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Background: The response rates to immune checkpoint inhibitors (ICI) remain low (13-20%) in metastatic head and neck cancer patients and better understanding of factors predictive of response to these agents is urgently needed. Here we explore the impact of smoking status, marijuana use and alcohol on treatment outcomes in recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with ICI. Methods: We performed a retrospective analysis of 201 R/M HNSCC patients treated with ICI between January 15th 2016 and April 9th 2020 at a single institution. Results: Gender: 154 male (77%), 47 female (23%). Median age 61 (IQR: 55-68). ICI drug: pembrolizumab 100 (50%), nivolumab 91 (45%), nivolumab+ipilimumab 10 (5%). Line of therapy: first: 98 (49%), second and beyond: 103 (51%). Tumor site: oropharynx 84 (42%), oral cavity 45 (22%), larynx 26 (13%), other sites 46 (23%). p16 tumor status: negative 132 (66%), positive 69 (34%). Smoking status: former 111 (55%), never 54 (27%), current 36 (18%), median pack-year 18 (IQR: 0-37). Alcohol use: yes 110 (55%), no 91 (54%). Marijuana use: yes 47 (23%), no 154 (77%). Overall response rate: 36 (18%). Median OS: 12 months (95% CI: 9.4-14.8). Tobacco: former (HR: 0.75, 95% CI: 0.50, 1.11), current (HR: 0.58, 95% CI: 0.33, 1.02). Marijuana: yes (HR: 0.93, 95% CI: 0.58, 1.49). Alcohol: yes (HR: 1.04, 95% CI: 0.72, 1.49). Conclusion: In our cohort, smoking status, marijuana use and alcohol consumption did not have a statistically significant impact on OS in patients with R/M HNSCC treated with ICI. Trial registration: retrospectively registered.

Latent trait space can be leveraged to harmonize small data into big data when the constituent datasets measure the same underlying (latent) domains using a set of partially overlapping measurement instruments in each domain. The latent trait space then acts as a common metric space for each dataset, thus ensuring the same scale for the latent traits across datasets, despite the use of non-identical sets of measurement instruments within datasets. This approach, as originally published, only applied to a narrow set of circumstances, namely, that each measurement instrument occurred in more than one dataset. Here, we extend the latent trait approach to drop this requirement by using matrix completion methods. Using a simulation study, we evaluate the reliability of this extension and offer guidance on circumstances when the latent trait approach to missing data is robust and practical on real datasets.

The standard treatment for patients with large brain metastases and limited intracranial disease is surgical resection and post-operative stereotactic radiosurgery (SRS). However, post-operative SRS still has elevated rates of local failure (LF) and is complicated by radiation necrosis (RN), and meningeal disease (MD). Pre-operative SRS may reduce the risk of RN and MD, while fractionated therapy may improve local control through delivering a higher biological effective dose. We hypothesize that pre-operative fractionated stereotactic radiation therapy (FSRT) will have less toxicity compared to patients who receive post-operative SRS or FSRT.A multi-institutional analysis was conducted and included patients who had surgical resection and stereotactic radiation therapy to treat at least one brain metastasis. Pertinent demographic, clinical, radiation, surgical, and follow up data were collected for each patient. The primary outcome was a composite endpoint defined as patients with one of the following adverse events: 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN.279 patients were eligible for analysis. The median follow-up time was 9 months. 87 % of patients received fractionated treatment. 29 % of patients received pre-operative treatment. The composite endpoint incidences for post-operative SRS (n = 10), post-operative FSRT (n = 189), pre-operative SRS (n = 27), and pre-operative FSRT (n = 53) were 0 %, 17 %, 15 %, and 7.5 %, respectively.In our study, the composite endpoint of 7.5% for pre-operative FSRT compares favorably to our post-operative FSRT rate of 17%. Pre-operative FSRT was observed to have low rates of LF, MD, and RN. Prospective validation is needed.

Background Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. Methods A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. Results 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. Conclusions Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.

Fluid overload leads to poor neonatal outcomes. Diuretics may lower the rates of mechanical ventilation (MV) and mortality in neonates with fluid overload.This is a retrospective study of preterm neonates ≤ 36 weeks of gestational age (GA) in the first 14 postnatal days in a level IV NICU in 2014-2020. We evaluated the epidemiology of fluid balance in the first 14 postnatal days and its association with MV and mortality and studied the association of diuretics with fluid balance, MV, and mortality.In 1383 included neonates, the overall median lowest and peak fluid balances were - 7.8% (IQR: - 11.7, - 4.6) and 8% (3, 16) on days 3 (2, 5) and 13 (5, 14), respectively. Fluid balance distribution varied significantly by GA. Peak fluid balance of ≥ 10% was associated with increased odds of MV on days 7 and 14 with highest odds ratios (OR) of MV in neonates with fluid balance ≥ 15%. Peak fluid balance of ≥ 15% was associated with the greatest odds of mortality. Diuretics were used more frequently in neonates with younger GA, smaller birthweight, positive fluid balance, and those on MV.Positive fluid balance negatively impacts pulmonary status. The odds of MV and death increase significantly as peak fluid balance percentage increases in all GA groups. The impact of diuretics on MV and death in preterm neonates needs further evaluation. A higher resolution version of the Graphical abstract is available as Supplementary information.

ImportanceLong-term outcomes of radiotherapy are important in understanding the risks and benefits of therapies for patients with brain metastases.ObjectiveTo determine how the use of postoperative whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) is associated with quality of life (QOL), cognitive function, and intracranial tumor control in long-term survivors with 1 to 4 brain metastases.Design, Setting, and ParticipantsThis secondary analysis of a randomized phase 3 clinical trial included 48 institutions in the US and Canada. Adult patients with 1 resected brain metastases but limited to those with 1 to 4 brain metastasis were eligible. Unresected metastases were treated with SRS. Long-term survivors were defined as evaluable patients who lived longer than 1 year from randomization. Patients were recruited between July 2011 and December 2015, and data were first analyzed in February 2017. For the present study, intracranial tumor control, cognitive deterioration, QOL, and cognitive outcomes were measured in evaluable patients who were alive at 12 months from randomization and reanalyzed in June 2017.InterventionsStereotactic radiosurgery or WBRT.Main Outcomes and MeasuresIntracranial tumor control, toxic effects, cognitive deterioration, and QOL.ResultsFifty-four patients (27 SRS arm, 27 WBRT arm; female to male ratio, 65% vs 35%) were included for analysis with a median follow-up of 23.8 months. Cognitive deterioration was less frequent with SRS (37%-60%) compared with WBRT (75%-91%) at all time points. More patients declined by 2 or more standard deviations (SDs) in 1 or more cognitive tests for WBRT compared with SRS at 3, 6, and 9 months (70% vs 22%, 46% vs 19%, and 50% vs 20%, respectively). A 2 SD decline in at least 2 cognitive tests was associated with worse 12-month QOL in emotional well-being, functional well-being, general, additional concerns, and total scores. Overall QOL and functional independence favored SRS alone for categorical change at all time points. Total intracranial control for SRS alone vs WBRT at 12 months was 40.7% vs 81.5% (difference, −40.7; 95% CI, −68.1% to −13.4%), respectively. Data were first analyzed in February 2017.Conclusions and RelevanceThe use of SRS alone compared with WBRT resulted in less cognitive deterioration among long-term survivors. The association of late cognitive deterioration with WBRT was clinically meaningful. A significant decline in cognition (2 SD) was associated with overall QOL. However, intracranial tumor control was improved with WBRT. This study provides detailed insight into cognitive function over time in this patient population.Trial RegistrationClinicalTrials.gov Identifier: NCT01372774; ALLIANCE/CCTG: N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group)

Summary Introduction Gomco clamp and Plastibell ring are common methods of office circumcision. While they possess similar features, the Plastibell is retained after the procedure which could impact perceived and true outcomes of the procedure. Objective This study evaluated differences in complications, interventions, and healthcare utilization between Gomco and Plastibell office circumcision techniques. Study design We retrospectively reviewed urology office performed circumcisions (January 2015–August 2018), limiting analysis to patients with follow-up. Patient demographics and circumcision technique were recorded. Complications, interventions, phone calls, emergency department (ED)/urgent care (UC) visits, and unplanned office visits directly related to the circumcision were recorded. Descriptive statistics for the number of patients experiencing an event and the number of days to event were summarized. Survival analysis with inverse probability of treatment weights was used to estimate hazard and incidence rate ratios (HR and IRR, respectively). Results 746 patients were included for analysis. Median time of follow-up was 2.7 weeks (interquartile range 2–5). 257 (34%) patients underwent Gomco circumcision; 489 (66%) underwent Plastibell circumcision. The techniques did not significantly differ for complications (HR = 0.9, p = 0.497), interventions (HR = 0.89, p = 0.498), and hospital visits (HR = 1.0, p = 0.985) (Table), although Plastibell patients presented to the ED/UC more (odds ratio = 1.6, p = 0.02). Plastibell patients generated proportionally more post-procedural phone calls (63 vs. 52%), though not significantly (IRR = 1.11; p = 0.426). Discussion Overall, the type of device used for office circumcision, between Gomco clamp and Plastibell ring, does not appear to impact the outcome of circumcision. Providers should perform the method of office circumcision with which they are familiar and comfortable. There is an overall reliance on healthcare resources suggesting poor family preparation of the post-procedural course regardless of the technique, necessitating better patient education. Limitations of this study include its retrospective nature, variability in follow-up between techniques, and variety of providers, limited to pediatric urologists, performing circumcision. Conclusions Gomco and Plastibell office circumcision techniques do not significantly differ in post-procedural complications, interventions, unplanned hospital visits, and office phone calls. Plastibell patients do present more often to the ED/UC perhaps as a result of increased anxiety and perceived immediacy of concerns with the device. Table . Recurrent event Cox proportional hazard survival model results for complications, interventions, and unplanned hospital visits Event Predictor Level Hazard Ratio Lower CI Upper CI p-value Complication Technique Gomco Reference Plastibell 0.9 0.67 1.21 0.497 Intervention Technique Gomco Reference Plastibell 0.89 0.64 1.24 0.498 Unplanned hospital visit Technique Gomco Reference Plastibell 1.0 0.66 1.53 0.985

Informatics researchers often need to combine data from many different sources to increase statistical power and study subtle or complicated effects. Perfect overlap of measurements across academic studies is rare since virtually every dataset is collected for a unique purpose and without coordination across parties not-at-hand (i.e., informatics researchers in the future). Thus, incomplete concordance of measurements across datasets poses a major challenge for researchers seeking to combine public databases. In any given field, some measurements are fairly standard, but every organization collecting data makes unique decisions on instruments, protocols, and methods of processing the data. This typically denies literal concatenation of the raw data since constituent cohorts do not have the same measurements (i.e., columns of data). When measurements across datasets are similar prima facie, there is a desire to combine the data to increase power, but mixing non-identical measurements could greatly reduce the sensitivity of the downstream analysis. Here, we discuss a statistical method that is applicable when certain patterns of missing data are found, namely, it is possible to combine datasets that measure the same underlying constructs (or latent traits) when there is only partial overlap of measurements across the constituent datasets. Our method, ROSETTA empirically derives a set of common latent trait metrics for each related measurement domain using a novel variation of factor analysis to ensure equivalence across the constituent datasets. The advantage of combining datasets this way is the simplicity, statistical power, and modeling flexibility of a single joint analysis of all the data. Three simulation studies show the performance of ROSETTA on datasets with only partially overlapping measurements (i.e., systematically missing information), benchmarked to a condition of perfectly overlapped data (i.e., full information). The first study examined a range of correlations, while the second study was modeled after the observed correlations in a well-characterized clinical, behavioral cohort. Both studies consistently show significant correlations &gt, 0.94, often &gt, 0.96, indicating the robustness of the method and validating the general approach. The third study varied within and between domain correlations and compared ROSETTA to multiple imputation and meta-analysis as two commonly used methods that ostensibly solve the same data integration problem. We provide one alternative to meta-analysis and multiple imputation by developing a method that statistically equates similar but distinct manifest metrics into a set of empirically derived metrics that can be used for analysis across all datasets.