Correct use of statistical methods is important to ensure the reliability and value of the published experimental pathology literature. Considering increasing interest in the quality of statistical reporting in pathology, the statistical methods used in 10 recent issues of the American Journal of Pathology were reviewed. The statistical tests performed in the articles were summarized, with attention to their implications for contemporary pathology research and practice. Among the 195 articles identified, 93% reported using one or more statistical tests. Retrospective statistical review of the articles revealed several key findings. First, tests for normality were infrequently reported, and parametric hypothesis tests were overutilized. Second, studies reporting multisample hypothesis tests (eg, analysis of variance) infrequently performed post hoc tests to explore differences between study groups. Third, correlation, regression, and survival analysis techniques were underutilized. On the basis of these findings, a primer on relevant statistical concepts and tests is presented, including issues related to optimal study design, descriptive and comparative statistics, and regression, correlation, survival, and genetic data analysis.

A subset of glioblastomas (GBMs) harbors potentially druggable oncogenic FGFR3-TACC3 (F3T3) fusions. However, their associated molecular and clinical features are poorly understood. Here we analyze the frequency of F3T3-fusion positivity, its associated genetic and methylation profiles, and its impact on survival in 906 IDH-wildtype GBM patients. We establish an F3T3 prevalence of 4.1% and delineate its associations with cancer signaling pathway alterations. F3T3-positive GBMs had lower tumor mutational and copy-number alteration burdens than F3T3-wildtype GBMs. Although F3T3 fusions were predominantly mutually exclusive with other oncogenic RTK pathway alterations, they did rarely co-occur with EGFR amplification. They were less likely to harbor TP53 alterations. By methylation profiling, they were more likely to be assigned the mesenchymal or RTK II subclass. Despite being older at diagnosis and having similar frequencies of MGMT promoter hypermethylation, patients with F3T3-positive GBMs lived about 8 months longer than those with F3T3-wildtype tumors. While consistent with IDH-wildtype GBM, F3T3-positive GBMs exhibit distinct biological features, underscoring the importance of pursuing molecular studies prior to clinical trial enrollment and targeted treatment.

OBJECTIVE: To report the mutational profile and clinical outcomes of a cohort of patients with KIT-mutant seminomas and nonseminomatous germ-cell tumors (SGCT/NSGCTs). PATIENTS AND METHODS: Retrospective cohort study of all patients with KIT-mutant GCTs sequenced at Memorial Sloan Kettering between March 2014 and March 2020. Tumors were assessed with MSK-IMPACT, a DNA next-generation sequencing assay for targeted sequencing of up to 468 key cancer genes. RESULTS: Among 568 patients with GCTs, 8.1% had somatic KIT mutations, including 28 seminomas and 18 mixed/NSGCTs. Exons 17 (67.3%), 11 (22.4%), and 13 (6.1%) were most commonly affected. KIT-mutant cases were enriched for oncogenic RAS/MAPK pathway alterations compared to KIT-wildtype cases (34.8% vs 19.2%, P = .02). Among KIT-mutant cases, concurrent mutations were noted in KRAS (21.7%), RRAS2 (11.8%), CBL (6.5%), NRAS (4.3%), MAP2K1 (2.2%), and RAC1 (2.2%). Mutations in KRAS, RRAS2, and NRAS were mutually exclusive. In all, 73.9% of patients developed metastases and 95.7% received chemotherapy. No patients received KIT-directed tyrosine kinase inhibitors (TKIs). Classification as a NSGCT rather than a SGCT was associated with an increased risk of death (hazard ratio 9.1, 95% confidence interval 1.1-78.4, P = .04) while the presence of a concurrent RAS/MAPK pathway alteration was not (hazard ratio 0.8, 95% confidence interval 0.1-4.3, P = .76). CONCLUSION: Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of KIT-directed TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy.

The grading and prognosis of prostatic adenocarcinoma with Paneth cell-like differentiation (PanEC) is controversial with limited available data. We identified 80 cases, not previously published, of PanEC first identified on biopsy (n = 69), transurethral resection of the prostate (n = 1), and radical prostatectomy (RP) (n = 10). Of 69 biopsies, 22 did not have a grade assigned. In the remaining 47 biopsies, the Grade Groups (GGs) of the associated usual prostatic adenocarcinoma were GG1-2 (n = 34) and GG3-5 (n = 13). Of 10 RPs, the GGs were as follows: GG1-2 (n = 8), GG4 (n = 1), and no grade due to treatment effect (n = 1); pathological stages were pT2 (n = 8) and pT3a (n = 2), all with negative lymph nodes. We analyzed 19 cases with available follow-up only associated with GG1-2 conventional cancer; 9 underwent RP, and GGs at RP were as follows: GG1-2 (n = 7), no grade due to treatment effect (n = 1), and missing data (n = 1); pathologic stages were pT2 (n = 6) and pT3a (n = 3); there were no positive regional lymph nodes; 3 were managed with active surveillance, without follow-up progression; 5 patients underwent radiation therapy with or without hormone therapy; none showed follow-up progression; 2 (10.5%) patients were recommended to undergo radiotherapy, with no further follow-up. Of the cases with available follow-up, 9 were not associated with conventional adenocarcinoma; the majority of these cases were treated with radiation therapy or active surveillance without evidence of progression. In summary, although a minority of PanECs are associated with conventional higher grade adenocarcinoma and have progression after treatment, the majority have favorable findings, justifying the consideration of them as more indolent tumors despite cases in which PanEC resembles Gleason pattern 5 adenocarcinoma.

INTRODUCTION: For patients with advanced NSCLC, cytologic samples may be the only diagnostic specimen available for molecular profiling. Although both rapid and comprehensive assessment are essential in this setting, an integrated multitest approach remains an important strategy in many laboratories, despite the risks and challenges when working with scant samples. In this study, we describe our experience and high success rate in using a multitest approach, focusing on the clinical validation and incorporation of ultrarapid EGFR testing using the Idylla system followed by comprehensive next-generation sequencing (NGS). METHODS: Cytology samples received for routine molecular testing were included in this study. The performance characteristics of the EGFR Idylla assay were assessed; tissue suitability parameters and interpretation criteria to supplement automated mutation calling were established. The assay performance was monitored for 1 year, comparing the results with those of concurrent NGS testing by MSK-IMPACT (primarily) or MSK-AmpliSeq and MSK-Fusion solid panel in a subset of cases. RESULTS: Overall, 301 samples were studied; 83 samples were included in validation (60.2% [50 of 83] were positive for EGFR mutations). Concordance with the reference method was 96.4% (80 of 83) of the samples with excellent reproducibility. The limit of detection was variable depending on the total tissue input and the specific mutation tested. Unextracted tissue inputs that maintained total EGFR cycle of quantification at less than 23 allowed all mutations to be detected if present at greater than 5% variant allele frequency. Mutations could be detected at 1% variant allele frequency with total EGFR cycle of quantification of 18. During the clinical implementation phase, 218 NSCLC samples were tested by Idylla (24.3% [53 of 218] were EGFR mutation positive). Concurrent NGS testing was requested on 165 samples and successfully performed on 96.4% (159 of 165) of the samples. The Idylla automated results were concordant with those obtained by NGS in 96.2% (153 of 159) of cases and improved to 98.7% (157 of 159) after incorporation of manual review criteria to supplement automated calling, resulting in a diagnostic sensitivity of 95.6% (95% confidence interval: 84.9%-99.5%). In general, 9% (14 of 159) of the cases tested by NGS had EGFR mutations not covered by the Idylla assay, primarily insertions in exon 19 and 20 and minor mutations cooccurring with canonical sensitizing mutations. CONCLUSIONS: Comprehensive molecular testing is feasible and has a high success rate in NSCLC cytology samples when using a multitest approach. Testing with the Idylla system enables rapid and accurate determination of the EGFR status without compromising subsequent NGS testing.

Implementation of Grade Groups (GrGrs) has been widely accepted for reporting prostate cancer grade since the 2014 International Society of Urological Pathology consensus meeting. Despite their undisputed value for risk stratification, some GrGr are, a priori, quite heterogeneous in that they contain multiple Gleason patterns (GPs). In this regard, the prognostic significance of GP5 in biopsies with highest GrGr4 is uncertain and evaluated in this study. A search of all core biopsies positive for prostate cancer reviewed after 2005 was performed, and 71 cases with highest GrGr4 containing GP5 (i.e., 3 + 5 = 8 or 5 + 3 = 8; referred to as GrGr4/GP5pos) eligible for inclusion were identified. In addition, 95 core biopsy cases with highest GrGr4 and no GP5 (i.e, 4 + 4 = 8; referred to as GrGr4/GP5neg) were selected for comparison. Multiple pathologic parameters, including volume and amount of GP4, and clinical variables were collected to evaluate the influence of GP5 on disease recurrence, development of metastases, and disease-specific death. GrGr4/GP5pos cases did not show, as a group, statistically significant differences in prostatectomy findings, disease recurrence, metastases, and disease-specific mortality when compared with GrGr4/GP5neg cases. In addition, the risk of all outcomes evaluated in the study did not differ between the whole GrGr4/GP5pos and GrGr4/GP5neg groups. However, Kaplan-Meier analysis found that GrGr4/GP5pos cases with a significant amount of GP4 did show a higher risk of prostate cancer-specific death as well as bone and visceral metastases. Univariate Cox regression demonstrated that preoperative prostate specific antigen (PSA), total number of positive cores, and global GrGr5 were also associated with a higher chance of disease-specific death. In a multivariate model, only global GrGr5 and PSA >20 ng/dL remained statistically significant. This study suggests that the mere presence of GP5 in core biopsies with highest GrGr4 disease may not portend a worse prognosis. In these cases, accounting for the case-wide volume of GP4 by reporting a global GrGr appears to be more relevant as it identifies a subset of GrGr4/GP5pos patients with global GrGr5 who have a higher risk of metastases and prostate cancer-specific mortality.

Importance: Depression is highly prevalent among physicians and has been associated with increased risk of medical errors. However, questions regarding the magnitude and temporal direction of these associations remain open in recent literature. Objective: To provide summary relative risk (RR) estimates for the associations between physician depressive symptoms and medical errors. Data Sources: A systematic search of Embase, ERIC, PubMed, PsycINFO, Scopus, and Web of Science was performed from database inception to December 31, 2018. Study Selection: Peer-reviewed empirical studies that reported on a valid measure of physician depressive symptoms associated with perceived or observed medical errors were included. No language restrictions were applied. Data Extraction and Synthesis: Study characteristics and RR estimates were extracted from each article. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using subgroup meta-analysis and metaregression. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was followed. Main Outcomes and Measures: Relative risk estimates for the associations between physician depressive symptoms and medical errors. Results: In total, 11 studies involving 21 517 physicians were included. Data were extracted from 7 longitudinal studies (64%; with 5595 individuals) and 4 cross-sectional studies (36%; with 15 922 individuals). The overall RR for medical errors among physicians with a positive screening for depression was 1.95 (95% CI, 1.63-2.33), with high heterogeneity across the studies (χ2 = 49.91; P < .001; I2 = 82%; τ2 = 0.06). Among the variables assessed, study design explained the most heterogeneity across studies, with lower RR estimates associated with medical errors in longitudinal studies (RR, 1.62; 95% CI, 1.43-1.84; χ2 = 5.77; P = .33; I2 = 13%; τ2 < 0.01) and higher RR estimates in cross-sectional studies (RR, 2.51; 95% CI, 2.20-2.83; χ2 = 5.44; P = .14; I2 = 45%; τ2 < 0.01). Similar to the results for the meta-analysis of physician depressive symptoms associated with subsequent medical errors, the meta-analysis of 4 longitudinal studies (involving 4462 individuals) found that medical errors associated with subsequent depressive symptoms had a pooled RR of 1.67 (95% CI, 1.48-1.87; χ2 = 1.85; P = .60; I2 = 0%; τ2 = 0), suggesting that the association between physician depressive symptoms and medical errors is bidirectional. Conclusions and Relevance: Results of this study suggest that physicians with a positive screening for depressive symptoms are at higher risk for medical errors. Further research is needed to evaluate whether interventions to reduce physician depressive symptoms could play a role in mitigating medical errors and thus improving physician well-being and patient care.

BACKGROUND: Stress is a key precipitant for many common diseases, but established biological markers to track stress and guide investigations into mechanisms linking stress and disease are lacking. Cross-sectional studies have identified correlations between stress and telomere attrition, but no large, longitudinal studies examining the impacts of chronic stress on telomere length exist. Residency training for physicians is a well-established stressful experience and can be used as a prospective stress model. METHODS: In a longitudinal cohort study of 250 interns (first-year residents) at 55 United States hospital systems serving during the 2015-2016 academic year, we examined associations between measures of the residency experience and saliva-measured telomere attrition. RESULTS: Telomere length shortened significantly over the course of internship year, from mean ± SD of 6465.1 ± 876.8 base pairs before internship to 6321.5 ± 630.6 base pairs at the end of internship (t = 2.69; p = .008). Stressful early family environments and neuroticism were significantly associated with shorter preinternship telomere length. Longer work hours were associated with greater telomere intern telomere loss over the year (p = .002). Of note, the mean telomere attrition during internship year was six times greater than the typical annual attrition rate identified in a recent meta-analysis. CONCLUSIONS: This work implicates telomere attrition as a biologically measurable consequence of physician training, with the magnitude of attrition associated with workload. Identification of an objective, biological sequela of residency stress may help to facilitate the development of effective interventions. Further, the findings implicate telomere attrition as an objective biomarker to follow the pathologic effects of stress, in general.

Objectives: To develop a curriculum for a commercial reference laboratory clinical pathology training elective. Methods: A 4-day elective at Quest Diagnostics was developed. The elective included 32 sessions composed of interactive didactic sessions and laboratory tours/demonstrations. Ten residents who attended the elective completed a written evaluation and scored each component of the curriculum. Results: Written comments were very positive and demonstrated the goals of the elective were achieved. Laboratory tours and one-on-one sessions with the medical directors were especially well received. Most of the residents stated that the rotation gave them exposure to an area of laboratory medicine that they were not familiar with. Conclusions: The elective provided a resident training experience that was highly regarded and exposed residents to an area of laboratory medicine not encountered in most pathology training programs. Our curriculum could serve as a model for establishing a similar elective in other training programs.

Importance: Burnout is a self-reported job-related syndrome increasingly recognized as a critical factor affecting physicians and their patients. An accurate estimate of burnout prevalence among physicians would have important health policy implications, but the overall prevalence is unknown. Objective: To characterize the methods used to assess burnout and provide an estimate of the prevalence of physician burnout. Data Sources and Study Selection: Systematic search of EMBASE, ERIC, MEDLINE/PubMed, psycARTICLES, and psycINFO for studies on the prevalence of burnout in practicing physicians (ie, excluding physicians in training) published before June 1, 2018. Data Extraction and Synthesis: Burnout prevalence and study characteristics were extracted independently by 3 investigators. Although meta-analytic pooling was planned, variation in study designs and burnout ascertainment methods, as well as statistical heterogeneity, made quantitative pooling inappropriate. Therefore, studies were summarized descriptively and assessed qualitatively. Main Outcomes and Measures: Point or period prevalence of burnout assessed by questionnaire. Results: Burnout prevalence data were extracted from 182 studies involving 109 628 individuals in 45 countries published between 1991 and 2018. In all, 85.7% (156/182) of studies used a version of the Maslach Burnout Inventory (MBI) to assess burnout. Studies variably reported prevalence estimates of overall burnout or burnout subcomponents: 67.0% (122/182) on overall burnout, 72.0% (131/182) on emotional exhaustion, 68.1% (124/182) on depersonalization, and 63.2% (115/182) on low personal accomplishment. Studies used at least 142 unique definitions for meeting overall burnout or burnout subscale criteria, indicating substantial disagreement in the literature on what constituted burnout. Studies variably defined burnout based on predefined cutoff scores or sample quantiles and used markedly different cutoff definitions. Among studies using instruments based on the MBI, there were at least 47 distinct definitions of overall burnout prevalence and 29, 26, and 26 definitions of emotional exhaustion, depersonalization, and low personal accomplishment prevalence, respectively. Overall burnout prevalence ranged from 0% to 80.5%. Emotional exhaustion, depersonalization, and low personal accomplishment prevalence ranged from 0% to 86.2%, 0% to 89.9%, and 0% to 87.1%, respectively. Because of inconsistencies in definitions of and assessment methods for burnout across studies, associations between burnout and sex, age, geography, time, specialty, and depressive symptoms could not be reliably determined. Conclusions and Relevance: In this systematic review, there was substantial variability in prevalence estimates of burnout among practicing physicians and marked variation in burnout definitions, assessment methods, and study quality. These findings preclude definitive conclusions about the prevalence of burnout and highlight the importance of developing a consensus definition of burnout and of standardizing measurement tools to assess the effects of chronic occupational stress on physicians.

Phenomenon: Global health education (GHE) is expanding to include socioculturally and resource-different settings, with the goal of developing a workforce with members who can promote health equity locally and globally. GHE is also no longer limited to students from high-income countries (HICs). However, it is unknown whether the motivations and experiences of medical students from HICs and from low- and middle-income countries (LMICs) participating in GHE clinical electives through institutional partnerships are similar or different. Such an understanding is needed to design programs that meet the needs of participants and effectively train them in the principles and practice of global health. APPROACH: This was a cross-sectional, mixed-methods survey of LMIC students from partner sites rotating at one U.S. medical school, and U.S. students from one medical school rotating at partner sites, between 2010 and 2015. Variables included demographic characteristics of participants, components of the curriculum at the home institution, and components of the away rotation, including perceptions of its content and impact. Content analysis was used to identify themes in the responses provided to open-ended questions. FINDINGS: In all, 63 of 84 (75%) LMIC and 61 of 152 (40%) U.S. students participated. Recall of predeparture training was low for both LMIC and U.S. students (44% and 55%, respectively). Opportunities to experience different healthcare systems, resource-different settings, and cultural exposure emerged as motivators for both groups. Both groups noted differences in doctor-patient relationships, interactions between colleagues, and use of diagnostic testing. U.S. respondents were more likely to perceive differences in the impact of social determinants of health and ethical issues. Both groups felt that their experience affected their interactions with patients and perspectives on education, but U.S. students were more likely to mention perspectives on healthcare delivery and social determinants of health, whereas LMIC respondents noted impacts on career goals. Insights: These results argue that GHE is not restricted to resource-constrained settings and that students from LMICs have similar reasons for participation as those from HICs. LMIC students also identified a lack of emphasis on GHE topics like social determinants of health during GH electives, which could diminish the effectiveness of these experiences. Both U.S. and LMIC students emphasized the cultural component of their GHE experience but had different perceptions regarding core tenets of GHE, such as the social determinants of health and health equity, during these experiences.

PURPOSE: Modification of the trigger used to induce final oocyte maturation in in vitro fertilization (IVF) is a major strategy used to reduce the risk of ovarian hyperstimulation syndrome (OHSS). A novel trigger composed of 1500 IU of human chorionic gonadotropin (hCG) plus 450 IU of follicle-stimulating hormone (FSH) has been developed to reduce OHSS risk. This study compares outcomes of the novel trigger to conventional triggers used in high-risk OHSS patients undergoing IVF. METHODS: In this retrospective cohort study, IVF cycles at high risk for OHSS based on a serum estradiol > 5000 pg/ml on trigger day conducted between January 2008 and February 2016 were evaluated. Oocyte maturation was induced with the novel trigger (1500 IU hCG plus 450 IU FSH) or a conventional trigger [3300 IU hCG, gonadotropin-releasing hormone agonist (GnRHa) alone, or GnRHa plus 1500 IU hCG]. IVF cycle outcomes were compared. Trigger strategies were examined for associations with OHSS development using logistic regression. RESULTS: Among 298 eligible IVF cycles identified, there were no differences in oocyte maturation, fertilization, embryo quality, or pregnancy outcomes among all triggers. After adjusting for serum estradiol level and number of follicles, the novel trigger was associated with lower odds of OHSS symptom development compared to the 3300 IU hCG and GnRHa plus hCG 1500 IU triggers (p = 0.007 and 0.04, respectively). CONCLUSIONS: This study suggests that 1500 IU hCG plus 450 IU FSH may be associated with decreased OHSS symptoms compared to conventional triggers, while producing similar IVF and pregnancy outcomes. More important, this novel trigger may provide a superior alternative in down-regulated cycles and in patients with hypothalamic dysfunction where GnRHa triggers cannot be utilized.

Importance: Depression is common among training physicians and may disproportionately affect women. The identification of modifiable risk factors is key to reducing this disease burden and its negative impact on patient care and physician career attrition. Objective: To determine the presence and magnitude of a sex difference in depressive symptoms and work-family conflict among training physicians; and if work-family conflict impacts the sex difference in depressive symptoms among training physicians. Design, Setting, and Participants: A prospective longitudinal cohort study of medical internship in the United States during the 2015 to 2016 academic year in which 3121 interns were recruited across all specialties from 44 medical institutions. Main Outcomes and Measures: Prior to and during their internship year, participants reported the degree to which work responsibilities interfered with family life using the Work Family Conflict Scale and depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9). Results: Mean (SD) participant age was 27.5 (2.7) years, and 1571 participants (49.7%) were women. Both men and women experienced a marked increase in depressive symptoms during their internship year, with the increase being statistically significantly greater for women (men: mean increase in PHQ-9, 2.50; 95% CI, 2.26-2.73 vs women: mean increase, 3.20; 95% CI, 2.97-3.43). When work-family conflict was accounted for, the sex disparity in the increase in depressive symptoms decreased by 36%. Conclusions and Relevance: Our study demonstrates that depressive symptoms increase substantially during the internship year for men and women, but that this increase is greater for women. The study also identifies work-family conflict as an important potentially modifiable factor that is associated with elevated depressive symptoms in training physicians. Systemic modifications to alleviate conflict between work and family life may improve physician mental health and reduce the disproportionate depression disease burden for female physicians. Given that depression among physicians is associated with poor patient care and career attrition, efforts to alleviate depression among physicians has the potential to reduce the negative consequences associated with this disease.

BACKGROUND: Sudden infant death syndrome (SIDS) is a leading cause of infant mortality in the United States. While thermal stress is implicated in many risk factors for SIDS, the association between ambient temperature and SIDS remains unclear. METHODS: We obtained daily individual-level infant mortality data and outdoor temperature data from 1972 to 2006 for 210 US cities. We applied a time-stratified case-crossover analysis to determine the effect of ambient temperature on the risk of SIDS by season. We stratified the analysis by race, infant age, and climate. RESULTS: There were a total of 60,364 SIDS cases during our study period. A 5.6°C (10°F) higher daily temperature on the same day was associated with an increased SIDS risk of 8.6% (95% confidence interval [CI] = 3.6%, 13.8%) in the summer, compared with a 3.1% decrease (95% CI = -5.0%, -1.3%) in the winter. Summer risks were greater among black infants (18.5%; 95% CI = 9.3%, 28.5%) than white infants (3.6%; 95% CI = -2.3%, 9.9%), and among infants 3-11 months old (16.9%; 95% CI = 8.9%, 25.5%) than infants 0-2 months old (2.7%; 95% CI = -3.5%, 9.2%). The temperature-SIDS association was stronger in climate clusters in the Midwest and surrounding northern regions. CONCLUSIONS: Temperature increases were associated with an elevated risk of SIDS in the summer, particularly among infants who were black, 3 months old and older, and living in the Midwest and surrounding northern regions.