Impact of First-Line Osimertinib and Other EGFR-Tyrosine Kinase Inhibitors on Overall Survival in Untreated Advanced EGFR-Mutated Non-small Cell Lung Cancer in Japan: Updated Data from TREAD Project 01.

BACKGROUND: Osimertinib shows higher effectiveness than first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in the initial treatment of EGFR-mutated non-small cell lung cancer. However, its superiority in terms of overall survival in the Asian population, especially Japanese patients, remains uncertain. OBJECTIVE: To evaluate the survival benefit of osimertinib over other EGFR-TKIs in Japanese patients, using real-world data. METHODS : As part of the Tokushukai REAl-world Data project, a retrospective multi-institutional study across 46 hospitals in Japan was conducted to evaluate the overall survival of patients with advanced EGFR-mutated non-small cell lung cancer using propensity score matching. The study involved patients receiving osimertinib as the first-line treatment (1L-Osi), those initially treated with other EGFR-TKIs (1L-non-Osi), and those receiving osimertinib after initial EGFR-TKI treatment (2L/later-Osi) between April 2010 and December 2022 and followed up until April 2023. RESULTS: Among 1062 Japanese patients with EGFR-mutated non-small cell lung cancer, 416 (39.2%) received 1L-Osi, while 646 (60.8%) received 1L-non-Osi, including 139 (13.1%) who received 2L/later-Osi. Within these groups, 416 (39.2%), 293 (27.6%), and 75 (7.1%) patients received first-line EGFR-TKI treatment post-osimertinib approval as a later-line treatment in Japan (March 2016). After propensity score matching, the overall survival of the 1L-Osi group was comparable to that of the 1L-non-Osi group in the post-March 2016 subset (n = 283, 42.0 vs 42.4 months). Similar trends were observed in the Del19 and L858R subgroups. The median overall survival of the 2L/later-Osi group was notably long: 60.2 months post-March 2016 (n = 75). A subgroup analysis based on initial EGFR-TKI treatment in the 1L-non-Osi and 2L/later-Osi groups revealed no significant differences among the gefitinib, erlotinib, and afatinib groups. CONCLUSIONS: Based on real-world data, osimertinib did not show a significant improvement in overall survival compared to other EGFR-TKIs as a first-line treatment for EGFR-mutated advanced non-small cell lung cancer in the Japanese (Asian) population. CLINICAL TRIAL REGISTRATION: This study was registered at the University Hospital Medical Information Network Clinical Trials Registry on 9 March, 2023 (identification UMIN000050552).

The effect of epidermal growth factor receptor mutation on adjuvant chemotherapy with tegafur/uracil for patients with completely resected, non-lymph node metastatic non-small cell lung cancer (> 2 cm): a multicenter, retrospective, observational study as exploratory analysis of the CSPOR-LC03 study.

BACKGROUND: The use of adjuvant osimertinib for epidermal growth factor receptor (EGFR) mutants is expected to expand to earlier stage I in the future, potentially competing with the current standard of care, oral tegafur/uracil (UFT), in Japan. However, the effect of EGFR mutation status on the therapeutic effect of UFT remains unclear. This study was conducted as an exploratory analysis of a retrospective observational study that investigated the real-world data of postoperative adjuvant chemotherapy in Japan (CSPOR-LC03). METHODS: Between 2008 and 2013, 1812 patients with completely resected adenocarcinoma diagnosed as pathologic stage I (T1 > 2 cm, TNM classification, sixth edition) who have maintained organ function, and no history of other cancers were included. The primary endpoint was the 5-year disease-free survival (DFS) rate, and we compared this rate between four groups classified based on the administration of adjuvant UFT and EGFR mutation status. RESULTS: Of the 933 (51%) patients with EGFR mutations, 394 underwent adjuvant UFT therapy. Of the 879 (49%) patients without EGFR mutations, 393 underwent adjuvant UFT therapy. The 5-year DFS of UFT+/EGFR+ and UFT-/EGFR+ patients were 82.0 and 87.1%, respectively, and those of UFT+/EGFR- and UFT-/EGFR- patients were 80.0 and 86.9%, respectively. DFS was significantly worse in the UFT+ group than in the UFT- group (P = 0.015). Adjuvant UFT therapy was not an independent prognostic factor for DFS, regardless of the EGFR mutation status. CONCLUSION: In pathologic stage I (>2 cm) lung adenocarcinomas with EGFR mutation, the survival benefit of adjuvant UFT was not observed.

Comparison of antimicrobial therapy termination in febrile and afebrile patients with acute cholangitis after drainage.

The standard treatment duration for acute cholangitis (AC) involves a 4-7-day antimicrobial treatment post-biliary drainage; however, recent studies have suggested that a ≤ 2-3 days is sufficient. However, clinical practice frequently depends on body temperature as a criterion for discontinuing antimicrobial treatment. Therefore, in this study, we assessed whether patients with AC can achieve successful outcomes with a ≤ 7-day antimicrobial treatment, even with a fever, assuming the infection source is effectively controlled. We conducted a single-center retrospective study involving patients with AC, defined following the Tokyo Guidelines 2018 for any cause, who underwent successful biliary drainage and completed a ≤ 7-day antimicrobial treatment. Patients were categorized into the febrile and afebrile groups based on their body temperature within 24 h before completing antimicrobial treatment. The primary outcome was the clinical cure rate, defined as no initial presenting symptoms by day 14 post-biliary drainage without recurrence or death by day 30. The secondary outcome was a 3-month recurrence rate. Logistic regression with inverse probability of treatment weighting was used. Overall, 408 patients were selected, among whom 40 (9.8%) were febrile. The two groups showed no significant differences in the clinical cure and 3-month recurrence rates. Notably, the subgroups limited to patients with a ≤ 3-day antibiotic treatment duration also showed no differences in these outcomes. Therefore, our results suggest that discontinuing antibiotics within the initially planned treatment period was sufficient for successful drainage cases of AC, regardless of the patient's fever status during the 24 h leading up to termination.

A New Criterion for Determining a Cutoff Value Based on the Biases of Incidence Proportions in the Presence of Non-differential Outcome Misclassifications.

When conducting database studies, researchers sometimes use an algorithm known as "case definition," "outcome definition," or "computable phenotype" to identify the outcome of interest. Generally, algorithms are created by combining multiple variables and codes, and we need to select the most appropriate one to apply to the database study. Validation studies compare algorithms with the gold standard and calculate indicators such as sensitivity and specificity to assess their validities. As the indicators are calculated for each algorithm, selecting an algorithm is equivalent to choosing a pair of sensitivity and specificity. Therefore, receiver operating characteristic curves can be utilized, and two intuitive criteria are commonly used. However, neither was conceived to reduce the biases of effect measures (e.g., risk difference and risk ratio), which are important in database studies. In this study, we evaluated two existing criteria from perspectives of the biases and found that one of them, called the Youden index always minimizes the bias of the risk difference regardless of the true incidence proportions under nondifferential outcome misclassifications. However, both criteria may lead to inaccurate estimates of absolute risks, and such property is undesirable in decision-making. Therefore, we propose a new criterion based on minimizing the sum of the squared biases of absolute risks to estimate them more accurately. Subsequently, we apply all criteria to the data from the actual validation study on postsurgical infections and present the results of a sensitivity analysis to examine the robustness of the assumption our proposed criterion requires.

Final analyses of the prospective controlled trial on the efficacy of uracil and tegafur/leucovorin as an adjuvant treatment for stage II colon cancer with risk factors for recurrence using propensity score-based methods (JFMC46-1201).

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. Using propensity score matching, we previously reported that the 3-year disease-free survival (DFS) rate was significantly higher in patients treated with uracil and tegafur plus leucovorin (UFT/LV) against surgery alone. We report the final results, including updated 5-year overall survival (OS) rates and risk factor analysis outcomes. METHODS: In total, 1902 high-risk stage II CC patients with T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and/or < 12 dissected lymph nodes were enrolled in this prospective, non-randomized controlled study based on their self-selected treatment. Oral UFT/LV therapy was administered for six months after surgery. RESULTS: Of the 1880 eligible patients, 402 in Group A (surgery alone) and 804 in Group B (UFT/LV) were propensity score-matched. The 5-year DFS rate was significantly higher in Group B than in Group A (P = 0.0008). The 5-year OS rates were not significantly different between groups. The inverse probability of treatment weighting revealed significantly higher 5-year DFS (P = 0.0006) and 5-year OS (P = 0.0122) rates in group B than in group A. Multivariate analyses revealed that male sex, age ≥ 70 years, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for DFS and/or OS. CONCLUSION: The follow-up data from our prospective non-randomized controlled study revealed a considerable survival advantage in DFS offered by adjuvant chemotherapy with UFT/LV administered for six months over surgery alone in individuals with high-risk stage II CC. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019), UMIN Clinical Trials Registry: UMIN000007783 (date of registration: 18/04/2012).

Validation of a New Scoring Method to Assess the Efficacy of Rapid Initiation and Titration of Combination Pharmacotherapy for Patients Hospitalized with Acute Decompensated Heart Failure with Reduced and Mildly Reduced Ejection Fraction.

Background: Despite the encouragement of early initiation and titration of guideline-directed medical therapy (GDMT) for the treatment of heart failure (HF), most patients do not receive an adequate type and dose of pharmacotherapy in the real world. Objectives: This study aimed to determine the efficacy of titrating composite GDMT in patients with HF with reduced and mildly reduced ejection fraction and to identify patient conditions that may benefit from titration of GDMT. Methods: This was a two-center, retrospective study of consecutive patients hospitalized with acute decompensated heart failure (ADHF). Patients were classified into two groups according to a scoring scale determined by combination and doses of four types of HF agents (ACEis/ARBs/ARNis, BBs, MRAs, and SGLT2is) at discharge. A score of 5 or greater was defined as titrated GDMT, and a score of 4 or less was regarded as sub-optimal medical therapy (MT). Results: A total of 979 ADHF patients were screened. After 553 patients were excluded based on exclusion criteria, 426 patients (90 patients in the titrated GDMT group and 336 patients in the sub-optimal MT group) were enrolled for the analysis. The median follow-up period was 612 (453-798) days. Following statistical adjustment using the propensity score weighting method, the 2-year composite endpoint (composite of cardiac death and HF rehospitalization) rate was significantly lower in the titrated GDMT group, at 19%, compared with the sub-optimal MT group: 31% (score 3-4 points) and 43% (score 0-2 points). Subgroup analysis indicated a marked benefit of titrated GDMT in particular patient subgroups: age < 80 years, BMI 19.0-24.9, eGFR > 20 mL/min/1.73 m2, and serum potassium level ≤ 5.5 mmol/L. Conclusions: Prompt initiation and dose adjustment of multiple HF medications, with careful monitoring of the patient's physiologic and laboratory values, is a prerequisite for improving the prognosis of patients with heart failure.

Valid instrumental variable selection method using negative control outcomes and constructing efficient estimator.

In observational studies, instrumental variable (IV) methods are commonly applied when there are unmeasured covariates. In Mendelian randomization, constructing an allele score using many single nucleotide polymorphisms is often implemented; however, estimating biased causal effects by including some invalid IVs poses some risks. Invalid IVs are those IV candidates that are associated with unobserved variables. To solve this problem, we developed a novel strategy using negative control outcomes (NCOs) as auxiliary variables. Using NCOs, we are able to select only valid IVs and exclude invalid IVs without knowing which of the instruments are invalid. We also developed a new two-step estimation procedure and proved the semiparametric efficiency of our estimator. The performance of our proposed method was superior to some previous methods through simulations. Subsequently, we applied the proposed method to the UK Biobank dataset. Our results demonstrate that the use of an auxiliary variable, such as an NCO, enables the selection of valid IVs with assumptions different from those used in previous methods.

Importance of circulating leptin and adiponectin in the causal pathways between obesity and the development of colorectal cancer in Japanese men.

BACKGROUND: The mechanistic associations between obesity and risk of colorectal cancer (CRC) remain unclear. Here, using body mass index (BMI) as an obesity indicator, we decomposed the total effects of obesity on the risk of CRC into: (1) direct effects, which are possibly mediated by unmeasured or currently unknown factors; (2) indirect effects mediated by circulating leptin and adiponectin; and (3) indirect effects that are not mediated by circulating leptin and adiponectin but by hyperinsulinemia and chronic inflammation (assessed via circulating connecting peptide and C-reactive protein, respectively). METHODS: We adopted a causal mediation framework, using data from a large prospective cohort study of 44,271 Japanese men. RESULTS: BMI was not associated with the risk of CRC due to direct and indirect effects that were not mediated by circulating leptin and adiponectin. By contrast, individuals with BMIs of 25.0-27.4 kg/m2 (risk ratio, 1.29; 95% confidence interval, 0.98-1.69) and ≥27.5 kg/m2 (risk ratio, 1.28; 95% confidence interval, 0.98-1.68) had a higher risk of CRC due to indirect effects of circulating leptin and adiponectin. CONCLUSIONS: Our mediation analyses suggest that the association between BMI and CRC risk may be largely mediated by a pathway involving circulating leptin and adiponectin.

Prognostic significance of ground-glass areas within tumours in non-small-cell lung cancer.

OBJECTIVES: To validate or refute the hypothesis that non-small-cell lung cancers (NSCLC) with ground-glass areas (GGA+) within the tumour on high-resolution computed tomography are associated with a more favourable prognosis than those without GGA (GGA-). METHODS: We analysed data from a multicentre observational cohort study in Japan including 5005 patients with completely resected pathological stage I NSCLC, who were excluded from the Japan Clinical Oncology Group (JCOG) 0707 trial on oral adjuvant treatment during the enrolment period. The patients' medical and pathological records were assessed retrospectively by physicians and re-staged according to the 8th tumour, node, metastasis edition. RESULTS: Of the 5005 patients, 2388 (48%) were ineligible for the JCOG0707 trial and 2617 (52%) were eligible but were not enrolled. A total of 958 patients (19.1%) died. Patients with GGA+ NSCLC and pathological invasion ≤3 cm showed significantly better overall survival than others. In patients with tumours with an invasive portion ≤4 cm, GGA+ was associated with better survival. The prognoses of patients with GGA+ T2a and GGA- T1c tumours were similar (5-year overall survival: 84.6% vs 83.1%, respectively). The survival with T2b or more tumours appeared unaffected by GGA, and GGA was not prognostic in these larger tumours. CONCLUSIONS: Patients with GGA+ NSCLC on high-resolution computed tomography and ≤4 cm invasion size may have a better prognosis than patients with solid GGA- tumours of the same T-stage. However, the presence or absence of radiological GGA has little impact on the prognosis of patients with NSCLC with greater (>4 cm) pathological invasion.

Inter- and intra-observer variability of qualitative visual breast-composition assessment in mammography among Japanese physicians: a first multi-institutional observer performance study in Japan.

BACKGROUND: Visual assessment of mammographic breast composition remains the most common worldwide, although subjective variability limits its reproducibility. This study aimed to investigate the inter- and intra-observer variability in qualitative visual assessment of mammographic breast composition through a multi-institutional observer performance study for the first time in Japan. METHODS: This study enrolled 10 Japanese physicians from five different institutions. They used the new Japanese breast-composition classification system 4th edition to subjectively evaluate the breast composition in 200 pairs of right and left normal mediolateral oblique mammograms (number determined using precise sample size calculations) twice, with a 1-month interval (median patient age: 59 years [range 40-69 years]). The primary endpoint of this study was the inter-observer variability using kappa (κ) value. RESULTS: Inter-observer variability for the four and two classes of breast-composition assessment revealed moderate agreement (Fleiss' κ: first and second reading = 0.553 and 0.587, respectively) and substantial agreement (Fleiss' κ: first and second reading = 0.689 and 0.70, respectively). Intra-observer variability for the four and two classes of breast-composition assessment demonstrated substantial agreement (Cohen's κ, median = 0.758) and almost perfect agreement (Cohen's κ, median = 0.813). Assessments of consensus between the 10 physicians and the automated software Volpara® revealed slight agreement (Cohen's κ; first and second reading: 0.104 and 0.075, respectively). CONCLUSIONS: Qualitative visual assessment of mammographic breast composition using the new Japanese classification revealed excellent intra-observer reproducibility. However, persistent inter-observer variability, presenting a challenge in establishing it as the gold standard in Japan.

BOIN-ETC: A Bayesian optimal interval design considering efficacy and toxicity to identify the optimal dose combinations.

One of the primary objectives of a dose-finding trial for novel anti-cancer agent combination therapies, such as molecular targeted agents and immune-oncology therapies, is to identify optimal dose combinations that are tolerable and therapeutically beneficial for subjects in subsequent clinical trials. The goal differs from that of a dose-finding trial for traditional cytotoxic agents, in which the goal is to determine the maximum tolerated dose combinations. This paper proposes the new design, named 'BOIN-ETC' design, to identify optimal dose combinations based on both efficacy and toxicity outcomes using the waterfall approach. The BOIN-ETC design is model-assisted, so it is expected to be robust, and straightforward to implement in actual oncology dose-finding trials. These characteristics are quite valuable from a practical perspective. Simulation studies show that the BOIN-ETC design has advantages compared with the other approaches in the percentage of correct optimal dose combination selection and the average number of patients allocated to the optimal dose combinations across various realistic settings.

Multi-institutional study of osimertinib dose-optimization in non-small cell lung cancer patients with EGFR activating mutation aged 70 years or older ('MONEY' trial).

Osimertinib is the standard of care for patients with epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer. Dose-toxicity has been previously reported, but no dose-response data within the range of 20-240 mg daily (mg/d). Thus, the current 80 mg/d dosing might be too high for elderly Japanese patients with an average body weight of only 50 kg, resulting in excessive toxicity and cost. We therefore initiated a study to investigate whether osimertinib at 40 mg/d is non-inferior to 80 mg/d in patients with advanced or recurrent epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer aged ≥70 years, using a regression discontinuity design. Osimertinib is administered at 40 mg/d for body weight ≤50 kg, and 80 mg/d for body weight >50 kg. The primary endpoint is progression-free survival. Sample size is 550 patients, based on a non-inferiority margin of the progression-free survival hazard ratio 1.333, 0.10 one-sided type I error and 80% power.

Transcatheter aortic valve replacement in patients with severe aortic stenosis reduced the frequency of intradialytic hypotension.

Intradialytic hypotension (IDH) is a common complication during hemodialysis that increases cardiovascular morbidity and mortality. Aortic stenosis (AS) is a cause of IDH. Transcatheter aortic valve replacement (TAVR) has become an established treatment for patients with severe AS. However, whether TAVR reduce the frequency of IDH has not been investigated. This study aims to verify the efficacy of TAVR for reduction of the frequency of IDH. Consecutive hemodialysis patients who underwent TAVR at Sendai Kosei Hospital from February 2021 to November 2021 with available records 1 month before and 3 months after TAVR were included in the study. IDH was defined as a decrease in systolic blood pressure by 20 mmHg or a decrease in the mean blood pressure by 10 mmHg associated with hypotensive symptoms or requiring intervention. Patients with ≥ 3 episodes of IDH in ten hemodialysis sessions comprised the IDH group. Overall, 18/41 (43.9%) patients were classified into the IDH group. In ten hemodialysis sessions, IDH events were observed 2.1, 4.3, and 0.4 times in the overall cohort, IDH group, and non-IDH group, respectively. After TAVR, the incidence of IDH decreased from 43.2 to 10.3% (p < 0.0001) and IDH improved significantly in 15 patients in the IDH group. The result suggested that severe AS was the major cause of IDH in this cohort, and TAVR may be an effective treatment option for reduction of the frequency of IDH in patients with severe AS.

Scoring system for diagnosis and pretreatment risk assessment of neuroblastoma using urinary biomarker combinations.

The urinary catecholamine metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA), are used for the adjunctive diagnosis of neuroblastomas. We aimed to develop a scoring system for the diagnosis and pretreatment risk assessment of neuroblastoma, incorporating age and other urinary catecholamine metabolite combinations. Urine samples from 227 controls (227 samples) and 68 patients with neuroblastoma (228 samples) were evaluated. First, the catecholamine metabolites vanillactic acid (VLA) and 3-methoxytyramine sulfate (MTS) were identified as urinary marker candidates through comprehensive analysis using liquid chromatography-mass spectrometry. The concentrations of these marker candidates and conventional markers were then compared among controls, patients, and numerous risk groups to develop a scoring system. Participants were classified into four groups: control, low risk, intermediate risk, and high risk, and the proportional odds model was fitted using the L2-penalized maximum likelihood method, incorporating age on a monthly scale for adjustment. This scoring model using the novel urine catecholamine metabolite combinations, VLA and MTS, had greater area under the curve values than the model using HVA and VMA for diagnosis (0.978 vs. 0.964), pretreatment risk assessment (low and intermediate risk vs. high risk: 0.866 vs. 0.724; low risk vs. intermediate and high risk: 0.871 vs. 0.680), and prognostic factors (MYCN status: 0.741 vs. 0.369, histology: 0.932 vs. 0.747). The new system also had greater accuracy in detecting missing high-risk neuroblastomas, and in predicting the pretreatment risk at the time of screening. The new scoring system employing VLA and MTS has the potential to replace the conventional adjunctive diagnostic method using HVA and VMA.

Multicenter randomized phase II study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases (YCOG1001).

PURPOSE: The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX). METHODS: In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3 weeks. The dose of S-1 was fixed at 80 mg/m2. The doses in the low- and high-dose oxaliplatin groups were 100 mg/m2 (low-dose group) and 130 mg/m2 (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs). RESULTS: Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3 years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705). CONCLUSIONS: SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.

Real-world treatment outcomes of metastatic biliary tract cancer patients in Japan: the Tokushukai REAl-world data project 04 (TREAD 04).

OBJECTIVES: To investigate temporal trends in treatment patterns and prognostic factors for overall survival in patients with metastatic biliary tract cancer. METHODS: From the Tokushukai REAl-world Data project, we identified 945 patients with metastatic biliary tract cancer treated with gemcitabine, tegafur/gimeracil/oteracil, gemcitabine plus cisplatin, gemcitabine plus tegafur/gimeracil/oteracil or gemcitabine plus cisplatin and tegafur/gimeracil/oteracil between April 2010 and March 2022. Stratified/conventional Cox regression analyses were conducted to examine the association between overall survival and patient- and tumour-related factors, study period, hospital volume, hospital type and first-line chemotherapy regimen. Using inverse probability of treatment weighting with propensity scores, overall survival was also compared between monotherapy and combination therapy groups. RESULTS: We enrolled 366 patients (199 men; median age, 72 years). Over a median follow-up of 5.2 months, the median overall survival was 7.0 months (95% confidence interval 6.2-9.0), and the median time to treatment failure was 3.5 months (95% confidence interval 3.1-4.5). Median overall survival and time to treatment failure for gemcitabine/tegafur-gimeracil-oteracil/gemcitabine plus cisplatin/gemcitabine plus tegafur-gimeracil-oteracil/gemcitabine plus cisplatin and tegafur-gimeracil-oteracil regimen were 6.2/6.6/7.9/16.2/15.1 and 2.8/3.4/4.1/15.3/7.4 months, respectively. Primary disease site, previous surgery, previous endoscopic procedures and hospital type were identified as significant prognostic factors. Inverse probability of treatment weighting analysis demonstrated that combination therapy had a significantly better prognosis than monotherapy (hazard ratio 0.61, 95% confidence interval 0.43-0.88, P = 0.006). CONCLUSIONS: Our real-world data analysis showed that standard care for metastatic biliary tract cancer is widely used in hospitals throughout Japan and verified the survival benefits of combination therapy over monotherapy observed in prior clinical trials. CLINICAL TRIAL NUMBER: UMIN000050590 (http://www.umin.ac.jp/ctr/index.htm).

Comparison of Postoperative Stress Urinary Incontinence between Anteroposterior Dissection and Modified Gilling Method in Holmium Laser Enucleation of the Prostate.

PURPOSE: Few studies have evaluated the usefulness of anteroposterior dissection holmium laser enucleation of the prostate (HoLEP). Thus, this study investigated the incidence of stress urinary incontinence (SUI) after HoLEP and usefulness of anteroposterior dissection HoLEP in preventing postoperative SUI. MATERIALS AND METHODS: In total, 288 patients who underwent HoLEP performed by a single experienced surgeon between May 2014 and September 2021 were enrolled. Furthermore, 134 patients underwent retrograde dissection using the modified Gilling method (surgery 1) and 154 patients underwent anteroposterior dissection HoLEP (surgery 2). The risk factors for SUI, as well as the rates of SUI improvement for the two surgical procedures, were evaluated. RESULTS: Postoperative SUI was observed in 58 (20.1%) of 288 patients, of whom, 48 (82.8%) recovered continence within 6 months. Ten patients (17.2%) required more than 6 months to recover continence. SUI incidence 1 month after HoLEP was 29.9% (40/134 patients) for surgery 1 and 11.7% (18/154 patients) for surgery 2; a statistically significant difference was observed between the two groups (odds ratio [OR], 0.311; 95% confidence interval [CI], 0.168-0.575; p < 0.001). In addition, surgery 2 was significantly associated with early recovery from SUI compared with surgery 1 (stratified hazard ratio, 0.782; 95% CI, 0.615------0.995; p < 0.001). The multivariable analysis demonstrated that only surgical procedure (OR, 0.350; 95%CI, 0.168-0.732; p=0.005) was an independent predictor of SUI.- Conclusion: We reaffirmed that anteroposterior dissection HoLEP is a useful procedure for reducing the risk of postoperative SUI and early recovery of urinary continence.

Associated factors and outcomes of crossover from a laser sheath to a bidirectional rotational mechanical sheath during transvenous lead extraction.

Background: During transvenous lead extraction (TLE), a GlideLight laser sheath (Philips) cannot always be advanced over the lead, and crossover to the Evolution system (i.e., an Evolution RL sheath or Evolution Shortie RL sheath [Cook Medical]) is required. We aimed to determine the associated factors and outcomes of such device crossover. Methods: This observational study included 112 patients who underwent TLE. The patients were divided into crossover and non-crossover groups. Outcomes and associated factors of crossover were evaluated. Results: Overall, 57 (50.9%) patients required crossover to the Evolution system (crossover group), whereas 55 (49.1%) patients did not require crossover (non-crossover group). Clinical success rate was similar between the two groups (98.3% vs. 100%; p = 1.00). No major intraprocedural complications related to powered sheaths occurred. Multivariate logistic regression analysis results showed that dwell time of the oldest extracted lead (per year) (odds ratio [OR]: 1.18, 95% confidence interval [CI]: 1.02-1.36; p = .026), number of leads extracted per procedure (OR: 7.23, 95% CI: 1.74-29.99; p = .007), and use of a femoral approach (OR: 21.09, 95% CI: 2.33-190.67; p = .007) were associated factors of crossover. The cutoff for crossover was 7.7 years from the implant (sensitivity 90.5%, specificity 64.9%, area under the curve 0.80). Conclusions: Both groups showed a high rate of clinical success. Switching to the Evolution system may facilitate a safe and effective TLE when a laser sheath does not advance despite laser activation.