A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial.

BACKGROUND: Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM. METHODS: ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events. DISCUSSION: Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development. TRIAL REGISTRATION: ISRCTN: 11460478. CLINICALTRIALS: Gov: NCT05629702.

Changes in Point of Maximal Curvature During Collagenase Clostridium Histolyticum Injections for Peyronie's Disease.

OBJECTIVE: To determine change in the point of maximal curvature (POMC) during Collagenase Clostridium histolyticum (CCH) injections for Peyronie's disease (PD). METHODS: A prospective database has been maintained of all men undergoing CCH injections since March 2014. For the current study, data were abstracted on the POMC with each curve assessment and correlated with demographic and clinical factors. Maximal changes were defined as the largest change in POMC from baseline. RESULTS: Six hundred and eighteen men underwent ≥1 series of CCH, with 313 having a baseline and subsequent POMC measurements available. Median baseline curvature was 60.0° and POMC 2.8 cm. Among 189 men who were satisfied or completed 8 CCH injections, the median improvement in penile curvature was -27.5° (40.9%). The median maximal change in POMC during CCH treatment was 1.0 cm (interquartile range, 0.5, 1.8). Overall, 55.6% had changes in POMC of ≥1 cm, 23.6% ≥2 cm, 8.9% ≥3 cm, and 3.8% ≥4 cm. Multivariate logistic regression identified ventral curvature as a predictor of larger change in POMC, after controlling for other variables. Study limitations included the observational, non-randomized study design and potential for intra- and inter-individual measurement variability. Strengths are the inclusion of an all-comer population, large series, prospective database, and routine objective assessments. CONCLUSION: Approximately half of men with PD undergoing CCH experience ≥1 cm of change in POMC during the treatment course, with nearly 1/4 experiencing ≥2 cm. Findings suggest that patients may benefit from repeat curvature assessments with each CCH series to optimize accuracy of drug administration.

Outcomes of collagenase Clostridium histolyticum in men with ventral curvatures: an updated series.

BACKGROUND: The efficacy and safety of collagenase Clostridium histolyticum (CCH) have been demonstrated in the treatment of men with Peyronie's disease (PD); however, the pivotal clinical trials excluded men with ventral penile curvature. AIM: The study sought to evaluate outcomes of CCH treatment in men with ventral curvatures secondary to PD. METHODS: Men with PD treated with CCH were identified from a prospective database. Patients received up to 4 series of CCH injections using a progressively modified protocol over time. Results were compared between those with baseline ventral vs nonventral penile curvatures. OUTCOMES: Changes in penile curvature, Peyronie's Disease Questionnaire scores, International Index of Erectile Function scores, nonstandardized assessments, and adverse events. RESULTS: A total of 560 men with PD (85 ventral curvature, 475 nonventral curvature) were included in the analysis. Baseline median curvature was 60.0° (interquartile range, 48.8°-75.0°) in the ventral cohort and 65.0° (interquartile range, 45.0°-80.0°) in the nonventral cohort. Median change from baseline penile curvature was -25.0° in the ventral cohort vs -24.0° in the nonventral cohort (P = .08, between-group comparison), which corresponded to curvature reductions of 44.7% and 33.6%, respectively (P = .03). In the subset of patients who completed CCH treatment (ie, received 8 injections or discontinued early because of patient satisfaction with curvature reduction), median change from baseline was -35.0° in the ventral cohort vs -25.0° in the nonventral cohort (P < .05); median percent improvement was 48.3% and 37.5%, respectively (P = .11). Median change from baseline in Peyronie's Disease Questionnaire and International Index of Erectile Function domain scores and adverse events were similar between cohorts, with the exception of possibly higher hematoma rates in the nonventral group (50% vs 37%; P = .05). No urethral injuries were sustained in either cohort. CLINICAL IMPLICATIONS: Data support the use of CCH for the treatment of ventral as well as nonventral penile curvatures in men with PD. STRENGTHS AND LIMITATIONS: Study strengths are the inclusion of a general clinical population of men with PD, the prospective design, and the relatively large series of men with ventral curvature. Limitations include the single-center and observational nature of the study. CONCLUSION: CCH was safe and effective in the treatment of both ventral and nonventral penile curvatures in men with PD.

7-Deazaguanines in DNA: functional and structural elucidation of a DNA modification system.

The modified nucleosides 2'-deoxy-7-cyano- and 2'-deoxy-7-amido-7-deazaguanosine (dPreQ0 and dADG, respectively) recently discovered in DNA are the products of the bacterial queuosine tRNA modification pathway and the dpd gene cluster, the latter of which encodes proteins that comprise the elaborate Dpd restriction-modification system present in diverse bacteria. Recent genetic studies implicated the dpdA, dpdB and dpdC genes as encoding proteins necessary for DNA modification, with dpdD-dpdK contributing to the restriction phenotype. Here we report the in vitro reconstitution of the Dpd modification machinery from Salmonella enterica serovar Montevideo, the elucidation of the roles of each protein and the X-ray crystal structure of DpdA supported by small-angle X-ray scattering analysis of DpdA and DpdB, the former bound to DNA. While the homology of DpdA with the tRNA-dependent tRNA-guanine transglycosylase enzymes (TGT) in the queuosine pathway suggested a similar transglycosylase activity responsible for the exchange of a guanine base in the DNA for 7-cyano-7-deazaguanine (preQ0), we demonstrate an unexpected ATPase activity in DpdB necessary for insertion of preQ0 into DNA, and identify several catalytically essential active site residues in DpdA involved in the transglycosylation reaction. Further, we identify a modification site for DpdA activity and demonstrate that DpdC functions independently of DpdA/B in converting preQ0-modified DNA to ADG-modified DNA.

Protocol for the Tessa Jowell BRAIN MATRIX Platform Study.

INTRODUCTION: Gliomas are the most common primary tumour of the central nervous system (CNS), with an estimated annual incidence of 6.6 per 100 000 individuals in the USA and around 14 deaths per day from brain tumours in the UK. The genomic and biological landscape of brain tumours has been increasingly defined and, since 2016, the WHO classification of tumours of the CNS incorporates molecular data, along with morphology, to define tumour subtypes more accurately. The Tessa Jowell BRAIN MATRIX Platform (TJBM) study aims to create a transformative clinical research infrastructure that leverages UK National Health Service resources to support research that is patient centric and attractive to both academic and commercial investors. METHODS AND ANALYSIS: The TJBM study is a programme of work with the principal purpose to improve the knowledge of glioma and treatment for patients with glioma. The programme includes a platform study and subsequent interventional clinical trials (as separate protocols). The platform study described here is the backbone data-repository of disease, treatment and outcome data from clinical, imaging and pathology data being collected in patients with glioma from secondary care hospitals. The primary outcome measure of the platform is time from biopsy to integrated histological-molecular diagnosis using whole-genome sequencing and epigenomic classification. Secondary outcome measures include those that are process centred, patient centred and framework based. Target recruitment for the study is 1000 patients with interim analyses at 100 and 500 patients. ETHICS AND DISSEMINATION: The study will be performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects, adopted by the 18th World Medical Association General Assembly, Helsinki, Finland and stated in the respective participating countries' laws governing human research, and Good Clinical Practice. The protocol was initially approved on 18 February 2020 by West Midlands - Edgbaston Research Ethics Committee; the current protocol (v3.0) was approved on 15 June 2022. Participants will be required to provide written informed consent. A meeting will be held after the end of the study to allow discussion of the main results among the collaborators prior to publication. The results of this study will be disseminated through national and international presentations and peer-reviewed publications. Manuscripts will be prepared by the Study Management Group and authorship will be determined by mutual agreement. TRIAL REGISTRATION NUMBER: NCT04274283, 18-Feb-2020; ISRCTN14218060, 03-Feb-2020.

Improved Peyronie's Disease Curvature Outcomes Using a Novel Collagenase Administration Protocol.

OBJECTIVE: To report outcomes of a novel collagenase clostridium histolyticum (CCH) injection protocol. METHODS: A prospective, sequential database was maintained of all Peyronie's men undergoing CCH injections since 2015. Our protocol has evolved to include changes with injection technique, timing, aggressive modeling/traction, and wrapping. Results of the "traditional" and "novel" techniques were compared using two definitions: "most recent" assessment and final assessments among men who "completed eight (injections) or were satisfied." RESULTS: A total of 509 men underwent greater than or equal to 1 CCH series (traditional, n = 280; novel n = 229). Baseline demographic/clinicopathologic characteristics were similar between groups. Results demonstrated significantly greater curve improvements with the novel technique ("most recent" median 30° vs 20° or 46% vs 28%; "completed eight or satisfied" 34° vs 20° or 58% vs 30%). Using the "completed eight or satisfied" definition, 94% vs 66% of men achieved greater than or equal to 20% improvement (odds ratio 7.6), and 60% vs 24% achieved greater than or equal to 50% improvements (odds ratio 5.0) in the novel cohort (all P < .0001). Importantly, the International Index of Erectile Function Erectile Function Domain score was unchanged, and subjective erectile function (50% vs 5%, P < .0001) and sensation improved (17% vs 8% improved, P = .01) with the new protocol. The novel cohort also reported higher rates of surgery prevention (53% vs 18%), restored/facilitated penetration (57% vs 21%), and hematomas (56% vs 26%), necessitating changes to wrapping procedures (all P < .0001). CONCLUSIONS: Use of the novel CCH protocol results in significant improvements with curvature without negatively impacting erectile function or sensation. Given its specialized nature, it is not recommended for low-volume CCH injectors.

Practical guidance for running late-phase platform protocols for clinical trials: lessons from experienced UK clinical trials units.

BACKGROUND: Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. METHODS: Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. RESULTS: We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement. DISCUSSION: Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently.

Subgroup analyses in randomized controlled trials frequently categorized continuous subgroup information.

BACKGROUND AND OBJECTIVES: To investigate how subgroup analyses of published Randomized Controlled Trials (RCTs) are performed when subgroups are created from continuous variables. METHODS: We carried out a review of RCTs published in 2016-2021 that included subgroup analyses. Information was extracted on whether any of the subgroups were based on continuous variables and, if so, how they were analyzed. RESULTS: Out of 428 reviewed papers, 258 (60.4%) reported RCTs with a subgroup analysis. Of these, 178/258 (69%) had at least one subgroup formed from a continuous variable and 14/258 (5.4%) were unclear. The vast majority (169/178, 94.9%) dichotomized the continuous variable and treated the subgroup as categorical. The most common way of dichotomizing was using a pre-specified cutpoint (129/169, 76.3%), followed by a data-driven cutpoint (26/169, 15.4%), such as the median. CONCLUSION: It is common for subgroup analyses to use continuous variables to define subgroups. The vast majority dichotomize the continuous variable and, consequently, may lose substantial amounts of statistical information (equivalent to reducing the sample size by at least a third). More advanced methods that can improve efficiency, through optimally choosing cutpoints or directly using the continuous information, are rarely used.

Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex): study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial.

INTRODUCTION: Event-free survival rates at 15 years for paediatric patients with relapsed/refractory acute lymphoblastic leukaemia (ALL) are 30%-50%, with 5-year survival for adult patients only 20%. Many patients with newly diagnosed and relapsed ALL harbour somatic RAS-signalling activation mutations. Induction therapy for ALL involves steroids, with preclinical data suggesting the combination of dexamethasone with the MEK1/2 inhibitor, selumetinib (ARRY-142886) has a synergistic anticancer effect. METHODS AND ANALYSIS: The SeluDex trial is an international, parallel-group, dose-finding with expansion, phase I/II trial to assess the selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL. The Cancer Research UK Clinical Trials Unit at University of Birmingham is the UK Coordinating Centre, with national hubs in Copenhagen, Denmark; Monza, Italy; Münster, Germany; Paris, France; and Utrecht, Netherlands. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-cell ALL, with demonstrated RAS pathway activating mutations are eligible. Adult patients are >18 years old, ECOG <2 and paediatric <18 years old, Lansky play scale ≥60% or Karnofsky score ≥60%. Phase I primary objective is the recommended phase II dose of selumetinib as defined by occurrence/non-occurrence of dose limiting toxicities using the continual reassessment method; phase II will evaluate preliminary antileukaemic activity of the combination, as defined by morphological response 28 days post-treatment using a Bayesian approach. Target recruitment is between 26 and 42 patients (minimum 13 and maximum 21 per group), depending the number of phase I patients included in phase II. ETHICS AND DISSEMINATION: Medical ethical committees of all the participating countries have approved the study protocol; initial (UK) ethics approval (17/YH/0123) was granted by Yorkshire & The Humber-Leeds West Research Ethics Committee. Participants are required to provide written informed consent/assent. Results will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN92323261.

Conservative management of suspected fractures in men undergoing collagenase clostridium histolyticum for Peyronie's Disease is not associated with worsening of erectile function.

The optimal management of suspected penile fractures post collagenase clostridium histolyticum (CCH) remains indeterminate, with some advocating for observation and others surgical repair. To address this issue, the current study sent surveys to 158 men with Peyronie's Disease (PD) who completed four CCH injection series. The survey included the Erectile Function Domain from the International Index of Erectile Function (IIEF-EFD) and questions regarding potential symptoms of corporal rupture (hematoma, popping, and detumescence). Men were categorized as having a suspected fracture (SF+) if they reported a popping sensation or rapid detumescence. All SF(+) men were managed conservatively without surgical intervention. Results were compared statistically against baseline IIEF-EFD values and between SF(+) and SF(-) groups. The key study objective was to determine whether erectile function was negatively impacted by conservative management of suspected fractures. Of the 53 returned surveys, 45 had complete data for review. The sample was statistically representative of the broader cohort of 158 men, except being older (60.0 vs 57.1 [SD 6.0 vs 9.0], p = 0.01) with shorter durations of PD (median 9 [IQR 5, 19] mo vs 13 [IQR 8, 24], p = 0.01). Overall, 7/45 (16%) of men were defined as SF(+), with all fractures occurring within 6 weeks of CCH administration. No demographic or pathophysiologic characteristics predicted SF(+). Importantly, SF(+) men did not experience worsened erectile function compared to SF(-), with a median IIEF-EFD change of +2 vs +1, p = 0.16, respectively. Curvatures were improved to a greater degree among SF(+) men (primary: median -30 [IQR -20, -32.5] vs -15 [-5, -26], p = 0.04; composite: -35 [-25, -40] vs -25 [-7, -30], p = 0.15). We concluded that suspected penile fractures in PD men undergoing CCH may be reasonably managed without surgical intervention and portend greater improvements in curvature correction.

CATALYST trial protocol: a multicentre, open-label, phase II, multiarm trial for an early and accelerated evaluation of the potential treatments for COVID-19 in hospitalised adults.

INTRODUCTION: Severe SARS-CoV-2 infection is associated with a dysregulated immune response. Inflammatory monocytes and macrophages are crucial, promoting injurious, proinflammatory sequelae. Immunomodulation is, therefore, an attractive therapeutic strategy and we sought to test licensed and novel candidate drugs. METHODS AND ANALYSIS: The CATALYST trial is a multiarm, open-label, multicentre, phase II platform trial designed to identify candidate novel treatments to improve outcomes of patients hospitalised with COVID-19 compared with usual care. Treatments with evidence of biomarker improvements will be put forward for larger-scale testing by current national phase III platform trials. Hospitalised patients >16 years with a clinical picture strongly suggestive of SARS-CoV-2 pneumonia (confirmed by chest X-ray or CT scan, with or without a positive reverse transcription PCR assay) and a C reactive protein (CRP) ≥40 mg/L are eligible. The primary outcome measure is CRP, measured serially from admission to day 14, hospital discharge or death. Secondary outcomes include the WHO Clinical Progression Improvement Scale as a principal efficacy assessment. ETHICS AND DISSEMINATION: The protocol was approved by the East Midlands-Nottingham 2 Research Ethics Committee (20/EM/0115) and given urgent public health status; initial approval was received on 5 May 2020, current protocol version (V.6.0) approval on 12 October 2020. The MHRA also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBERS: EudraCT2020-001684-89, ISRCTN40580903.

Vascular Necrosis of the Upper Extremity After Self-Treatment for Peyronie's Disease.

Peyronie's disease (PD) is associated with significant psychosocial distress, including anxiety, depression, and negative effects on interpersonal relationships. We report outcomes in a patient who researched an enzymatic supplement intended for oral administration for treatment of PD and subsequently self-injected it intravascularly. The enzyme, a combination of serrapeptase and nattokinase, resulted in vascular necrosis of the upper extremity. Despite attempts to salvage the limb, he ultimately required transhumeral amputation. Although extreme, this case illustrates the potential risks of non-Food and Drug Administration-approved therapies, the significant psychosocial impact that PD can have on patients' emotional well-being, and the extent to which some may go to seek treatment. Yang D, Savage J, Kohler T, et al. Vascular Necrosis of the Upper Extremity After Self-Treatment for Peyronie's Disease. Sex Med 2021;9:100282.

Outcomes of RestoreX Penile Traction Therapy in Men With Peyronie's Disease: Results From Open Label and Follow-up Phases.

BACKGROUND: A randomized, controlled clinical trial evaluating the efficacy of RestoreX traction therapy in men with Peyronie's disease (PD) has been completed, with the 3-month results previously reported. The present study presents outcomes from the open-label and follow-up phases of the original trial. AIM: To report 6-month (open-label phase) and 9-month (follow-up phase) outcomes from a randomized, controlled trial (NCT03389854). METHODS: A randomized controlled trial was performed from 2017 to 2019 in 110 all-comer men with PD. Men were randomized 3:1 to RestoreX (PTT) or no therapy (control) for 3 months, followed by 3-month open-label and follow-up phases. Key outcomes included adverse events (AEs), changes in penile curvature and length, erectile function, and standardized and nonstandardized assessments of PD. OUTCOMES: The primary outcomes are safety, penile length, penile curvature, Peyronie's Disease Questionnaire, International Index of Erectile Function, and satisfaction. RESULTS: 6-month (n = 64) and 9-month (n = 63) outcomes were reported, with a mean duration of PTT use of 31.1 minutes. No significant AEs were reported, with temporary erythema and discomfort being most common and resolving within minutes. On intent-to-treat analysis, control-to-PTT men experienced significant length (1.7-2.0 cm) and curvature improvements (18-20%). PTT-to-PTT men also achieved additional length (0.6-0.8 cm) without further curvature improvements. An as-treated analysis of PTT use ≥15 minute/day demonstrated 2.0- to 2.3-cm length gains (largest of any PTT to date) and 18-21% curve improvement. All sexual function domains of the International Index of Erectile Function and Peyronie's Disease Questionnaire were significantly improved (except orgasmic domain). 95% of men treated for 6 months experienced length gains (mean 2.0-2.2 cm), and 61% had curve improvements (16.8-21.4° [32.8-35.8%]). RestoreX was preferred 3-4:1 over all other PD treatments, and 100% preferred it over other PTT devices. CLINICAL IMPLICATIONS: Use of RestoreX 30 minutes daily results in significant length and curve improvements in PD men without significant AEs. STRENGTHS & LIMITATIONS: Strengths include largest randomized study of PTT, blinded assessments, and inclusion of all-comers with few restrictions; limitations include sample size that precludes comparisons between treatment cohorts and lack of long-duration (>3-9 hours) treatment arm. CONCLUSION: PTT with RestoreX results in significant improvements in length, curve, and subjective and objective measures of sexual function without significant AEs. RestoreX PTT represents a safe, conservative, low-cost option for managing men with PD. Joseph J, Ziegelmann M, Alom M, et al. Outcomes of RestoreX Penile Traction Therapy in Men With Peyronie's Disease: Results From Open Label and Follow-up Phases. J Sex Med 2020;17:2462-2471.

Publisher Correction: The National Lung Matrix Trial of personalized therapy in lung cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The National Lung Matrix Trial of personalized therapy in lung cancer.

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.

Phase I trial of WEE1 inhibition with chemotherapy and radiotherapy as adjuvant treatment, and a window of opportunity trial with cisplatin in patients with head and neck cancer: the WISTERIA trial protocol.

INTRODUCTION: Patients with head and neck squamous cell carcinoma with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological features postsurgery. While cure rates are improved, overall survival remains suboptimal and treatment has a significant negative impact on quality of life.Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the therapeutic effects of chemoradiation. Our hypothesis is that combining chemoradiation with a WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, thereby enhancing clinical outcomes, without increased toxicity. This trial explores the associated effect of WEE1 kinase inhibitor adavosertib (AZD1775). METHODS AND ANALYSIS: This phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of AZD1775 in combination with cisplatin chemotherapy preoperatively (group A) as a window of opportunity trial, and in combination with postoperative cisplatin-based chemoradiation (group B).Modified time-to-event continual reassessment method will determine the recommended dose, recruiting up to 21 patients per group. Primary outcomes are recommended doses with predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days (group A), and 30% monitored up to 12 weeks (group B). Secondary outcomes are disease-free survival times (groups A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) effects, identification and correlation of potential biomarkers with PD markers of DNA damage, determine rate of resection status and surgical complications for group A; and quality of life in group B. ETHICS AND DISSEMINATION: Research Ethics Committee, Edgbaston, West Midlands (REC reference 16/WM/0501) initial approval received on 18/01/2017. Results will be disseminated via peer-reviewed publication and presentation at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN76291951 and NCT03028766.

Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial.

BACKGROUND: Therapeutic blockade of the axis of programmed cell death 1 (PD-1) and its ligand (PD-L1) has transformed the management of non-small-cell lung cancer (NSCLC). Clinical trials with pembrolizumab have enrolled patients with performance status (PS) 0-1. However, around 18% of patients with NSCLC are PS2, and the activity and safety of pembrolizumab in these patients is unclear. We aimed to evaluate the safety and efficacy of pembrolizumab in these patients. METHODS: We did a multicentre, single-arm, open-label, phase 2 trial (PePS2) in ten hospitals in the UK, in which patients with NSCLC and a rigorous ascription of PS2 were given pembrolizumab 200 mg every 3 weeks. No masking was used in this trial. We stratified the treatment evaluation by tumour proportion score (TPS) and line of therapy. Co-primary outcomes were: (1) durable clinical benefit (DCB), defined as the occurrence of complete response, partial response, or stable disease that continues until at least the second CT scan scheduled at 18 weeks; and (2) toxicity, defined as the occurrence at any time of treatment-related dose delay or treatment discontinuation due to an adverse event. Analysis included all patients who received any pembrolizumab. As well as reporting simple observed incidence for the co-primary outcomes, DCB and toxicity, we also estimated incidence using a model-based method for correlated binary outcomes. This study is registered with ClinicalTrials.gov, NCT02733159; EudraCT, 2015-002241-55; and ISRCTN, 10047797. FINDINGS: Between Jan 4, 2017, and Feb 13, 2018, of 112 patients assessed for eligibility, we recruited 62 patients. 60 patients were evaluable for the co-primary outcomes. Median age was 72 years (IQR 65-75); 33 (55%) of participants were male and 27 (45%) were female. The observed incidence for DCB was 38% (95% CI 21-57) in first-line patients (n=24) and 36% (22-52) in subsequent-line patients (n=36); DCB was 22% (11-41) in patients with a TPS less than 1% (n=27), 47% (25-70) in patients with a TPS of 1-49% (n=15), and 53% (30-75) in patients with a TPS of 50% or greater (n=15). An increase in DCB incidences with TPS was also shown in model-based estimates. Toxicity was observed in 28% (95% CI 19-41) of patients, 11 (18%) of 60 due to dose delay and 6 (10%) of 60 due to drug discontinuation. No grade 5 treatment-related adverse events were observed and no early deaths were attributed to hyperprogression. The most common grade 3-4 adverse events were dyspnoea (n=9), hyponatraemia (n=5), and anorexia (n=4). There were ten serious adverse events considered to be related to treatment, comprising diarrhoea (n=3) and acute kidney injury, adrenal insufficiency, hyperbilirubinaemia, oral mucositis, rash, urinary tract infection, and vomiting (n=1 each). INTERPRETATION: Patients with NSCLC of PS2 are a group of patients of unmet therapeutic need. The PePS2 trial shows that pembrolizumab can be safely administered to these patients, with no increase in the risk of immune-related or other toxicities. Efficacy outcomes are at least as good as those in patients with PS0-1 and the data provides clinicians with the confidence to incorporate pembrolizumab into the treatment pathway of patients with NSCLC of PS2. FUNDING: Merck, Sharp & Dohme.

Reinforcing vasal suture technique improves sperm concentration and pregnancy rates in men undergoing vasovasostomy for vasectomy reversal.

BACKGROUND: Vasovasostomy (VV) is a well-described surgical technique with few notable modifications since microsurgical adaptation in the 1970s. Although contemporary reversal success rates are 70-90%, these most often are based on a lenient definition of >0 sperm (patency) and include only VV procedures. With stricter definitions, success rates drop >30%. To improve outcomes, a novel surgical technique (reinforcing vasal suture, ReVas) was developed, and outcomes were compared prior to and following implementation. METHODS: A prospective registry of sequential patients undergoing vasectomy reversal was queried from Jan 2014 to June 2019. The ReVas technique was implemented in Jan 2018, wherein the abdominal and testicular vasa are secured side-to-side to alleviate strain on the anastomosis. Primary outcomes were changes in sperm concentration: >0/mL, >100,000/mL, >1 million/mL, >5 million/mL, >15 million/mL, and most recent. Secondary outcome was pregnancy rate. Demographic, clinical, and select operative variables were statistically compared between ReVas (+) and (-) cohorts. RESULTS: A total of 200 men underwent reversal, of whom 169 represented first-time attempts (61 receiving the new technique) and comprise the current cohort. ReVas (+) and (-) cohorts were similar in demographic, clinical, and operative factors with the exception of operative time [longer in ReVas (+) group]. Median duration since vasectomy was 9 years, and 68.6% of men received a bilateral VV. Follow-up was significantly longer in the ReVas (-) arm (37 vs. 10 months). All primary outcomes were significantly higher in the ReVas (+) cohort, with odds ratios ranging from 5.8 to 11.1 (P<0.01 to 0.0001). Pregnancy rates within the first 2 years post reversal were also 8.1× higher in the ReVas (+) group (P=0.02). A subset of men with bilateral VV exhibited a 95% likelihood of achieving >15 million/mL in ReVas (+) men compared to 54% in ReVas (-). Multivariable analysis confirmed ReVas as an independent predictor of success. CONCLUSIONS: Implementation of the ReVas technique resulted in significantly higher sperm concentrations, which were particularly pronounced when stricter success criteria were used. Patients were also 8.1× more likely to achieve a pregnancy within the first 2 years, confirming clinical relevance. External validation is warranted.

Safety and Efficacy of Collagenase Clostridium Histolyticum in Peyronie's Disease Men With Ventral Curvatures.

OBJECTIVE: To evaluate the safety and efficacy of collagenase clostridium histolyticum (CCH) in men with ventral penile curvatures secondary to Peyronie's Disease (PD). METHODS: A prospective registry has been maintained of PD men undergoing CCH at our institution. Curvature assessments and subjective questioning were obtained at baseline and following 2 and 4 injection series. Clinicopathologic data were abstracted including history, exam, ultrasound, and end-point curvature assessments. Primary outcomes were adverse events (AE), and secondary outcomes included improvements in curvature by direction and subjective responses to questionnaires. RESULTS: A total of 228 patients undergoing CCH for PD (mean age 57.2 years, mean PD duration 24.3 months) were identified from March 2014 through March 2018. Baseline curvature directions were individually analyzed (total of 329 measures), including 83%, 50%, and 11% with some degree of dorsal, lateral, and ventral angulation. Mean primary and secondary (where applicable) curvatures were 52.9 and 11.4 degrees, respectively. Following treatment, ventral and lateral curvatures experienced greater relative improvements in curvature compared to dorsal (ventral 29.5 degrees [49%], lateral 11.4 [38%], dorsal 15.0 [25%], P < .05). Ventral and lateral curvatures were also more likely to experience ≥50%, ≥75%, and ≥90% improvements compared to dorsal. AEs were similar among curvature directions, and no urethral complications occurred. CONCLUSION: Men with ventral PD may be effectively treated with CCH with similar AEs compared to other directions. Ventral and lateral curvatures are more likely to experience significant improvements (50% or more) compared to dorsal.