Response Evaluation Criteria in Solid Tumors (RECIST) is the primary tool for assessing tumor response in solid tumors. Immunotherapy elicits unique response patterns, and assessment of their contribution to overall survival (OS) is of interest. We evaluated tumor size changes (TSC) for association with OS, evaluated whether deeper response had greater association with OS than the 30

Venous thromboembolism (VTE) is a serious complication in patients undergoing brain tumor surgery, particularly those requiring neurological intensive care unit (NICU) monitoring. Risk factors for VTE vary among tumor types, and effective early warning tools remain scarce. This study aimed to develop a nomogram-based clinical prediction model to identify independent risk factors for postoperative VTE in brain tumor patients. A total of 400 NICU patients (aged 18–82 years; mean age 52.5 ± 15.6 years; 46.5

With the recent advancement in immuno-oncology, next-stage early oncology development is focusing on identifying the best combinations of established immunotherapies with new agents to either overcome drug resistance or achieve synergic effects. Although the combination is the focus, safety profile of the new agent alone must be explored. Therefore, many trials have both monotherapy and add-on combination therapy arms. Finding the maximum tolerable dose (MTD) for the new agent in both arms is critical. Traditional oncology dose-finding methods and MTD estimation algorithm do not handle the correlation and interplay between the two arms and the selected MTDs may contradict with each other. To overcome these issues, we applied a two-dimensional pool-adjacent-violators algorithm to MTD estimation and modified the standard Bayesian optimal interval design (BOIN) to allow for information flow between arms during dose-finding. We also showed that a naïve adaptation of standard BOIN that is much simpler to implement demonstrated empirically similar performance. These new approaches were assessed with simulations and demonstrated improvement for trials with both monotherapy and add-on combination therapy arms. Albeit proposed in the context with immunotherapy as the backbone drug, our approaches can be applied to any new agent in combination with a fixed dose of another drug. Supplementary materials for this article are available online.

PURPOSE:We evaluated the activity of intratumoral Coxsackievirus A21 (V937) in 57 patients with unresectable stage IIIC or IV melanoma.PATIENTS AND METHODS:In this multicenter, open-label, phase II study, patients received up to a total V937 dose of 3 × 108 TCID50 (50% tissue culture infectious dose) in a maximum 4.0-mL volume by intratumoral injection. Ten sets of V937 injections were administered between days 1 and 127 (NCT01227551). Patients who had stable disease or were responding could continue treatment in an extension study (NCT01636882). Response and progression status were based on contrast-enhanced computed tomography, magnetic resonance imaging, or caliper measurement and were categorized using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Other evaluations included monitoring of adverse events and serum levels of V937 and anti-V937 antibody titers. The primary efficacy end point was 6-month progression-free survival (PFS) rate per irRECIST.RESULTS:The primary efficacy end point, 6-month PFS rate per irRECIST, was 38.6% (95% CI, 26.0 to 52.4). Durable response rate (partial or complete response for ≥ 6 months) was 21.1% per irRECIST. Best overall response rate (complete plus partial response) was 38.6% (unconfirmed) and 28.1% (confirmed) per irRECIST. Regression of melanoma was observed in noninjected lesions. Based on Kaplan-Meier estimation, 12-month PFS was 32.9% (95% CI, 19.5 to 46.9) per irRECIST and 12-month overall survival was 75.4% (95% CI, 62.1 to 84.7). No treatment-related grade ≥ 3 adverse events occurred. Viral RNA was detected in serum within 30 minutes of administration. Neutralizing antibody titers increased to > 1:16 in all patients after day 22, without effect on clinical or immunologic response.CONCLUSION:V937 was well tolerated and warrants further investigation for treatment of patients with unresectable melanoma. Studies of combination approaches with V937 and immune checkpoint inhibitors are ongoing.

Importance:Phase 2 trials and early efficacy end points play a crucial role in informing decisions about whether to continue to phase 3 trials. Conventional end points, such as objective response rate (ORR) and progression-free survival (PFS), have demonstrated inconsistent associations with overall survival (OS) benefits in immune checkpoint inhibitor (ICI) trials. Restricted mean duration of response (DOR) is a rigorous metric that combines both response status and duration information. However, its utility in clinical development has not been comprehensively explored.Objective:To determine whether using restricted mean DOR in phase 2 trials can advance promising regimens to phase 3 trials sooner and eliminate unfavorable regimens earlier and with a higher degree of confidence compared with PFS and ORR.Design, Setting, and Participants:This simulated modeling study randomized phase 2 screening trials by resampling 1376 patients from 2 completed randomized phase 3 trials of ICIs. Data were analyzed from August 2019 to July 2020.Exposures:Use of ICIs.Main Outcomes and Measures:Restricted mean DOR, PFS, ORR, and OS were estimated and compared between groups. Three scenarios were considered: (1) significant differences in OS, PFS, and ORR; (2) significant differences in OS and noticeable differences in ORR but not PFS; and (3) no differences in OS, PFS, or ORR. For each setting, 5000 randomized phase 2 trials with different sample sizes were simulated, with additional censoring applied to mimic staggered accruals and ensure fair comparisons between different analysis methods. Probabilities of concluding positive phase 2 trials using PFS, ORR, and DOR were summarized and compared.Results:The restricted mean DOR difference correctly estimated a positive OS benefit more frequently than did the ORR or PFS tests, across different sample sizes, significance levels, and censoring levels evaluated. When both OS and PFS differed, the ranges of true-positive or power rates were 79.2% to 98.7% for DOR, 56.3% to 93.2% for PFS, and 67.0% to 96.0% for ORR. When OS differed but PFS did not, the ranges of power rates were 24.0% to 76.0% for DOR, 3.0% to 19.0% for PFS, and 10.5% to 38.0% for ORR. When OS was similar, the false-positive rate of restricted mean DOR test was close to the chosen significance level.Conclusions and Relevance:These findings suggest that restricted mean DOR in randomized phase 2 trials is potentially more sensitive and useful than PFS and ORR in estimating the subsequent phase 3 conclusions and, thus, may be considered to complementarily facilitate decision-making in future clinical development.

BACKGROUND:In oncology clinical development, objective response rate, disease control rate and early tumor size changes are commonly used as efficacy metrics for early decision-making. However, for immunotherapy trials, it is unclear whether these early efficacy metrics are still predictive of long-term clinical benefit such as overall survival. The goal of this paper is to identify appropriate early efficacy metrics predictive of overall survival for immunotherapy trials.METHODS:Based on several checkpoint blockade based immunotherapy studies in metastatic melanoma, we evaluated the predictive value of early tumor size changes and RECIST-based efficacy metrics at various time points on overall survival. The cut-off values for tumor size changes to predict survival were explored via tree based recursive partitioning and validated by external data. Sensitivity analyses were performed for the cut-offs.RESULTS:The continuous tumor size change metric and RECIST-based trichotomized response metric at different landmark time points were found to be statistically significantly associated with overall survival. The predictive values were higher at Week 12 and 18 than those at Week 24. The percentage of tumor size changes appeared to have comparable or lower predictive values than the RECIST-based trichotomized metric, and a cut-off of approximately 10% tumor reduction appeared to be reasonable for predicting survival.CONCLUSIONS:An approximate 10% tumor reduction may be a reasonable cut-off for early decision-making while the RECIST-based efficacy metric remains the primary tool. Early landmark analysis is especially useful for decision making when accrual is fast. Composite response rate (utilizing different weights for PR/CR and SD) may be worth further investigation.TRIAL REGISTRATION:Clinical trials gov, NCT01295827 , Registered February 15, 2011; NCT01704287 , Registered October 11, 2012; NCT01866319 , Registered May 31, 2013.

We identify a series of topological transitions occurring in electronic spin transport when manipulating spin-guiding fields controlled by the geometric shape of mesoscopic interferometers. They manifest as distinct inversions of the interference pattern in quantum conductance experiments. We establish that Rashba square loops develop weak-(anti)localization transitions (absent in other geometries as Rashba ring loops) as an in-plane Zeeman field is applied. These transitions, boosted by nonadiabatic spin scattering, prove to have a topological interpretation in terms of winding numbers characterizing the structure of spin modes in the Bloch sphere.

PURPOSE:To evaluate the toxicity and efficacy of adjuvant temozolomide (TMZ) and irinotecan (CPT-11) for 12 months after concurrent chemoradiation in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS:Trial RTOG 04-20, a single-arm, multi-institutional phase 2 trial, was designed to determine the efficacy and toxicity of concomitant TMZ and radiation therapy (RT) followed by adjuvant TMZ combined with CPT-11 given for 12 cycles compared with historical controls of adjuvant TMZ alone given for 6 cycles. RESULTS:A total of 170 patients were enrolled, 152 of whom were eligible. Adjuvant CPT-11 combined with TMZ was more toxic than expected. A higher rate of hematologic and gastrointestinal toxicities was more frequently noted with the combination regimen compared with adjuvant TMZ alone. Grade 3/4 hematologic toxicity was 38% compared with 14% reported in the Stupp trial. After an early interim analysis, the adjuvant CPT-11 dose was reduced to 100 mg/m2 on days 1 and 5 for the first cycle. CPT-11 dose escalation proceeded over the first 3 cycles if tolerated. Median overall survival for all eligible patients was 16.9 months compared with 13.7 months of the historical control (P = .03). Post hoc subgroup analysis suggested an improvement in overall survival for patients with Radiation Therapy Oncology Group recursive partitioning analysis class 3, although improvement was limited to 22 patients (14% of eligible patients). CONCLUSIONS:Although irinotecan and TMZ for 12 cycles given after chemoradiation for patients with newly diagnosed glioblastoma significantly improved median survival compared with historical control data at the time the study was conducted, the historical control median survival time of 13.7 months does not represent the current benchmark for this patient population. Treatment intensification does prolong overall survival compared with the current standard.

Background. The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome.Methods. Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+ TMZ (n = 97) or RT+ NU (n = 99). The study closed early because the target accrual rate was not met.Results. Median follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P =.36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+ NU arm experienced more grade = 3 toxicity (75.8% vs 47.9%, P <.001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1R132H status (60 RT+ TMZ and 51 RT+ NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P =.004, HR = 0.50; 95% CI, 0.31-0.81).Conclusions. RT+ TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+ TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival.

In this study, laser-processed multi-walled carbon nanotube (MWCNT)/Cu conductors are introduced as potential passive components to mitigate the skin effect of Cu at high frequencies (0–10 MHz). Suppressed skin effect is observed in the MWCNT/Cu conductors compared to primitive Cu. At an AC frequency of 10 MHz, a maximum AC resistance reduction of 94% was observed in a MWCNT/Cu conductor after being irradiated at a laser power density of 189 W/cm2. The reduced skin effect in the MWCNT/Cu conductors is ascribed to the presence of MWCNT channels which are insensitive to AC frequencies. The laser irradiation process is observed to play a crucial role in reducing contact resistance at the MWCNT-Cu interfaces, removing impurities in MWCNTs, and densifying MWCNT films.

A late‐stage clinical development program typically contains multiple trials. Conventionally, the program's success or failure may not be known until the completion of all trials. Nowadays, interim analyses are often used to allow evaluation for early success and/or futility for each individual study by calculating conditional power, predictive power and other indexes. It presents a good opportunity for us to estimate the probability of program success (POPS) for the entire clinical development earlier. The sponsor may abandon the program early if the estimated POPS is very low and therefore permit resource savings and reallocation to other products. We provide a method to calculate probability of success (POS) at an individual study level and also POPS for clinical programs with multiple trials in binary outcomes. Methods for calculating variation and confidence measures of POS and POPS and timing for interim analysis will be discussed and evaluated through simulations. We also illustrate our approaches on historical data retrospectively from a completed clinical program for depression. Copyright © 2015 John Wiley & Sons, Ltd.

BACKGROUND: Oligodendroglial tumors harbor IDH mutations and risk of this type of cancer is associated with a germ-line polymorphism at 8q. In addition, when these tumors harbor a co-deletion of 1p19q, they can be highly chemo-sensitive. Indeed, patients with anaplastic tumors (i.e., AO/AOA) with 1p19q co-deletion lived nearly twice as long after chemotherapy and radiation (CRT; 14-16 years) as radiotherapy alone (RT; 7-9 years) in two large randomized trials. In RTOG 9402, some patients with non-co-deleted AO/AOA also lived longer after CRT: for these participants, the survival curves separated after the median had been reached, and significantly more lived 10 years or longer after CRT than RT (25% vs. 10%). Since co-deletion status did not identify all patients benefiting from CRT, we asked whether other molecular hallmarks of AO/AOA – IDH or G-allele status – might be more inclusive markers of benefit from CRT. METHODS: We used tissues and data from RTOG 9402 to explore this hypothesis. RESULTS: IDH status was evaluable in 210 of 291 participants: 156 (74%) had a mutation of IDH1/2. The G allele of rs55705857 was evaluable in 245 of 291 participants: 76 (31%) carried the risk-allele in their germ-line. Presence of either an IDH mutation or the G risk-allele was associated with significantly longer progression-free survival after CRT, and an IDH mutation with much longer overall survival [9.4 vs. 5.7 years, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.40, 0.86), P = 0.006]. For cases in which IDH was intact, CRT did not prolong median survival time [1.3 vs. 1.8 years, HR 1.14, CI (0.63, 2.04), P = 0.67] or 10-year survival rates (CRT 6% vs. RT 4%). As expected, patients with mutated, co-deleted AO/AOA lived longer after CRT than RT (14.7 vs. 6.8 years, HR 0.49, CI (0.28, 0.85), P = 0.01], but so too did those with mutated, non-co-deleted AO/AOA [5.5 vs. 3.3 years, HR 0.56, CI (0.32, 0.99), P < 0.05]. Among the latter, ATRX positive and negative cases had longer overall survival after CRT than RT, but these differences were not significant. CONCLUSIONS: In AO/AOA cases in RTOG 9402, the presence or risk of an IDH mutation was associated with ‘benefit’ from CRT. Wild-type IDH was associated with poor overall and long-term survival, and absence of benefit from CRT. IDH mutation status identified more patients who benefited from CRT than did 1p/19q co-deletion status, but patients with co-deleted AO/AOA lived much longer.

PURPOSEPatients with 1p/19q codeleted anaplastic oligodendroglial tumors who participated in RTOG (Radiation Therapy Oncology Group) 9402 lived much longer after chemoradiotherapy (CRT) than radiation therapy (RT) alone. However, some patients with noncodeleted tumors also benefited from CRT; survival curves separated after the median had been reached, and significantly more patients lived ≥ 10 years after CRT than RT. Thus, 1p/19q status may not identify all responders to CRT.PATIENTS AND METHODSUsing trial data, we inquired whether an IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas identified the patients in RTOG 9402 who benefited from CRT.RESULTSIDH status was evaluable in 210 of 291 patients; 156 (74%) had mutations. rs55705857 was evaluable in 245 patients; 76 (31%) carried the G risk allele. Both were associated with longer progression-free survival after CRT, and mutant IDH was associated with longer overall survival (9.4 v 5.7 years; hazard ratio [HR], 0.59; 95% CI, 0.40 to 0.86; P = .006). For those with wild-type tumors, CRT did not prolong median survival (1.3 v 1.8 years; HR, 1.14; 95% CI, 0.63 to 2.04; P = .67) or 10-year survival rate (CRT, 6% v RT, 4%). Patients with codeleted mutated tumors (14.7 v 6.8 years; HR, 0.49; 95% CI, 0.28 to 0.85; P = .01) and noncodeleted mutated tumors (5.5 v 3.3 years; HR, 0.56; 95% CI, 0.32 to 0.99; P < .05) lived longer after CRT than RT.CONCLUSIONIDH mutational status identified patients with oligodendroglial tumors who did (and did not) benefit from alkylating-agent chemotherapy with RT. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after CRT.

A new design of ITER Glow Discharge Cleaning (GDC) system based on a fixed electrode concept replaces the previous design which was based on a movable electrode integrated with the ITER In-Vessel-Viewing-System. Recently the conceptual design of the GDC system was reviewed successfully on the functions, safety, operation and maintenance. The design proposed was checked against the requirements and found to be feasible. This paper gives an overall description of the requirements from physics and operation viewpoints and introduces the design at the conceptual level. Main R&D activities are listed and summarized. Further detailed studies are to be performed in the following design stage. (C) 2014 Published by Elsevier B.V.

The Radiation Therapy Oncology Group (RTOG) initiated the single-arm, phase II study 9806 to determine the safety and efficacy of daily thalidomide with radiation therapy in patients with newly diagnosed glioblastoma. Patients were treated with thalidomide (200 mg daily) from day one of radiation therapy, increasing by 100–200 to 1,200 mg every 1–2 weeks until tumor progression or unacceptable toxicity. The median survival time (MST) of all 89 evaluable patients was 10 months. When compared with the historical database stratified by recursive partitioning analysis (RPA) class, this end point was not different [hazard ratio (HR) = 1.18; 95 % CI: 0.95–1.46; P = 0.93]. The MST of RPA class III and IV patients was 13.9 versus 12.5 months in controls (HR = 0.99; 95 % CI: 0.73–1.36; P = 0.48), and 4.3 versus 8.6 months in RPA class V controls (HR = 1.63, 95 % CI: 1.17–2.27; P = 0.99). In all, 34 % of patients discontinued thalidomide because of adverse events or refusal. The most common grade 3–4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy. In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.

Purpose To determine the safety and efficacy of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with radiation for newly diagnosed glioblastoma (GBM) patients. Methods and Materials Between March 21, 2002, and May 3, 2004, Radiation Therapy Oncology Group (RTOG) 0211 enrolled 31 and 147 GBM patients in the phase 1 and 2 arms, respectively. Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy (RT) and continued post RT for 18 months or until progression. Tissue microarrays from 68 cases were analyzed for EGFR expression. Results The maximum tolerated dose (MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs (non-EIAEDs). All patients in the phase 2 component were treated at a gefitinib dose of 500 mg; patients receiving EIADSs could be escalated to 750 mg. The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal. Median survival was 11.5 months for patients treated per protocol. There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone, matched by RTOG recursive partitioning analysis (RPA) class distribution. Younger age was significantly associated with better outcome. Per protocol stratification, EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients. Conclusions The addition of gefitinib to RT is well tolerated. Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone.

BACKGROUND In a previous study, the European Organisation for Research and Treatment of Cancer (EORTC) reported a scoring system to predict survival of patients with low-grade gliomas (LGGs). A major issue in the diagnosis of brain tumors is the lack of agreement among pathologists. New models in patients with LGGs diagnosed by central pathology review are needed. METHODS Data from 339 EORTC patients with LGGs diagnosed by central pathology review were used to develop new prognostic models for progression-free survival (PFS) and overall survival (OS). Data from 450 patients with centrally diagnosed LGGs recruited into 2 large studies conducted by North American cooperative groups were used to validate the models. RESULTS Both PFS and OS were negatively influenced by the presence of baseline neurological deficits, a shorter time since first symptoms (<30 wk), an astrocytic tumor type, and tumors larger than 5 cm in diameter. Early irradiation improved PFS but not OS. Three risk groups have been identified (low, intermediate, and high) and validated. CONCLUSIONS We have developed new prognostic models in a more homogeneous LGG population diagnosed by central pathology review. This population better fits with modern practice, where patients are enrolled in clinical trials based on central or panel pathology review. We could validate the models in a large, external, and independent dataset. The models can divide LGG patients into 3 risk groups and provide reliable individual survival predictions. Inclusion of other clinical and molecular factors might still improve models' predictions.