Moderately hypofractionated proton beam therapy for localized prostate cancer: 5-year outcomes of a phase II trial.

The usefulness of moderately hypofractionated radiotherapy for localized prostate cancer has been extensively reported, but there are limited studies on proton beam therapy (PBT) using similar hypofractionation schedules. The aim of this prospective phase II study is to confirm the safety of a shortened PBT course using 70 Gy relative biological effectiveness (RBE) in 28 fractions. From May 2013 to June 2015, 102 men with localized prostate cancer were enrolled. Androgen deprivation therapy was administered according to risk classification. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.0. Of the 100 patients ultimately evaluated, 15 were classified as low risk, 43 as intermediate risk, and 42 as high risk. The median follow-up time of the surviving patients was 96 months (range: 60-119 months). The 5-year cumulative incidences of grade 2 gastrointestinal/genitourinary adverse events were 1% (95% CI: 0.1-6.9) and 4% (95% CI: 1.5-10.3), respectively; no grade ≥ 3 gastrointestinal/genitourinary adverse events were observed. The current study revealed a low incidence of late adverse events in prostate cancer patients treated with moderately hypofractionated PBT of 70 Gy (RBE) in 28 fractions, indicating the safety of this schedule.

Preoperative albumin-bilirubin score and liver resection percentage determine postoperative liver regeneration after partial hepatectomy.

BACKGROUND: The success of liver resection relies on the ability of the remnant liver to regenerate. Most of the knowledge regarding the pathophysiological basis of liver regeneration comes from rodent studies, and data on humans are scarce. Additionally, there is limited knowledge about the preoperative factors that influence postoperative regeneration. AIM: To quantify postoperative remnant liver volume by the latest volumetric software and investigate perioperative factors that affect posthepatectomy liver regeneration. METHODS: A total of 268 patients who received partial hepatectomy were enrolled. Patients were grouped into right hepatectomy/trisegmentectomy (RH/Tri), left hepatectomy (LH), segmentectomy (Seg), and subsegmentectomy/nonanatomical hepatectomy (Sub/Non) groups. The regeneration index (RI) and late regeneration rate were defined as (postoperative liver volume)/[total functional liver volume (TFLV)] × 100 and (RI at 6-months - RI at 3-months)/RI at 6-months, respectively. The lower 25th percentile of RI and the higher 25th percentile of late regeneration rate in each group were defined as "low regeneration" and "delayed regeneration". "Restoration to the original size" was defined as regeneration of the liver volume by more than 90% of the TFLV at 12 months postsurgery. RESULTS: The numbers of patients in the RH/Tri, LH, Seg, and Sub/Non groups were 41, 53, 99 and 75, respectively. The RI plateaued at 3 months in the LH, Seg, and Sub/Non groups, whereas the RI increased until 12 months in the RH/Tri group. According to our multivariate analysis, the preoperative albumin-bilirubin (ALBI) score was an independent factor for low regeneration at 3 months [odds ratio (OR) 95%CI = 2.80 (1.17-6.69), P = 0.02; per 1.0 up] and 12 months [OR = 2.27 (1.01-5.09), P = 0.04; per 1.0 up]. Multivariate analysis revealed that only liver resection percentage [OR = 1.03 (1.00-1.05), P = 0.04] was associated with delayed regeneration. Furthermore, multivariate analysis demonstrated that the preoperative ALBI score [OR = 2.63 (1.00-1.05), P = 0.02; per 1.0 up] and liver resection percentage [OR = 1.02 (1.00-1.05), P = 0.04; per 1.0 up] were found to be independent risk factors associated with volume restoration failure. CONCLUSION: Liver regeneration posthepatectomy was determined by the resection percentage and preoperative ALBI score. This knowledge helps surgeons decide the timing and type of rehepatectomy for recurrent cases.

Relationship between changes in pulmonary function and patient-reported outcomes of lung cancer surgery.

PURPOSE: To investigate the relationship between changes in pulmonary function (PF) and patient-reported outcomes (PROs) of lung cancer surgery. METHODS: We recruited 262 patients who underwent lung resection for lung cancer, to evaluate the PROs, using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the Lung Cancer 13-question supplement (LC13). The patients underwent PF tests and PRO assessments preoperatively (Pre) and 1 year after surgery (Y1). Changes were calculated by subtracting the value at Pre from the value at Y1. We set two cohorts: patients under the ongoing protocol (Cohort 1) and patients who were eligible for lobectomy with clinical stage I lung cancer (Cohort 2). RESULTS: Cohorts 1 and 2 comprised 206 and 149 patients, respectively. In addition to dyspnea, changes in PF were also correlated with scores for global health status, physical and role function scores, fatigue, nausea and vomiting, pain, and financial difficulties. Absolute correlation coefficient values ranged from 0.149 to 0.311. Improvement of emotional and social function scores was independent of PF. Sublobar resection preserved PF more than lobectomy did. Wedge resection mitigated dyspnea in both cohorts. CONCLUSION: The correlation between PF and PROs was found to be weak; therefore, further studies are needed to improve the patient's postoperative experience.

Effect of cardiopulmonary bypass on coagulation factors II, VII and X in a primate model: an exploratory pilot study.

OBJECTIVES: The use of cardiopulmonary bypass (CPB) in cardiac surgery is a major risk factor for postoperative bleeding. We hypothesized that consumptive coagulopathy and haemodilution influence the coagulation factors; therefore, we aimed to estimate the activity profiles of coagulation factors II, VII and X during CPB circulation. METHODS: A 120-min bypass was surgically established in cynomolgus monkeys (n = 7). Activities of coagulation factors II, VII and X were measured at 6 time points during the experiment (baseline, 0, 30, 60, 120 min of bypass and 60 min after bypass). To assess the influence of consumptive coagulopathy, the values were adjusted for haemodilution using the haematocrit values. Data were expressed as mean (standard deviation). RESULTS: Activities of coagulation factors decreased during the experiment. In particular, the activities for II, VII and X were decreased the most by 44.2% (5.0), 61.4% (4.3) and 49.0% (3.7) at 30 min following CPB initiation (P < 0.001, P < 0.001 and P < 0.001, respectively). Following adjustments for haemodilution, change magnitudes lessened but remained significant for factor VII. The adjusted concentration of factor VII was observed to decrease from the baseline to the initiation of bypass circulation. CONCLUSIONS: In conclusion, coagulation factor II, VII and X concentrations decreased during CPB. Following adjustment for haemodilution, a decrease in concentration was observed with factor VII.

Prediction of Posthepatectomy Liver Failure with a Combination of Albumin-Bilirubin Score and Liver Resection Percentage.

BACKGROUND: Posthepatectomy liver failure (PHLF) is a main cause of death after partial hepatectomy. The aim of this study was to develop a practical stratification system using the albumin-bilirubin (ALBI) score and liver resection percentage to predict severe PHLF and conduct safe hepatectomy. METHODS: Between January 2002 and March 2021, 361 hepatocellular carcinoma (HCC) patients who underwent partial hepatectomy were enrolled. Medical image analysis software was applied postoperatively to accurately simulate hepatectomy. The liver resection percentage was calculated as follows: (postoperatively reconstructed resected specimen volume [ml] - tumor volume [ml])/total functional liver volume (ml) × 100. Multivariate analysis was performed to identify risk factors for PHLF grade B/C. A heatmap for predicting grade B/C PHLF was generated by combining the ALBI score and liver resection percentage. RESULTS: Thirty-nine patients developed grade B/C PHLF; 2 of these patients (5.1%) died. Multivariate analysis demonstrated that a high ALBI score and high liver resection percentage were independent predictors of severe PHLF (odds ratio [OR], 8.68, p < 0.001; OR, 1.10, p < 0.001). With a threshold PHLF probability of 50% for the heatmap, hepatectomy was performed for 346 patients meeting our criteria (95.8%) and 325 patients meeting the Makuuchi criteria (90.0%). The positive predictive value and negative predictive value for severe PHLF were 91.6% and 66.7% for our system and 91.7% and 33.3% for the Makuuchi criteria. CONCLUSION: Our stratification system could increase the number of hepatectomy candidates and is practical for deciding the surgical indications and determining the upper limit of the liver resection percentage corresponding to each patient's liver function reserve, which could prevent PHLF and yield better postoperative outcomes.

Tumor-infiltrating FoxP3+ T cells are associated with poor prognosis in oral squamous cell carcinoma.

OBJECTIVES: Squamous cell carcinoma is the most common malignancy in the oral cavity. Moreover, human papillomavirus (HPV) infection has been recently implicated in the onset of oral squamous cell carcinoma (OSCC). Regulatory T cells (Tregs) are Forkhead box P3 (FoxP3) positive and are normally involved in the mechanism by which organisms escape attacks from their own immune system; however, in tumors, these cells are known to suppress antitumor immunity and block the attack against tumors. The present study evaluated the associations of the number of Tregs and HPV infection with prognoses in patients with OSCC. MATERIAL AND METHODS: Samples from 106 patients diagnosed with OSCC were evaluated by immunohistochemical staining for the identification of FoxP3+ Tregs and HPV. The relationship between the observed number of Foxp3-positive cells, the presence/absence of HPV infection and associations with clinicopathological indicators were analyzed. RESULTS: Tissues were classified into high (High) and low (Low) Treg count groups, with 69 patients classified as High and 37 classified as Low. The prognoses were significantly better in the Low group compared with the High group (p = 0.04). FoxP3 expression may have had some effect on nodal metastases (p = 0.09). HPV antigens were detected in 65 patients, but there were no significant associations with prognosis (p = 0.34). HPV-infected tumors were more common in the gums and tongues than in the lips, cheeks, and floor of the mouth (p = 0.05). CONCLUSIONS: These results indicate that Tregs in tumor sites are associated with worsened prognoses of patients with OSCC and suggest potential therapies targeting Tregs in OSCC.

Inflammation-Based Score (Combination of Platelet Count and Neutrophil-to-Lymphocyte Ratio) Predicts Pharyngocutaneous Fistula After Total Laryngectomy.

OBJECTIVES/HYPOTHESIS: Postoperative complications may depend on the systemic inflammatory response. We evaluated the predictive potential of the combination of platelet count and neutrophil-to-lymphocyte ratio (COP-NLR) for the incidence of pharyngocutaneous fistula (PCF) in patients who have undergone total laryngectomy. STUDY DESIGN: Retrospective cohort study. METHODS: Patients who underwent total laryngectomy between 2000 and 2020 were recruited from four hospitals. The correlations between the incidence of PCF and several risk factors, including the COP-NLR, were examined. Patients with both elevated platelet count and elevated neutrophil-to-lymphocyte ratio (NLR) were categorized as COP-NLR 2, and patients with either one or no abnormal values of both parameters were assigned as COP-NLR 1 and COP-NLR 0, respectively. RESULTS: A total of 235 patients were identified. The overall incidence of PCF was 12.3%. The cut-off value for NLR before surgery was set at 3.95 (sensitivity = 58.6%, specificity = 69.4%, area under the curve [AUC] = 0.635), and the platelet count was set at 320 × 109 /L (sensitivity = 27.6%, specificity = 87.9%, AUC = 0.571). Multivariate analysis revealed that COP-NLR was an independent risk factor for PCF (COP-NLR 1 vs. COP-NLR 0: odds ratio [OR], 4.17; 95% confidence interval [CI], 1.64 to 10.59; and COP-NLR 2 vs. COP-NLR 0: OR, 5.33; 95% CI, 1.38 to 20.56). CONCLUSIONS: COP-NLR is a novel predictive factor for the development of PCF in patients undergoing total laryngectomy. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1582-1587, 2022.

Comparison of Postoperative Quality of Life and Pain with and without a Metal Rib Spreader in Patients Undergoing Lobectomy through Axillary Mini-Thoracotomy for Stage I Lung Cancer.

PURPOSE: To evaluate postoperative patient-reported quality of life (QOL) and pain with and without a metal rib spreader (MRS) in patients with stage I lung cancer who underwent lobectomy through axillary mini-thoracotomy (AMT). METHODS: This single-institution prospective observational study enrolled patients between January 2015 and April 2018. Their QOL and pain were evaluated using the EQ-5D and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 items (QLQ-C30). The EQ-5D was completed preoperatively (Pre) and on days 1/3/5/7 (D1/3/5/7), at 1 month (M1), and at 1 year postoperatively (Y1). The EORTC QLQ-C30 was completed at Pre, M1, and Y1. RESULTS: The data of 140 patients were analyzed (video-assisted without MRS: VA/noMRS: 67, AMT with MRS: AMT/MRS: 73). Although the AMT/MRS group had more preoperative comorbidities, longer operative times, and more blood loss than the VA/noMRS group, the EQ-5D visual analog scale scores were not significantly different at any assessment point (Pre/D1/D3/D5/D7/M1/Y1) (VA/noMRS: 82/48/60/67/73/77/85, AMT/MRS: 80/46/60/66/73/76/85). Postoperative pain in the EQ-5D descriptive system and the EORTC QLQ-C30 was comparable between the groups. CONCLUSION: VA/noMRS and AMT/MRS showed similar postoperative QOL and pain scores, indicating that MRS negligibly impacts the postoperative QOL and pain.

Clinical Impact of Primary Tumor Location in Metastatic Colorectal Cancer Patients Under Later-Line Regorafenib or Trifluridine/Tipiracil Treatment.

BACKGROUND: Primary tumor location (PTL) is an important prognostic and predictive factor in the first-line treatment of metastatic colorectal cancer (mCRC). Although regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been introduced recently, the clinical impact of PTL in these treatments is not well understood. MATERIALS AND METHODS: We retrospectively evaluated patients with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, angiogenesis inhibitors, anti-epidermal growth factor receptor therapy (if RAS wild-type), and no prior use of REG and FTD/TPI. The impact of PTL on overall survival (OS) was evaluated using Cox proportional hazard models based on baseline characteristics. RESULTS: A total of 550 patients (223 patients in the REG group and 327 patients in the FTD/TPI group) were included in this study, with 122 patients with right-sided tumors and 428 patients with left-sided tumors. Although the right-sided patients had significantly shorter OS compared with the left-sided patients by univariate analysis (p = 0.041), a multivariate analysis revealed that PTL was not an independent prognostic factor (hazard ratio, 0.95; p = 0.64). In a subgroup analysis, the OS was comparable between the REG and FTD/TPI groups regardless of PTL (p for interactions = 0.60). CONCLUSIONS: In the present study, PTL is not a prognostic and predictive factor in patients with mCRC under later-line REG or FTD/TPI therapy.

Association between Endocrine Therapy and Weight Gain after Breast Cancer Diagnosis among Japanese Patients: A Retrospective Cohort Study.

BACKGROUND: This study aimed to investigate the association between endocrine therapy and weight gain with a history of breast cancer. METHODS: This was a retrospective cohort study. Recruited patients consisted of those receiving endocrine therapy and those not receiving endocrine therapy. Weight at diagnosis was collected from medical records, and current body mass was measured using a digital scale (time since diagnosis was 4.0 ± 1.9 years). Moreover, we measured current physical activity using an accelerometer and dietary intake using a validated questionnaire. The primary analysis was a t-test for the body-mass change after diagnosis between the two groups. RESULTS: We recruited 300 patients and collected data from 292. Mean weight gain after diagnosis was 1.3 ± 3.9 kg, and the change in body mass of patients taking endocrine therapy (1.3 ± 4.0 kg) was not significantly different from that of patients not taking endocrine therapy (1.4 ± 3.8 kg, p = 0.92). There was no association of endocrine therapy, physical activity, and dietary intake with a 5% weight gain after adjusting confounding factors (e.g., breast cancer stage and chemotherapy). CONCLUSIONS: Caution is required with generalization because of sampling bias and ethnic differences.

Survival Benefit of Crossover Administration of Regorafenib and Trifluridine/Tipiracil Hydrochloride for Patients With Metastatic Colorectal Cancer: Exploratory Analysis of a Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study (REGOTAS).

Background: The survival benefits of regorafenib (REG) and trifluridine/tipiracil hydrochloride (TFTD) have been demonstrated in chemorefractory patients with metastatic colorectal cancer (mCRC). However, the effects of crossover administration of REG and TFTD on patient survival remain unclear. The present study evaluated the association between exposure to REG and TFTD and overall survival (OS) in patients with mCRC using data from the REGOTAS study. Patients and Methods: We analyzed patients registered in the REGOTAS study, which retrospectively compared the efficacy and safety of use of REG or TFTD as later-line chemotherapy for chemorefractory mCRC patients. We compared the survival outcomes of cohort A (treated using both REG and TFTD) and cohort B (treated using either REG or TFTD). Results: A total of 550 patients (cohort A, n = 252; cohort B, n = 298) met the inclusion criteria. The median OS was significantly increased in cohort A compared with cohort B [9.6 months (95% confidence interval (CI), 8.9-10.9 months) vs. 5.2 months (95% CI, 4.4-6.0 months), P < 0.001]. Multivariate analysis revealed that cohort A was independently associated with a significant increase in OS [A vs. B: Hazard ratios (HR), 0.58; 95% CI, 0.47-0.72; P < 0.001]. Subgroup analysis adjusted using multivariate Cox model revealed a consistently better trend in most subgroups for cohort A compared with cohort B. Conclusions: Our study revealed prolonged survival in patients treated with REG and TFTD. Therefore, all active agents, including REG and TFTD, should be made available to mCRC patients.

Trajectory and profile of quality of life in patients undergoing lung resection for lung cancer during hospitalization according to the EQ-5D.

OBJECTIVE: To clarify the trajectory and profile of quality of life (QOL) in lung cancer patients undergoing surgery during hospitalization. METHODS: Among prospectively enrolled 279 patients between 2015 and 2018, we used the EQ-5D-5 levels (EQ-5D-5L), which consist of a descriptive system of five dimensions and a visual analog scale (VAS) (from 0 to 100). The five dimensions are mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, which are rated according to a 5-grade evaluation. QOL assessments were performed preoperatively (Pre) and on postoperative day 1/3/5/7 (D1/D3/D5/D7). To observe the trajectory of QOL, the EQ-5D VAS was used. To define the profile of QOL, we applied univariate linear regression analysis to predict EQ-5D VAS based on the five dimensions of EQ-5D as explanatory variables and to determine the rank of absolute values of the standardized coefficient of each dimension that represented strength of the effect on the EQ-5D VAS. RESULTS: The means of VAS scores were as follows: Pre/D1/D3/D5/D7 = 79/45/58/64/71. Younger age, fewer comorbidities, and surgical indications decreased the VAS at D1. More comorbidities, advanced cancer stage, postoperative adverse events, and chest tube placements hampered restoration of the VAS. Regarding QOL profiles, anxiety/depression was the highest rank preoperatively while usual activity, but not pain/discomfort, was the highest postoperatively. CONCLUSIONS: This is the first study to visualize the trajectory of QOL in surgical patients with lung cancer during hospitalization. This information may help improve perioperative patient care.

Preoperative predictors of restoration in quality of life after surgery for lung cancer.

BACKGROUND: The preoperative predictors of quality of life (QOL) in patients who undergo lung resection for lung cancer are poorly known. Here, we investigated these predictors in such patients using two QOL measures. METHODS: In this single-institutional prospective cohort study, we administered the EQ-5D-5 levels (EQ-5D-5L) from January 2015, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire with 30 items from April 2015 to April 2018 preoperatively (Pre) and at one month postoperatively (M1), and one year postoperatively (Y1). General health status was measured by the EQ-5D visual analogue scale (VAS) and EORTC global health status/QOL (GHS) scores. Multivariable linear regression analyses were used to explore the preoperative predictors of QOL at Y1. RESULTS: A total of 223 patients were included in the study. The EQ-5D VAS and EORTC GHS scores, at Pre, M1, and Y1, were 80 ± 15, 77 ± 15, and 84 ± 11; and 74 ± 19, 65 ± 20, and 78 ± 17, respectively. In the multivariable analyses, the albumin level, preoperative VAS score, and preoperative pain/discomfort and anxiety/depression were identified as predictors by the EQ-5D VAS score. The preoperative EORTC GHS score, absence of diabetes mellitus, preoperative cognitive function score, and preoperative symptom score of pain were identified as predictors by the EORTC GHS score. CONCLUSIONS: The EQ-5D VAS and EORTC GHS scores traced similar trajectories of QOL. In both QOL measures, preoperative pain was found as a common predictor. These predictors may help improve patient/survivor care in the future.

The Geriatric Nutritional Risk Index as a Prognostic Factor in Patients with Advanced Head and Neck Cancer.

OBJECTIVE: The Geriatric Nutritional Risk Index (GNRI) is a simple and well-established nutritional assessment tool and is a significant prognostic factor in various cancers. However, the role of the GNRI in predicting clinical outcomes in patients with advanced head and neck cancer (AHNC) has not been investigated. The aim of the present study was to examine the association between the GNRI and prognosis in patients with AHNC. STUDY DESIGN: Retrospective cohort study. METHODS: Data collected between 2002 and 2013 from Tsukuba University Hospital were reviewed. The GNRI was calculated according to the equation, 1.489 × serum albumin (g/l) + 41.7 × (body weight/ideal body weight). Characteristics and prognosis were compared among three risk groups: high (GNRI <82); intermediate (GNRI 82-98); and normal (GNRI >98). The primary endpoint was overall survival. RESULTS: A total of 248 AHNC patients were enrolled, among whom 134 (54%) exhibited no nutritional risk, 53 (21%) had an intermediate risk for malnutrition, and 61 (25%) exhibited a high risk for malnutrition. Three-year survival rates according to the three-group GNRI scores for normal, intermediate, and high risk were 76.6%, 56.3%, and 19.5%, respectively. As the three-group GNRI score increased, the risk for mortality significantly increased (adjusted hazard ratio [HR] for intermediate to normal, 1.73 [95% CI, 1.02-2.92]; adjusted HR for high to normal, 4.31 [95% CI, 2.71-6.84]). CONCLUSIONS: The GNRI could be considered a useful prognostic factor in patients with AHNC. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E151-E156, 2021.

Optimal Maintenance Strategy for First-Line Oxaliplatin-Containing Therapy with or without Bevacizumab in Patients with Metastatic Colorectal Cancer: A Meta-Analysis.

PURPOSE: Maintenance therapy after oxaliplatin withdrawal is useful in patients with metastatic colorectal cancer (mCRC). This study aimed to investigate the timing of discontinuation or reintroduction of oxaliplatin and the optimal maintenance therapy regimen for survival. MATERIALS AND METHODS: PubMed and conference abstracts were searched to select phase II and III trials of first-line oxaliplatin-containing therapy with or without bevacizumab using maintenance therapy for mCRC. Correlations of median overall survival (OS) with induction therapy regimens, induction therapy duration, maintenance therapy regimens (fluoropyrimidine plus bevacizumab [FP+Bev], FP/Bev alone, and no treatment), and oxaliplatin reintroduction were investigated using correlation and weighted multivariate regression analyses. RESULTS: Twenty-two treatment arms were analyzed, including 2,581 patients. The maintenance therapy regimen FP+Bev showed the strongest correlation with a prolonged OS (Spearman's partial correlation coefficient=0.42), and the other three variables correlated weakly with the OS. The maintenance therapy regimen significantly interacted with the induction chemotherapy duration (p=0.019). The predicted OS for FP+Bev crossed the lines of FP/Bev alone at 18 weeks of induction therapy, and of no treatment at 23 weeks. The corresponding OS at 12 and 27 weeks of induction therapies were 28.6 and 24.2 months for FP+Bev, 25.9 and 28.8 months for FP/Bev alone, and 20.5 and 27.5 months for no treatment. CONCLUSION: The optimal maintenance therapy regimen for the OS is a continuous induction therapy as long as possible followed by FP/Bev alone and switching to FP+Bev within approximately 4 months if induction therapy is discontinued.

Optimal Androgen Deprivation Therapy Combined with Proton Beam Therapy for Prostate Cancer: Results from a Multi-Institutional Study of the Japanese Radiation Oncology Study Group.

BACKGROUND: Androgen deprivation therapy (ADT) combined with radiation therapy benefits intermediate- and high-risk prostate cancer (PC) patients. The optimal ADT duration in combination with high-dose proton beam therapy (PBT) remains unknown. METHODS: Intermediate- and high-risk PC patients treated with PBT combined with ADT for various durations were analyzed retrospectively. To assess the relationship between ADT and biochemical relapse-free (bRF) rate, Cox proportional hazards models including T stage, prostate specific antigen (PSA) level, Gleason score (GS), and total radiation dose were used. RESULTS: In the intermediate-risk PC patients (n = 520), ADT use improved bRF (HR 0.49, 95% CI 0.26-0.93; p = 0.029), especially in those with multiple intermediate-risk factors (T2b-2c, PSA 10-20 ng/mL, and GS 7). In the high-risk PC patients (n = 555), a longer ADT duration (>6 months) conferred a benefit for bRF (HR 0.54, 95% CI 0.32-0.90; p = 0.018), which was most apparent in patients with multiple high-risk factors (T3a-4, PSA > 20 ng/mL, and GS ≥ 8) treated with ADT for ≥21 months. CONCLUSIONS: Short-term (≤6 months) ADT is beneficial for intermediate-risk PC patients, but likely unnecessary for those with a single risk factor, whereas ADT for >6 months is necessary for high-risk PC patients and ADT for ≥21 months might be optimal for those with multiple risk factors in combination of high-dose PBT.

Assessment of Hazard Ratios in Oncology Clinical Trials Terminated Early for Superiority: A Systematic Review.

Importance: Group sequential designs allow potential early trial termination at the interim analysis, before study completion. Traditional maximum likelihood estimate is commonly used to quantify the treatment effect in group sequential design trials; however, in published clinical trials, a bias-adjusted estimator has rarely been reported. Objective: To emphasize the need for considering overestimation of treatment effect by applying 2 bias-adjusted estimators to previously published, early-terminated oncology clinical trials. Evidence Review: Trials published from 2013 to 2017 were identified by searching MEDLINE and Embase on February 23, 2018. This review was restricted to oncology clinical trials using group sequential designs with a single preplanned interim analysis as well as 2-arm randomized clinical trials that were subsequently stopped for efficacy reasons. Each article was independently reviewed by 3 biostatisticians during text screening, and differences in opinion were resolved by discussion. This report presents the unadjusted hazard ratio (HR) of an experimental arm to a reference arm and 2 bias-adjusted HRs calculated by using the conditional mean-adjusted estimator (CMAE) and weighted CMAE (WCMAE). Findings: In total, 198 abstracts were screened for eligibility, of which, 19 eligible clinical trials were identified as applicable to the bias-adjusted estimators. Unadjusted HRs ranged from 0.203 (95% CI, 0.150-0.276) to 0.71 (95% CI, 0.60-0.84), number of events at the interim analysis from 58 to 540, and information time from 48% to 82%. In each study, the HRs adjusted by CMAE and WCMAE were higher than the unadjusted HR. Bias-adjusted estimates in large trials (243 and 414 events at the interim analysis) were similar to the unadjusted HR. However, in small trials (eg, with 58 events at the interim analysis), bias-adjusted estimates were highly disparate from the unadjusted HR. In trials with large treatment effects (eg, HRs of 0.20 and 0.22), the difference between unadjusted and bias-adjusted HRs was small even though the number of events at the interim analysis was small; larger differences were observed when the unadjusted HR was greater than 0.5. Conclusions and Relevance: In this systematic review of oncology clinical trials that were stopped for efficacy at the interim analysis, relatively large differences were noted between the unadjusted and adjusted HRs when the number of events at the interim analysis was small or when the unadjusted HR was close to the boundaries. These findings suggest presenting the 2 bias-adjusted HRs along with the unadjusted HR in the data monitoring committee meeting.

Curved single-plane clear corneal incision made under anterior chamber collapse by aqueous humor aspiration prevents leakage after cataract surgery.

PURPOSE: To evaluate the self-sealing on curved single-plane clear corneal incisions (CCIs) after cataract surgery. The collapse of the anterior chamber was made by aspirating the aqueous humor in order to make curved single-plane CCI. METHODS: A retrospective study was conducted at Asai Hospital in Japan. There were 189 eyes of 132 patients scheduled from February to April 2017 for single-plane CCI. There were 175 eyes of 128 patients from February to April 2018 for curved single-plane CCI. Curved single-plane CCIs were made with aqueous humor aspiration via aqueous humor pipette, and single-plane CCIs were made without the aspiration. In case of leakage of aqueous humor from the CCI at the end of surgery, sutures were used. The main outcome measure was the proportion of sutures for CCI. Secondary outcomes included CCI length and surgically induced astigmatism (SIA) magnitude. RESULTS: The proportions of suture in single-plane CCI and in curved single-plane CCIs were 25.4% (48/189) and 0% (0/175), respectively (p < 0.001). The length of curved single-plane CCI (2.06 ± 0.18 mm) was significantly greater than that of single-plane CCI (1.66 ± 0.12 mm; p < 0.001). The median postoperative SIAs of single-plane and curved single-plane CCIs were 0.64 D (n = 89) and 0.73 D (n = 85) for nasal incision, and 0.46 D (n = 100) and 0.47 D (n = 90) for temporal incision at examination 3 months after surgery, respectively, without significant change (p = 0.12 for nasal incision and p = 0.37 for temporal incision). CONCLUSION: The curved single-plane CCI achieved by only aqueous humor aspiration showed significant effectiveness in self-sealing. TRIAL REGISTRATION: UMIN clinical trials registry UMIN000032480, retrospectively registered on 6 May 2018.

Short-duration triple antithrombotic therapy for atrial fibrillation patients who require coronary stenting: results of the SAFE-A study.

AIMS: We aimed to determine whether shortening the duration of P2Y12 inhibitor therapy can reduce the risk of bleeding without increasing the risk of major adverse cardiovascular events following coronary stenting in patients with atrial fibrillation (AF). METHODS AND RESULTS: The SAFE-A is a randomised controlled trial that compared one-month and six-month P2Y12 inhibitor therapy, in combination with aspirin and apixaban for patients with AF who require coronary stenting. The primary endpoint was the incidence of any bleeding events, defined as Thrombolysis In Myocardial Infarction major/minor bleeding, bleeding with various Bleeding Academic Research Consortium grades, or bleeding requiring blood transfusion within 12 months after stenting. The study aimed to enrol 600 patients but enrolment was slow. Enrolment was terminated prematurely after enrolling 210 patients (72.7±8.2 years; 81% male). The incidence of the primary endpoint did not differ between the one-month and six-month groups (11.8% vs 16.0%; hazard ratio [HR] 0.70, 95% confidence interval [CI]: 0.33-1.47; p=0.35). CONCLUSIONS: The study evaluated the safety of withdrawing the P2Y12 inhibitor from triple antithrombotic prescription one month after coronary stenting. However, enrolment was prematurely terminated because it was slow. Therefore, statistical power was not sufficient to assess the differences in the primary endpoint.

Endoscopic Detachable Snare Ligation Improves the Treatment for Colonic Diverticular Hemorrhage.

BACKGROUND/AIMS: Recently, endoscopic detachable snare ligation (EDSL) has become increasingly common as treatment for colonic diverticular hemorrhage. This study aimed to evaluate the efficacy and safety of EDSL in comparison with endoscopic clipping (EC) as treatment for colonic diverticular hemorrhage. METHODS: From April 2013 to September 2017, 131 patients were treated with EDSL or EC at the Tokyo Metropolitan Bokutoh Hospital. We retrospectively evaluated patient characteristics and clinical outcomes, including early rebleeding rates (rebleeding within 30 days after initial hemostasis) and complications for each procedure. RESULTS: Of 131 patients, 44 and 87 were treated with EDSL and EC respectively. We initially achieved endoscopic hemostasis in all patients. The early rebleeding rate was significantly lower for EDSL (6.8%, 3 patients) than for EC (23.0%, 20 patients). There were no differences in the total procedure time (43 vs. 45 min, p = 0.84) or time to hemostasis after identification of bleeding site (12 vs. 10 min, p = 0.23). There were no severe complications following EDSL. CONCLUSION: The results of this study suggest that EDSL is superior to EC as treatment for colonic diverticular hemorrhage. EDSL may provide improvements in the clinical course of patients with colonic diverticular hemorrhage.