sufficient processing speed. These findings suggest the potential of a new real-time automated navigation system for LLR.

Bridging horizons beyond CIRCULATE-Japan: a new paradigm in molecular residual disease detection via whole genome sequencing-based circulating tumor DNA assay.

Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer. Notably, the project underscores the prognostic significance of the ctDNA status at 4 weeks post-surgery and its correlation to adjuvant therapy efficacy at interim analysis. This substantiates the hypothesis that MRD is a critical prognostic indicator of relapse in patients with colorectal cancer. Despite remarkable advancements, challenges endure, primarily attributable to the exceedingly low ctDNA concentration in peripheral blood, particularly in scenarios involving low tumor shedding and the intrinsic error rates of current sequencing technologies. These complications necessitate more sensitive and sophisticated assays to verify the clinical utility of MRD across all solid tumors. Whole genome sequencing (WGS)-based tumor-informed MRD assays have recently demonstrated the ability to detect ctDNA in the parts-per-million range. This review delineates the current landscape of MRD assays, highlighting WGS-based approaches as the forefront technique in ctDNA analysis. Additionally, it introduces our upcoming endeavor, WGS-based pan-cancer MRD detection via ctDNA, in our forthcoming project, SCRUM-Japan MONSTAR-SCREEN-3.

Epigenome editing reveals core DNA methylation for imprinting control in the Dlk1-Dio3 imprinted domain.

The Dlk1-Dio3 imprinted domain is controlled by an imprinting control region (ICR) called IG-DMR that is hypomethylated on the maternal allele and hypermethylated on the paternal allele. Although several genetic mutation experiments have shown that IG-DMR is essential for imprinting control of the domain, how DNA methylation itself functions has not been elucidated. Here, we performed both gain and loss of DNA methylation experiments targeting IG-DMR by transiently introducing CRISPR/Cas9 based-targeted DNA methylation editing tools along with one guide RNA into mouse ES cells. Altered DNA methylation, particularly at IG-DMR-Rep, which is a tandem repeat containing ZFP57 methylated DNA-binding protein binding motifs, affected the imprinting state of the whole domain, including DNA methylation, imprinted gene expression, and histone modifications. Moreover, the altered imprinting states were persistent through neuronal differentiation. Our results suggest that the DNA methylation state at IG-DMR-Rep, but not other sites in IG-DMR, is a master element to determine whether the allele behaves as the intrinsic maternal or paternal allele. Meanwhile, this study provides a robust strategy and methodology to study core DNA methylation in cis-regulatory elements, such as ICRs and enhancers.

Relationships between physical and immunological tumor microenvironment in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is physically palpated as a hard tumor with an unfavorable prognosis. Assessing physical features and their association with pathological features could help to elucidate the mechanism of physical abnormalities in cancer tissues. A total of 93 patients who underwent radical surgery for pancreatic and bile duct cancers at a single center hospital during a 28-month period were recruited for this study that aimed to estimate the stiffness of PDAC tissues compared to the other neoplasms and assess relationships between tumor stiffness and pathological features. Physical alterations and pathological features of PDAC, with or without preoperative therapy, were analyzed. The immunological tumor microenvironment was evaluated using multiplexed fluorescent immunohistochemistry. The stiffness of PDAC correlated with the ratio of Azan-Mallory staining, α-smooth muscle actin, and collagen I-positive areas of the tumors. Densities of CD8+ T cells and CD204+ macrophages were associated with tumor stiffness in cases without preoperative therapy. Pancreatic ductal adenocarcinoma treated with preoperative therapy was softer than that without, and the association between tumor stiffness and immune cell infiltration was not shown after preoperative therapy. We observed the relationship between tumor stiffness and immunological features in human PDAC for the first time. Immune cell densities in the tumor center were smaller in hard tumors than in soft tumors without preoperative therapies. Preoperative therapy could alter physical and immunological aspects, warranting further study. Understanding of the correlations between physical and immunological aspects could lead to the development of new therapies.

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

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

NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases.

BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.

A novel predictive model for postoperative delirium using multiple geriatric screening factors.

OBJECTIVES: The purpose of this study was to develop a new composite score to accurately predict postoperative delirium (POD) after major urological cancer surgery. METHODS: Our retrospective analysis included, in total, 449 consecutive patients who experienced major urological cancer surgery and a preoperative geriatric functional assessment at our institution (development cohort). Geriatric functional assessments included Geriatric 8, Instrumental Activities of Daily Living, and mini-cognitive assessment instrument (Mini-Cog). Multivariate analysis was used to identify factors related to POD and combined to create a predictive score. The composite score was externally validated using a cohort of 92 consecutive pancreatic cancer patients who underwent pancreaticoduodenectomy and a preoperative geriatric functional assessment (validation cohort). The predictive accuracy and performance of the composite score were evaluated using the area under the receiver operating characteristic curves (AUC) and calibration plots. RESULTS: In multivariate analysis of a development cohort, the following factors were significantly associated with POD: a Mini-Cog score of <3 (odds ratio [OR] = 9.5; p < 0.001), disability in the responsibility for medication (OR = 4.1; p = 0.03), and the preoperative use of benzodiazepine (OR = 6.4; p < 0.001). The composite score of these three factors showed excellent discrimination in predicting POD, with AUC values of 0.819 and 0.804 in development and validation cohorts, respectively. Calibration plots showing predicted probability and actual observation in both cohorts showed good agreement. CONCLUSIONS: A combined model of Mini-Cog, a disability in the responsibility for medication, and preoperative benzodiazepine use showed excellent discriminative power in predicting POD.

Internet research of utilization of social media in patients with urological disease and their families in Japan.

OBJECTIVES: To survey the utilization of social media (SoMe) in patients with urological disease and their families. METHODS: Among the panel members registered in NEO Marketing Inc. (Tokyo, Japan), 300 people who or whose families were visiting the urological department regularly were included. Study subjects were randomly chosen and surveyed using the questionnaire over the internet. RESULTS: This study included 203 (68%) males and 97 (32%) females. The mean age was 62 (21-85) in males and 49 (22-75) in females. One hundred and ten subjects (37%) had no account for any SoMe. The account holders of YouTube, Twitter, Facebook, Instagram, and TikTok were 119 (40%), 117 (39%), 101 (34%), 90 (30%), and 33 (11%), respectively. The proportions of account holders were different depending on gender, age, and platforms. Frequent viewers on YouTube, Twitter, Facebook, Instagram, and TikTok were 100 (84%), 89 (76%), 63 (62%), 66 (73%), and 24 (73%), respectively. Of 190 who had accounts for any SoMes, 64 (34%) found any information about urological diseases of themselves or their families. Among the all subjects, 162 (54%) thought that they would like to view the medical contents on SoMes submitted by medical societies. CONCLUSIONS: Patients with urological disease and their families in Japan occasionally utilize SoMe to obtain information on their diseases and prefer professional medical information on SoMe. The gender and age of SoMe users and the optimal platform should be considered when posting medical information on SoMe.

Liver functional assessment using time-associated change in the liver-to-spleen signal intensity ratio on enhanced magnetic resonance imaging: a retrospective study.

BACKGROUND: Liver-to-spleen signal intensity ratio (LSR) is evaluated by magnetic resonance imaging (MRI) in the hepatobiliary phase and has been reported as a useful radiological assessment of regional liver function. However, LSR is a passive (non-time-associated) assessment of liver function, not a dynamic (time-associated) assessment. Moreover, LSR shows limitations such as a dose bias of contrast medium and a timing bias of imaging. Previous studies have reported the advantages of time-associated liver functional assessment as a precise assessment of liver function. For instance, the indocyanine green (ICG) disappearance rate, which is calculated from serum ICG concentrations at multiple time points, reflects a precise preoperative liver function for predicting post-hepatectomy liver failure without the dose bias of ICG or the timing bias of blood sampling. The aim of this study was to develop a novel time-associated radiological liver functional assessment and verify its correlation with traditional liver functional parameters. METHODS: A total of 279 pancreatic cancer patients were evaluated to clarify fundamental time-associated changes to LSR in normal liver. We defined the time-associated radiological assessment of liver function, calculated using information on LSR from four time points, as the "LSR increasing rate" (LSRi). We then investigated correlations between LSRi and previous liver functional parameters. Furthermore, we evaluated how timing bias and protocol bias affect LSRi. RESULTS: Significant correlations were observed between LSRi and previous liver functional parameters such as total bilirubin, Child-Pugh grade, and albumin-bilirubin grade (P < 0.001 each). Moreover, considerably high correlations were observed between LSRi calculated using four time points and that calculated using three time points (r > 0.973 each), indicating that the timing bias of imaging was minimal. CONCLUSIONS: This study propose a novel time-associated radiological assessment, and revealed that the LSRi correlated significantly with traditional liver functional parameters. Changes in LSR over time may provide a superior preoperative assessment of regional liver function that is better for predicting post-hepatectomy liver failure than LSR using the hepatobiliary phase alone.

[Pre-Operative Factors Affecting Trifecta Achievement in the Initial Series of Robot-Assisted Partial Nephrectomy].

We investigated pre-operative factors affecting trifecta achievement in robot-assisted partial nephrectomy (RAPN). We retrospectively analyzed 81 patients who underwent RAPN from December 2016 to September 2021 with final malignant pathologies. Trifecta was defined as negative resection margin (RM),warm ischemic time (WIT) less than 25 minutes, and no severe perioperative complications (Clavien-Dindo＜III). Factors affecting trifecta achievement were analyzed using sex, age, body mass index, RENAL nephrometry score (low or moderate/high complexity), surgical approach (transabdominal or retroperitoneal), tumor diameter and surgical experiences of each surgeon. Negative RM, WIT less than 25 minutes, and no severe complications were obtained in 75 (93%), 65 (80%), and 79 patients (98%), respectively. The trifecta was achieved in 60 patients (74%). In multivariate regression analysis, surgical experience (OR:0.92, 95% CI : 0.86-0.99) was significantly associated with trifecta achievement. Receiver operating characteristic curve analysis identified 9 cases as the optimal cut-off values for the predication of trifecta achievement (AUC＝0.69,p ＝0.11). The achievement of WIT less than 25 minutes (65 vs 90%, p＜0.01) and trifecta (58 vs 84%,p ＜0.05) were significantly lower in surgical experiences less than 9 cases than in 9 or greater. We conclude that surgical experience in RAPN is an important factor affecting WIT and trifecta achievement in the initial series.

Component with abundant immune-related cells in combined hepatocellular cholangiocarcinoma identified by cluster analysis.

Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a heterogeneous tumor sharing histological features with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The tumor immune microenvironment (TIME) of cHCC-CCA is unclear. We compared the TIME of cHCC-CCA with that of HCC and iCCA. Twenty-three patients with cHCC-CCA after hepatectomy were evaluated in this study. Twenty-three patients with iCCA and HCC were also included. iCCA was matched for size, and HCC was matched for size and hepatitis virus infection with cHCC-CCA. Immune-related cells among the iCCA-component of cHCC-CCA (C-com), HCC-component of cHCC-CCA (H-com), iCCA, and HCC were assessed using multiplex fluorescence immunohistochemistry. Among C-com, H-com, iCCA, and HCC, multiple comparisons and cluster analysis with k-nearest neighbor algorithms were performed using immunological variables. Although HCC had more T lymphocytes and lower PD-L1 expression than iCCA (P < 0.05), there were no significant differences in immunological variables between C-com and H-com. C-com tended to have more T lymphocytes than iCCA (P = 0.09), and C-com and H-com had fewer macrophages than HCC (P < 0.05). In cluster analysis, all samples were classified into two clusters: one cluster had more immune-related cells than the other, and 12 of 23 H-com and eight of 23 C-com were identified in this cluster. The TIME of C-com and H-com may be similar, and some immunological features in these components were different from those in HCC and some iCCA. Cluster analysis identified components with abundant immune-related cells in cHCC-iCCA.

Development of an in vitro carcinogenesis model of human papillomavirus-induced cervical adenocarcinoma.

Cervical adenocarcinoma (ADC) is the second most common pathological subtype of cervical cancer after squamous cell carcinoma. It accounts for approximately 20% of cervical cancers, and the incidence has increased in the past few decades, particularly among young patients. The persistent infection of high-risk human papillomavirus (HPV) is responsible for most cervical ADC. However, almost all available in vitro models are designed to study the carcinogenesis of cervical squamous cell carcinoma. To gain better insights into molecular background of ADC, we aimed to establish an in vitro carcinogenesis model of ADC. We previously reported the establishment of an in vitro model for cervical squamous cell carcinoma by introducing defined viral and cellular oncogenes, HPV16 E6 and E7, c-MYC, and activated RAS to human cervical keratinocytes. In this study, the expression of potential lineage-specifying factors and/or SMAD4 reduction was introduced in addition to the defined four oncogenes to direct carcinogenesis toward ADC. The cell properties associated with the cell lineage were analyzed in monolayer and organoid cultures and the tumors in mouse xenografts. In the cells expressing Forkhead box A2 (FOXA2), apparent changes in cell properties were observed, such as elevated expression of columnar cell markers and decreased expression of squamous cell markers. Strikingly, the histopathology of tumors expressing FOXA2 resembled cervical ADC, proposing that FOXA2 plays a vital role in dictating the histopathology of cervical cancers.

Early postoperative decrease of skeletal muscle mass predicts recurrence and poor survival after surgical resection for perihilar cholangiocarcinoma.

BACKGROUND: Preoperative sarcopenia is a predictor of poor survival in cancer patients. We hypothesized that sarcopenia could progress as occult metastasis arose, especially after highly invasive surgery for highly aggressive malignancy. This study aimed to evaluate the associations of postoperative changes in skeletal muscle mass volume with survival outcomes in patients who underwent surgery for perihilar cholangiocarcinoma. METHODS: Fifty-six patients who underwent major hepatectomy with extrahepatic bile duct resection for perihilar cholangiocarcinoma were studied. The skeletal muscle index (SMI) at the third lumbar vertebra was calculated from axial computed tomography images taken preoperatively and 3-6 months postoperatively (early postoperative period). The associations of clinicopathological variables, including changes of SMI after surgery, with overall survival and recurrence-free survival were evaluated. Moreover, the associations of decreased SMI and elevated serum carbohydrate antigen 19-9 level with early recurrence and poor survival was compared. RESULTS: Among 56 patients, 26 (46%) had sarcopenia preoperatively and SMI decreased in 29 (52%) in the early postoperative period. During the median follow-up of 57.9 months, 35 patients (63%) developed recurrence and 29 (50%) died. Decreased SMI in the early postoperative period was independently associated with a shorter overall survival (hazard ratio, 2.39; 95% confidence interval, 1.00-6.18; P = 0.049) and a shorter recurrence-free survival (hazard ratio, 2.14; 95% confidence interval, 1.04-4.57; P = 0.039), whereas elevated carbohydrate antigen 19-9 level was not. CONCLUSIONS: Decreased SMI in the early postoperative period may be used as a predictor for recurrence and poor survival in patients undergoing surgery for perihilar cholangiocarcinoma.

Laparoscopic liver resection can be performed safely without intraoperative drain placement.

BACKGROUND: Laparoscopic liver resection (LLR) has become a standardized procedure with advances in surgical techniques and perioperative management in the last decade; however, the necessity of routine drain placement in LLR has not been fully investigated. This study aimed to evaluate the need for intraoperative drain placement (IDP) in LLR. METHODS: A total of 607 patients who underwent LLR for liver tumor at our institution between January 2015 and August 2021 were studied. Clinicopathological data, including intraoperative factors and postoperative outcomes, were compared between patients with and without IDP before and after propensity score matching. Variables shown to be different between the two groups were used for matching. Then, risk analysis for additional drainage procedure after surgery was performed in the original and matched cohorts. RESULTS: Of the 607 patients, 4 (0.7%) and 14 (2.3%) developed incisional and organ/space surgical site infections, respectively, and 9 (1.5%) required additional drainage procedure after surgery. Ninety-three patients (15.3%) underwent IDP. The incidence and severity of postoperative complications were similar between patients with and without IDP in both the original and matched cohorts. In the matched cohort, simultaneous colectomy (odds ratio, 14.051, 95% confidence interval, 1.103-178.987; P = 0.042), rather than IDP (odds ratio, 1.836, 95% confidence interval, 0.157-21.509; P = 0.629), was independently associated with the risk of additional drainage procedure after surgery. CONCLUSIONS: This study demonstrated that LLR could be performed safely without IDP.

[Clinical Significance of Preoperative Image Classification Systems in Robot-Assisted Laparoscopic Partial Nephrectomy].

Robot-assisted laparoscopic partial nephrectomy (RAPN) is being used in Japan as a less invasive procedure. RENAL nephrometry (RN) score, Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) Classification and Simplified PADUA Renal (SPARE) nephrometry system are tumor-specific morphometry scoring systems used for predicting the difficulty of partial nephrectomy. Adherent perinephric fat (APF) is one of the patient-specific factors related to the difficulty of partial nephrectomy. Mayo Adhesive Probability (MAP) score measures the difficulty of partial nephrectomy due to APF. Whether these scoring systems were associated with perioperative outcome of RAPN was retrospectively analyzed in 57 patients who underwent RAPN by two experienced surgeons at our hospital from December 2016 to March 2020. Forty-five patients were male and 12 were female. The right side was resected in 25 and the left side in 32 patients. The approach was transperitoneal in 42 and retroperitoneal in 15 patients. There were significant correlations among RN, PADUA and SPARE scores, while MAP score was independent from the other scores. Warm ischemic time was significantly correlated with RN (r＝0.46, p＜0.001), PADUA (r＝0.45, p＜0.001) and SPARE scores (r＝0.44, p＜0.001). Time for console was significantly correlated with MAP score (r＝0.28, p＝0.035). In conclusion, RN and MAP scores might be useful parameters to predict warm ischemic time and time for console during RAPN, respectively.

[Comparison of Perioperative Outcomes between Open and Robot-Assisted Laparoscopic Radical Cystectomy].

We compared the perioperative outcomes of open (ORC) and robot-assisted laparoscopic radical cystectomy (RARC) for patients with bladder cancer. We retrospectively investigated the intraoperative and 90-day postoperative complications of ORC and RARC performed from March 2014 to September 2021 based on the medical records. Perioperative complications were categorized according to the Clavien- Dindo classification. We used the propensity score matching to adjust for the inherent bias of the different patient characteristics at baseline including gender, age, preoperative chemotherapy, and pathological T classification. Surgery time of RARC was significantly shorter than that of ORC, and blood transfusion was significantly less frequent in RARC than in ORC (3% vs 81%, p＜0.01). The rate of overall complications of Grade III/IV was lower in RARC (8%) than in ORC (25%) (P＝0.09). The prevalence of perioperative urinary tract infection, ileus, and abscess/infectious cyst was similar in ORC and RARC. In patients who underwent RARC, the complication rate was similar in extracorporeal and intracorporeal urinary diversion. Compared to ORC, RARC is more beneficial to reduce blood loss and severe complications.

Sarcomatoid hepatocellular carcinoma is distinct from ordinary hepatocellular carcinoma: Clinicopathologic, transcriptomic and immunologic analyses.

Sarcomatoid hepatocellular carcinoma (SHCC), which was a rare histological subtype of hepatocellular carcinoma (HCC), is currently subclassified as poorly differentiated HCC because of insufficient evidence to define SHCC as a subtype of HCC. We aimed to assess the feasibility of classifying SHCC as a histological subtype of HCC by comprehensively identifying novel and distinct characteristics of SHCC compared to ordinary HCC (OHCC). Fifteen SHCCs (1.4%) defined as HCC with at least a 10% sarcomatous component, 15 randomly disease-stage-matched OHCCs and 163 consecutive OHCCs were extracted from 1106 HCCs in the Pathology Database (1997-2019) of our hospital. SHCC patients showed poor prognosis, and the tumors could be histologically subclassified into the pleomorphic, spindle and giant cell types according to the subtype of carcinomas with sarcomatoid or undifferentiated morphology in other organs. The transcriptomic analysis revealed distinct characteristics of SHCC featuring the upregulation of genes associated with epithelial-to-mesenchymal transition and inflammatory responses. The fluorescent multiplex immunohistochemistry results revealed prominent programmed death-ligand 1 (PD-L1) expression on sarcomatoid tumor cells and higher infiltration of CD4+ and CD8+ T cells in SHCCs compared to OHCCs. The density of CD8+ T cells in the nonsarcomatous component of SHCCs was also higher than that in OHCCs. In conclusion, the comprehensive analyses in our study demonstrated that SHCC is distinct from OHCC in terms of clinicopathologic, transcriptomic and immunologic characteristics. Therefore, it is reasonable to consider SHCC as a histological subtype of HCC.

Impact of Preoperative Circulating Tumor DNA Status on Survival Outcomes After Hepatectomy for Resectable Colorectal Liver Metastases.

BACKGROUND: The optimal perioperative management of patients who undergo hepatectomy for resectable colorectal liver metastases (CRLM) remains unclear due to the lack of reliable methods to stratify the risk of recurrence. METHODS: A single-center retrospective study was performed to investigate the impact of preoperative circulating tumor DNA (ctDNA) on survival outcomes of patients who underwent initial hepatectomy for solitary resectable CRLM between January 2005 and December 2017 using the comprehensive genotyping platform Guardant360®. RESULTS: Of 212 patients who underwent initial hepatectomy for solitary resectable CRLM, 40 patients for whom pre-hepatectomy plasma was available underwent ctDNA analysis. Among them, 32 (80%) had at least 1 somatic alteration in their ctDNA, while the other 8 (20%) had no detectable ctDNA. Among the patients with undetectable ctDNA, only one had recurrence and none died during a median follow-up period of 39.0 months. The recurrence-free survival was significantly shorter in patients who were positive for ctDNA than in those who were negative for ctDNA [median, 12.5 months vs not reached (NR); HR, 7.6; P = 0.02]. The overall survival also tended to be shorter in patients who were positive for ctDNA than those who were negative for ctDNA (median, 78.1 months vs NR; P = 0.14; HR not available). CONCLUSIONS: In patients undergoing hepatectomy for solitary resectable CRLM, the absence of detectable preoperative ctDNA identified patients with a high chance for a cure. Risk stratification according to preoperative ctDNA analysis may be an effective tool that can improve the perioperative management of these patients.

Peptide vaccine as an adjuvant therapy for glypican-3-positive hepatocellular carcinoma induces peptide-specific CTLs and improves long prognosis.

There is no established postoperative adjuvant therapy for hepatocellular carcinoma (HCC), and improvement of patient prognosis has been limited. We conducted long-term monitoring of patients within a phase II trial that targeted a cancer antigen, glypican-3 (GPC3), specifically expressed in HCC. We sought to determine if the GPC3 peptide vaccine was an effective adjuvant therapy by monitoring disease-free survival and overall survival. We also tracked GPC3 immunohistochemical (IHC) staining, CTL induction, and postoperative plasma GPC3 for a patient group that was administered the vaccine (n = 35) and an unvaccinated patient group that underwent surgery only (n = 33). The 1-y recurrence rate after surgery was reduced by approximately 15%, and the 5-y and 8-y survival rates were improved by approximately 10% and 30%, respectively, in the vaccinated group compared with the unvaccinated group. Patients who were positive for GPC3 IHC staining were more likely to have induced CTLs, and 60% survived beyond 5 y. Vaccine efficacy had a positive relationship with plasma concentration of GPC3; high concentrations increased the 5-y survival rate to 75%. We thus expect GPC3 vaccination in patients with HCC, who are positive for GPC3 IHC staining and/or plasma GPC3 to induce CTL and have significantly improved long-term prognosis.