Diagnosis, management, and outcomes of immune checkpoint inhibitor induced acute interstitial nephritis: A single-center experience.

BACKGROUND: Immune checkpoint inhibitor (ICI)-associated acute interstitial nephritis (AIN) is a recognized complication of immunotherapy (IO), but literature on its management and outcomes is limited. METHODS: We retrospectively reviewed patients who received ICIs and developed biopsy-proven or clinically-suspected ICI-associated AIN at the University of Virginia Comprehensive Cancer Center from 2012-2023. We analyzed baseline characteristics and clinical outcomes, including treatment interruption and rechallenge rates. Acute kidney injury (AKI) was defined as a ≥ 1.5-fold increase in baseline creatinine under seven days, a two-fold increase above the upper limit of normal, or an increase by ≥0.3 mg/dL. Kidney function returning to within 0.3 mg/dL or less than twice baseline was considered complete (CRc) and partial (PRc) recovery, respectively. RESULTS: We identified 12 cases of ICI-AIN: four by biopsy (33%) and eight (67%) by clinical suspicion. Two patients received anti-CTLA-4 and anti-PD1, six received anti-PD1 alone, and four received chemo-immunotherapy. The majority (58%) of patients developed AIN within the first 5 cycles. Eight patients developed ≥ Grade 3 AKI, and six developed multiple irAEs. ICI was permanently discontinued in seven patients (58%) and temporarily interrupted in four (30%). The CRc and PRc rates were 67% and 8%, respectively. Upon AIN onset, the best disease response was stable disease in five patients, partial response in three, and progressive disease in three. Median overall survival was 4.87 years, and progression-free survival was 1.5 years. CONCLUSIONS: Rechallenge with IO after kidney irAE may be possible in some patients but requires careful evaluation on an individual basis.

The quasi-CRM shift method for partially ordered groups.

This paper proposes a phase-I clinical trial design that uses ordinal toxicity to locate group-specific doses when groups are partially or completely ordered prior to the start of the trial. There has been previous work on dose-finding for groups and on dose-finding with ordinal toxicity but a solution to the problem of dose-finding for groups with ordinal toxicity has not been proposed. Simulations compared the proposed method against two methods; one that uses ordinal toxicity but does not use group information and one that uses group information but does not use ordinal toxicity. One issue with the first method is the potential for reversals, when the recommended dose for a more sensitive group is higher than the recommended dose for a less sensitive group. The proposed method avoids reversals, allocates patients to optimal doses more frequently during the trial, and selects optimal doses more frequently at the end of the trial.

Improved recognition of lung function decline as signal of cystic fibrosis pulmonary exacerbation: a Cystic Fibrosis Learning Network Innovation Laboratory quality improvement initiative.

INTRODUCTION: Cystic fibrosis (CF) is a systemic autosomal recessive condition characterised by progressive lung disease. CF pulmonary exacerbations (PEx) are episodes of worsening respiratory status, and frequent PEx are a risk factor for accelerated lung function decline, yet many people with CF (PwCF) go untreated at the time of decline. The goal of this quality improvement (QI) initiative was to improve recognition, treatment and follow-up of PEx in PwCF. METHODS: Using the Model for Improvement, the Cystic Fibrosis Learning Network (CFLN) initiated a QI innovation laboratory (iLab) with a global aim to decrease the rate of lung function decline in PwCF. The iLab standardised definitions for signals of PEx using a threshold for decline in forced expiratory volume in one second (FEV1) and/or changes in symptoms. The FEV1 decline signal was termed FIES (FEV1-indicated exacerbation signal). Processes for screening and recognition of FIES and/or symptom changes, a treatment algorithm and follow-up in the presence of a signal were tested concurrently in multiple settings. SPECIFIC AIMS: The specific aim is to increase the per cent of PwCF assessed for a PEx signal at ambulatory encounters and to increase the per cent of recommendations to follow-up within 6 weeks for PwCF experiencing a PEx signal. RESULTS: FIES recognition increased from 18.6% to 73.4% across all teams during the iLab, and every team showed an improvement. Of PwCF assessed, 15.8% experienced an FIES event (>10% decline in FEV1 per cent predicted (FEV1pp)). Follow-up within 6 weeks was recommended for an average of 70.5% of those assessed for FIES and had an FEV1pp decline greater than 5%. CONCLUSION: The CFLN iLab successfully defined and implemented a process to recognise and follow-up PEx signals. This process has the potential to be spread to the larger CF community. Further studies are needed to assess the impact of these processes on PwCF outcomes.

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell death-promoting signaling lipid that plays a central role in therapy-induced cell death. Acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug, LCL-805, across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Phase I Study of Entinostat, Atezolizumab, Carboplatin, and Etoposide in Previously Untreated Extensive-Stage Small Cell Lung Cancer, ETCTN 10399.

BACKGROUND: CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to targeting with HDAC inhibitors. METHODS: Patients with treatment-naïve extensive-stage SCLC, ECOG ≤2 were enrolled and treated with entinostat orally weekly (4 dose levels, DL) in combination with standard dose carboplatin, etoposide, and atezolizumab. Cohort allocation was determined by Bayesian optimal interval (BOIN) design targeting an MTD with a DLT rate of 20%. RESULTS: Three patients were enrolled and treated at DL1 with entinostat 2 mg. Patients were aged 69-83; 2 male, 1 female; 2 were ECOG 1, and 1 was ECOG 0. The most common adverse events (AEs) were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), and hypocalcemia (2). Two experienced DLTs during cycle 1: (1) grade (Gr) 4 febrile neutropenia, and (1) Gr 5 sepsis. BOIN design required stopping accrual to DL1, and the trial was closed to further accrual. Entinostat and atezolizumab pharmacokinetics were both comparable to historical controls. CONCLUSION: Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029).

Hepatotoxicity from high-dose methotrexate in primary central nervous system lymphoma.

Background: High-dose methotrexate (HDMTX) is a mainstay of primary central nervous system lymphoma (PCNSL) treatment. Transient hepatotoxicity from HDMTX has been characterized in pediatric patients but not in adults. We sought to characterize hepatotoxicity in adult PCNSL patients undergoing HDMTX treatment. Methods: Retrospective study of 65 PCNSL patients treated at the University of Virginia from 02/01/2002 to 04/01/2020 was performed. Hepatotoxicity was defined using National Cancer Institute Common Toxicity Criteria (CTC) for adverse events, fifth version. High-grade hepatotoxicity was defined as a bilirubin or aminotransferase CTC grade of 3 or 4. Relationships between clinical factors and hepatotoxicity were assessed with logistic regression. Results: Most patients (90.8%) had a rise of at least one aminotransferase CTC grade during HDMTX treatment. 46.2% had high-grade hepatotoxicity based on aminotransferase CTC grade. No patients developed high-grade bilirubin CTC grades during chemotherapy. Liver enzyme test values decreased to low CTC grade or normal in 93.8% of patients after the conclusion of HDMTX treatment without treatment regimen changes. Prior ALT elevation (P = .0120) was a statistically significant predictor of high-grade hepatotoxicity during treatment. Prior history of hypertension was associated with increased risk of toxic serum methotrexate levels during any cycle (P = .0036). Conclusions: Hepatotoxicity develops in the majority of HDMTX-treated PCNSL patients. Transaminase values decreased to low or normal CTC grades in almost all patients after treatment, without modification of MTX dosage. Prior ALT elevation may predict patients' increased hepatotoxicity risk, and hypertension history may be a risk factor for delayed MTX excretion.

Prognostic significance of extra-nodal extension and positive surgical margins in HPV positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Whether extra-nodal extension (ENE+) and surgical margin positivity (margin+) are poor prognostic factors in HPV-associated (HPV+) oropharyngeal carcinoma (OPC) remains uncertain. RESULTS: Our study evaluated if microscopic ENE+ and/or margin+ are associated poorer recurrence free survival (RFS) and overall survival (OS) in HPV+ OPC. Patients were classified as high risk (ENE+ and/or margin+) or low risk (ENE- and margins-). Of a total of 176 patients HPV+ OPC, 81 underwent primary surgery and dad data on ENE and margin status. There was no statistically significant difference in RFS (p = 0.35) or OS (p = 0.13) for high-risk versus low-risk groups. Ongoing smoking (p = 0.023), alcohol use (p = 0.044) and advanced stage (p = 0.019) were associated with higher risk of recurrence. Only advanced stage (p-value <0.0001) was associated poorer overall survival. CONCLUSIONS: The presence of ENE+ and/or margin+ was not an independent predictor of poor RFS or OS in HPV+ OPC.

A Telemedicine-Delivered Nursing Intervention for Cancer-Related Distress in Rural Survivors.

OBJECTIVES: To evaluate preliminary efficacy, fidelity, and integrity of data collection of a nurse-led, telemedicine-delivered video visit intervention aimed at improving management of rural survivors' cancer-related distress symptoms. SAMPLE & SETTING: 21 rural survivors participated in a nurse-led telemedicine intervention delivered six weeks after the end of active cancer treatment. METHODS & VARIABLES: Participants' symptom management was measured with the Short Form Survivor Unmet Needs Survey, a four-factor, 30-item instrument that measures the unmet needs of adult survivors. Data were collected preintervention and six weeks postintervention. RESULTS: The mean difference between pre- and postintervention survey scores was -0.24, representing an overall improvement in management of unmet needs. The unmet emotional needs domain had the highest mean preintervention score and the largest mean reduction. All effect sizes were small. IMPLICATIONS FOR NURSING: A nurse-led, telemedicine-delivered video visit intervention may improve rural survivors' symptom management during early survivorship. Comparison with a control group using a sample size powered to detect clinically meaningful differences is an important next step to fully evaluate the impact of this model of care.

A Global Collaboration to Develop and Pilot Test a Mobile Application to Improve Cancer Pain Management in Nepal.

Introduction: Quality palliative care, which prioritizes comfort and symptom control, can reduce global suffering from non-communicable diseases, such as cancer. To address this need, the Nepalese Association of Palliative Care (NAPCare) created pain management guidelines (PMG) to support healthcare providers in assessing and treating serious pain. The NAPCare PMG are grounded in World Health Organization best practices but adapted for the cultural and resource context of Nepal. Wider adoption of the NAPCare PMG has been limited due to distribution of the guidelines as paper booklets. Methods: Building on a long-standing partnership between clinicians and researchers in the US and Nepal, the NAPCare PMG mobile application ("app") was collaboratively designed. Healthcare providers in Nepal were recruited to pilot test the app using patient case studies. Then, participants completed a Qualtrics survey to evaluate the app which included the System Usability Scale (SUS) and selected items from the Mobile App Rating Scale (MARS). Descriptive and summary statistics were calculated and compared across institutions and roles. Regression analyses to explore relationships (α = 0.05) between selected demographic variables and SUS and MARS scores were also conducted. Results: Ninety eight healthcare providers (n = 98) pilot tested the NAPCare PMG app. Overall, across institutions and roles, the app received an SUS score of 76.0 (a score > 68 is considered above average) and a MARS score of 4.10 (on a scale of 1 = poor, 5 = excellent). 89.8% (n = 88) "agreed" or "strongly agreed" that the app will help them better manage cancer pain. Age, years of experience, and training in palliative care were significant in predicting SUS scores (p-values, 0.0124, 0.0371, and 0.0189, respectively); institution was significant in predicting MARS scores (p = 0.0030). Conclusion: The NAPCare PMG mobile app was well-received, and participants rated it highly on both the SUS and MARS. Regression analyses suggest end-user variables important to consider in designing and evaluating mobile apps in lower resourced settings. Our app design and pilot testing process illustrate the benefits of cross global collaborations to build research capacity and generate knowledge within the local context.

Outcomes From Cytotoxic Chemotherapy Following Progression on Immunotherapy in Metastatic Melanoma: An Institutional Case-Series.

Introduction: The role of chemotherapy in the management of advanced melanoma is limited due to low response rates and short survival. Improved outcomes to chemotherapy administered after immunotherapy for metastatic melanoma and other solid tumors have been reported. We studied the outcomes of subjects treated at the University of Virginia (UVA) with chemotherapy following progression on prior systemic immunotherapy and compared the results with the existing literature. Materials and Methods: Subjects were identified through an institutional database of patients treated with immunotherapy at UVA. Demographic, pathologic and clinical factors were collected, along with dates of therapy, investigator-assessed best response as per Response Evaluation Criteria for Solid Tumors version 1.1 and dates of death or last follow up. Kaplan-Meier survival estimates and log-rank tests were used to perform time to event analysis of progression free survival and overall survival. Results: Forty-five patients were identified who met the inclusion criteria including 24 men and 21 women with a median age of 61 years. All patients had received at least one line of immunotherapy including 64.4% with prior anti-PD1 treatment. The cytotoxic chemotherapy regimens used included carboplatin with paclitaxel (55.6%), temozolomide (31.1%) and nab-paclitaxel (13.3%). The overall response rate for cytotoxic chemotherapy 22.2% and the disease control rate was 35.6%. The median progression-free survival was 1.7 months and median overall survival was 4.7 months. Nineteen (42.2%) patients survived greater than 6 months and seven (15.5%) patients survived over 12 months. Fourteen patients were able to proceed to further therapy. Discussion: Our results reveal that receipt of immunotherapy prior to chemotherapy for metastatic melanoma does not appear to improve the benefit of chemotherapy. The palliation of symptoms, maintenance of performance status and disease control may be valuable for some patients during this time of robust research and discovery for metastatic melanoma.

Examination of a distress screening intervention for rural cancer survivors reveals low uptake of psychosocial referrals.

PURPOSE: To determine the impact of a telemedicine-delivered intervention aimed at identifying unmet needs and cancer-related distress (CRD) following the end of active treatment on supportive care referral patterns. METHODS: We used a quasi-experimental design to compare supportive care referral patterns between a group of rural cancer survivors receiving the intervention and a control group (N = 60). We evaluated the impact of the intervention on the number and type of referrals offered and whether or not the participant accepted the referral. CRD was measured using a modified version of the National Comprehensive Cancer Network Distress Thermometer and Problem List. RESULTS: Overall, 30% of participants received a referral for further post-treatment supportive care. Supporting the benefits of the intervention, the odds of being offered a referral were 13 times higher for those who received the intervention than those in the control group. However, even among the intervention group, only 28.6% of participants who were offered a referral for further psychosocial care accepted. CONCLUSIONS: A nursing telemedicine visit was successful in identifying areas of high distress and increasing referrals. However, referral uptake was low, particularly for psychosocial support. Distance to care and stigma associated with seeking psychosocial care may be factors. Further study to improve referral uptake is warranted. IMPLICATIONS FOR CANCER SURVIVORS: Screening for CRD may be inadequate for cancer survivors unless patients can be successfully referred to further supportive care. Strategies to improve uptake of psychosocial referrals is of high importance for rural survivors, who are at higher risk of CRD.

Bayesian Design for Identifying Cohort-Specific Optimal Dose Combinations Based on Multiple Endpoints: Application to a Phase I Trial in Non-Small Cell Lung Cancer.

Immunotherapy and chemotherapy combinations have proven to be a safe and efficacious treatment approach in multiple settings. However, it is not clear whether approved doses of chemotherapy developed to achieve a maximum tolerated dose are the ideal dose when combining cytotoxic chemotherapy with immunotherapy to induce immune responses. This trial of a modulated dose chemotherapy and Pembrolizumab, with or without a second immunomodulatory agent, uses a Bayesian design to select the optimal treatment combination by balancing both safety and efficacy of the chemotherapy and immunotherapy agents within each of two cohorts. The simulation study provides evidence that the proposed Bayesian design successfully addresses the primary study aim to identify the optimal dose combination for each of the two independent patient cohorts. This conclusion is supported by the high percentage of simulated trials which select a treatment combination that is both safe and highly efficacious. The proposed trial was funded and was being finalized when the sponsoring company decided not to proceed due to negative findings in another patient population. The proposed trial design will continue to be relevant as multiple chemotherapy and immunotherapy combinations become the standard of care and future research will require evaluating the appropriate doses of various components of multiple drug regimens.

Operating characteristics are needed to properly evaluate the scientific validity of phase I protocols.

PURPOSE: Operating characteristics for proposed clinical trial designs provide insight into performance regarding safety and accuracy, allowing the study team and review entities to determine the design's suitability to achieve the study's proposed objectives. Advances in cancer therapeutics have augmented the needs of early phase clinical trial design. Additionally, advances in research on early-phase trial design have led to the availability of a wide range of methods that show vast improvement over outdated approaches. METHODS: Three trials utilizing variations of the 3 + 3 decision rule are discussed. The protocols lacked detail, including operating characteristics and guidance for decision-making that deviated from the 3 + 3 decision rule and MTD determination. We provide a discussion of the statistical issues associated with each design and operating characteristics for the proposed design compared to alternatives better suited to achieve the aims of each trial. RESULTS: Our results illustrate how operating characteristics inform a design's safety and accuracy. Operating characteristics can unmask poor behavior, such as a high percentage of particiapnts exposed to overly toxic doses, a low probability of correctly identifying the MTD, and inappropriate early study termination. CONCLUSION: Selection of early-phase trial design has significant implications on a trial's ability to meet its objectives. Operating characteristics are a necessary component in the design and review of a protocol, determining if the study's objectives can be achieved and documenting the study's scientific validity. Continued use of outdated approaches due to historical acceptance hinders scientific rigor and the effort to move effective agents through the drug development process.

"Moving Away From Cancer" Prospective Exercise Trial for Female Rural Cancer Survivors: How Can We Step It Up?

PURPOSE: This prospective trial's objective was to determine feasibility and outcomes of an exercise-based intervention for rural overweight/obese female cancer survivors. MATERIALS AND METHODS: Survivors of endometrial, breast, or ovarian cancer enrolled in a 6-month program of increased aerobic activity (30 minutes daily walking) and strength-training exercises using exercise bands (THERABAND; Akron, OH) with personalized telephone motivational coaching. Baseline demographics, anthropomorphic measurements, quality of life (QOL), fitness, and readiness to adopt exercise changes were assessed; daily steps, band use, and follow-up measurements were assessed at 3 and 6 months. Study completion was modeled using logistic regression. RESULTS: The mean age of the 99 women was 59.9 years, the mean body mass index (BMI) was 35.9 kg/m2, 88.9% were white, and 41.4% reported current exercise. Fifty-five women (55.6%) completed the 6-month program, and 36 (36.4%) completed exercise interventions. Using logistic regression to model study completion, only baseline QOL scores (physical component summary) and mental component summary) remained significant predictors. The mean weight change was a gain (0.88 kg). Higher MCS baseline scores and prior regular exercise predicted continued exercise and increased step counts, whereas higher BMI and baseline sleep predicted decreased QOL. Top walking barriers were feeling unwell and weather; barriers to strength exercises were band dislike and pain. CONCLUSION: The most significant predictor of trial completion and improved exercise outcomes was a higher baseline mental QOL. Motivation, belief in the importance of exercise, and prescribed/monitored exercise regimens were not sufficient; supportive and cognitive behavioral therapy interventions for survivors are needed to sustain uptake.

Optimizing Telemedicine Technologic Infrastructure with Animal Models: A Case in Telecystoscopy.

Background: Rapid evolution of telemedicine technology requires procedures in telemedicine to adapt frequently. An example in urology, telecystoscopy, allows certified advanced practice providers to perform cystoscopy, endoscopic examination of the bladder, in rural areas with real-time interpretation and guidance by an off-site urologist. We have previously shown the technological infrastructure for optimized video quality. Introduction: Newer models of cystoscope and coder/decoder (codec) are available with anticipation that components used in our original model will become unavailable. Our objective is to assess the diagnostic ability of two cystoscopes (Storz, Wolf) with old (SX20) and new (DX70) codecs. Materials and Methods: A single urologist performed flexible cystoscopy on an ex vivo porcine bladder. Combinations of cystoscope (Storz vs. Wolf), codec (SX20 vs. DX70), and internet transmission speed were used to create eight distinct recordings. Deidentified videos were reviewed by expert urologist reviewers via electronic survey with questions on video quality and diagnostic ability. A logistic regression model was used to assess the ability to make a diagnosis. Results: Eight transmitted cystoscopy videos were reviewed by 16 urologists. Despite new technology, the Storz cystoscope combined with the SX20 codec (the original combination) provides the best diagnostic capacity. Discussion: Technical infrastructure must be routinely validated to assess the component impact on overall quality because newer is not always better. Should the SX20 become obsolete, ex vivo animal models are safe, inexpensive anatomic models for testing. Conclusions: As technology continues to evolve, procedures in telemedicine must critically scrutinize the impact of new technologic components to uphold quality.

Blinded Comparison of Clarity, Proficiency and Diagnostic Capability of Tele-Cystoscopy Compared to Traditional Cystoscopy: A Pilot Study.

PURPOSE: In order to expand the availability of cystoscopy to underserved areas we have proposed using advanced practice providers to perform cystoscopy with real-time interpretation by the urologist on a telemedicine platform, termed "tele-cystoscopy." The purpose of this study is to have blinded external reviewers retrospectively compare multisite, prospectively collected video data from tele-cystoscopy with the video of traditional cystoscopy in terms of video clarity, practitioner proficiency and diagnostic capability. MATERIALS AND METHODS: Each patient underwent tele-cystoscopy by a trained advanced practice provider and traditional cystoscopy with an onsite urologist. Prospectively collected tele-cystoscopy transmitted video, tele-cystoscopy onsite video and traditional cystoscopy video were de-identified and blinded to external reviewers. Each video was evaluated and rated twice by independent reviewers and diagnostic agreement was quantified. RESULTS: Six tele-cystoscopy encounters were reviewed for a total of 36 assessments. Video clarity, defined by speed of transmission and image resolution, was better for onsite compared to transmitted tele-cystoscopy. Practitioner proficiency for thoroughness of inspection was rated at 92% for tele-cystoscopy and 100% for traditional cystoscopy. Confidence in identification of an abnormality was equivalent. Four of 6 videos had 100% agreement between reviewers for next action taken, indicating high diagnostic agreement. Additionally, provider performing cystoscopy and location did not statistically influence the ability to make a diagnosis or action taken. CONCLUSIONS: This model has excellent completeness of examination, equivalent ability to identify abnormalities and external validation of action taken. This pilot study demonstrates that tele-cystoscopy may expand access to bladder cancer surveillance.

Consequences of Performing Parallel Dose Finding Trials in Heterogeneous Groups of Patients.

Patient heterogeneity, in which patients can be grouped by risk of toxicity, is a design challenge in early phase dose finding trials. Carrying out independent trials for each group is a readily available approach for dose finding. However, this often leads to dose recommendations that violate the known order of toxicity risk by group, or reversals in dose recommendation. In this manuscript, trials for partially ordered groups are simulated using four approaches: independent parallel trials using the continual reassessment method (CRM), Bayesian optimal interval design, and 3 + 3 methods, as well as CRM for partially ordered groups. Multiple group order structures are considered, allowing for varying amounts of group frailty order information. These simulations find that parallel trials in the presence of partially ordered groups display a high frequency of trials resulting in reversals. Reversals occur when dose recommendations do not follow known order of toxicity risk by group, such as recommending a higher dose level in a group of patients known to have a higher risk of toxicity. CRM for partially ordered groups eliminates the issue of reversals, and simulation results indicate improved frequency of maximum tolerated dose selection as well as treating a greater proportion of trial patients at this dose compared with parallel trials. When information is available on differences in toxicity risk by patient subgroup, methods designed to account for known group ordering should be considered to avoid reversals in dose recommendations and improve operating characteristics.

Shift models for dose-finding in partially ordered groups.

BACKGROUND: Limited options are available for dose-finding clinical trials requiring group-specific dose selection. While conducting parallel trials for groups is an accessible approach to group-specific dose selection, this approach allows for maximum tolerated dose selection that does not align with clinically meaningful group order information. METHODS: The two-stage continual reassessment method is developed for dose-finding in studies involving three or more groups where group frailty order is known between some but not all groups, creating a partial order. This is an extension of the existing continual reassessment method shift model for two ordered groups. This method allows for dose selection by group, where maximum tolerated dose selection follows the known frailty order among groups. For example, if a group is known to be the most frail, the recommended maximum tolerated dose for this group should not exceed the maximum tolerated dose recommended for any other group. RESULTS: With limited alternatives for dose-finding in partially ordered groups, this method is compared to two alternatives: (1) an existing method for dose-finding in partially ordered groups which is less computationally accessible and (2) independent trials for each group using the two-stage continual reassessment method. Simulation studies show that when ignoring information on group frailty, using independent continual reassessment method trials by group, 30% of simulations would result in maximum tolerated dose selection that is out of order between groups. In addition, the two-stage continual reassessment method for partially ordered groups selects the maximum tolerated dose more often and assigns more patients to the maximum tolerated dose compared to using independent continual reassessment method trials within each group. Simulation results for the proposed method and the less computationally accessible approach are similar. CONCLUSION: The proposed continual reassessment method for partially ordered groups ensures appropriate maximum tolerated dose order and improves accuracy of maximum tolerated dose selection, while allowing for trial implementation that is computationally accessible.

Risk of Major Bleeding with Ibrutinib.

BACKGROUND: The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B-cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater. MATERIALS AND METHODS: A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications. RESULTS: We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4-18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7-33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P < .01). CONCLUSION: The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.