Survival and treatment in older patients with ewing sarcoma: an analysis of the national cancer database.

BACKGROUND: Ewing sarcoma (EWS) is a malignancy which primarily arises in adolescence and has been studied extensively in this population. Much less is known about the rare patient cohort over the age of 40 at diagnosis. In this study, we describe the survival outcomes and clinical characteristics of this population. METHODS: This retrospective cohort study utilized the National Cancer Database (NCDB) to identify 4600 patients diagnosed between 2004 through 2019. Of these patients, 4058 were under the age of 40 and 542 were over 40. Propensity score 1:1 matching was performed according to sex and race. Univariate and multivariate logistic regression was performed to generate odds ratios (OR) and a Multivariate Cox regression model was used to generate a hazard ratio (HR) for patients over 40. Kaplan-Meier curves were used to estimate survival from diagnosis to death between age groups. Chi-square tests were used to compare demographic and socioeconomic patient characteristics. IBM statistics version 27.0 was used. p < 0.05 was used to indicate statistical significance. RESULTS: EWS patients older than 40 experienced worse survival outcomes compared to patients under the age of 40. 5-year survival was 44.6% for older patients vs. 61.8% for younger patients (p < 0.05). A multivariate Cox proportional hazards model showed that age was independently associated with inferior survival. (HR 1.96; p < 0.05). EWS patients over the age of 40 were more likely to have tumors originating from the vertebral column (16.1% vs 8.9%; p < 0.05) and cranium (5.3% vs. 2.9%; p < 0.05) and had a higher rate of axial tumors (31.6% vs. 18.5%; p < 0.05) compared to patients under 40. Additionally, patients older than 40 experienced a significantly longer delay between the date of diagnosis and initiation of systemic treatment (36.7 days vs. 24.8 days; p < 0.05) and were less likely to receive adjuvant chemotherapy (93.4% vs. 97.9%; p < 0.05). CONCLUSION: An age over 40 is associated with decreased survival for patients with EWS. Due to the rarity of EWS in this cohort, the optimal role of systemic treatment remains unknown and has yet to be clearly elucidated. Consequently, our findings suggest that older patients receive disparities in treatment which may be contributing to decreased survival rates.

First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer: A Living Systematic Review and Network Meta-analysis.

Importance: The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown. Objective: To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups. Data Sources: For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available. Study Selection: Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC. Data Extraction and Synthesis: Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022. Main Outcomes and Measures: Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life. Results: This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT. Conclusions and Relevance: The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy for Primary and Secondary Central Nervous System Lymphoma: A Systematic Review of Literature.

Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities, including high-dose chemotherapy-autologous stem cell transplantation. The pivotal ZUMA-1 and JULIET trials that led to FDA approval of Axicabtagene ciloleucel and Tisagenlecleucel for relapsed refractory large cell lymphoma excluded patients with CNS involvement due to concerns of increased toxicity. However, TRANSCEND study for Lisocabtagene maraleucel in relapsed refractory large cell lymphoma allowed patients with CNS involvement and reported manageable CNS toxicities in these patients. In the real-world experience, chimeric antigen receptor T-cell (CAR T) therapy has been deemed safe and effective for these patients with poor prognosis. In this systematic review, we analyzed available literature to evaluate the role of CAR T-cell therapy in both primary and secondary CNS lymphoma using Embase, Cochrane, and PubMed databases. A total of 14 studies, including 8 retrospective analyses and 6 prospective studies/clinical trials, were included in the qualitative synthesis to study the safety and efficacy of CAR T. Based on our analysis, CAR T-cell therapy appears to be associated with reasonable efficacy and a manageable safety for primary and secondary CNS lymphoma.

Quantifying absolute benefit for adjuvant treatment options in renal cell carcinoma: A living interactive systematic review and network meta-analysis.

OBJECTIVE: To assess comparative effectiveness of adjuvant therapies for renal cell carcinoma and quantify the absolute benefit of adjuvant treatments by clinicopathological risk groups. METHODS: This 'living' review was conducted using Living Interactive Evidence (LIvE) synthesis framework. RESULTS: The 'living' results are available on an interactive website. This network meta-analysis, including six RCTs with 7525 participants, showed that pembrolizumab (rank 1) significantly improved disease-free survival and overall survival compared with sunitinib but not when compared to pazopanib, and axitinib. The risk of treatment-related grade 3 or higher adverse events was increased with pembrolizumab as compared to placebo and axitinib but not when compared to sunitinib. The absolute benefit of adjuvant pembrolizumab increases substantially with larger tumor size, nodal positivity and higher Leibovich scores. CONCLUSION: Current evidence suggests that pembrolizumab delays disease progression compared to sunitinib. A risk-adapted strategy should be used in patients undergoing consideration for treatment with adjuvant pembrolizumab.

Disparities in Representation of Women, Older Adults, and Racial/Ethnic Minorities in Immune Checkpoint Inhibitor Trials.

PURPOSE: We aim to describe reporting and representation of minority patient populations in immune checkpoint inhibitor (ICI) clinical trials and assess predictors of enrollment disparity. METHODS: Trial-level data were acquired from eligible phase II and III trials. Population-based estimates were acquired from the SEER 18 and Global Burden of Disease incidence databases. Trials reporting race, age, and sex were summarized using descriptive statistics. Enrollment-incidence ratio (EIR) was used to assess representation of subgroups. Average annual percentage change (AAPC) in EIR was calculated using Joinpoint Regression Analysis. Trial-level characteristics associated with EIR were assessed using multivariable linear regression. RESULTS: A total of 107 trials with 48,095 patients were identified. Participation of Black, White, Asian, Native American, Pacific Islander, and Hispanic participants was reported in 65 (61%), 77 (72%), 68 (64%), 40 (37%,) and 24 trials (22%), respectively. Subgroup analyses of clinical outcomes by race, age, and sex were reported in 17 (22%), 62 (78%), and 57 (57%) trials, respectively. Women (trial proportion [TP]: 32%; EIR: 0.90 [95% confidence interval [CI]: 0.84-0.96]), patients aged ≥65 years (TP: 42%; EIR: 0.78 [95% CI: 0.72-0.84]), Black participants (TP: 1.9%; EIR: 0.17 [95% CI: 0.13-0.22]) and Hispanics (TP: 5.9%; EIR: 0.67 [95% CI: 0.53-0.82]) were underrepresented. Representation of Black patients decreased significantly from 2009 to 2020 (AAPC: -23.13). Black participants were significantly underrepresented in phase III trials (P < .001). CONCLUSION: The reporting of participation by racial or ethnic subgroup categories is inadequate. Women, older adults, as well as Black and Hispanic participants are significantly underrepresented in ICI clinical trials.

Impact of autologous transplantation on survival in patients with newly diagnosed multiple myeloma who have high-risk cytogenetics: A meta-analysis of randomized controlled trials.

BACKGROUND: Despite routine evaluation of cytogenetics in myeloma, little is known regarding the impact of high-dose therapy (HDT) consolidation on overall survival (OS) or progression-free survival (PFS) in patients who have high-risk cytogenetics. The authors performed a meta-analysis of randomized controlled trials (RCTs) to assess the heterogeneity of HDT efficacy according to cytogenetic risk. METHODS: All RCTs in patients who had newly diagnosed myeloma from 2000 to 2021 that compared upfront HDT versus standard-dose therapy (SDT) consolidation were included. The primary objective was to assess the difference in HDT efficacy between standard-risk and high-risk cytogenetics in terms of the OS or PFS log(hazard ratio) (HR). The pooled OS and PFS HR was calculated according to cytogenetic-risk subgroup using a random-effects model, and heterogeneity (I2 ) (the percentage of total observed variability explained by between-study differences) was assessed using an interaction test. RESULTS: After screening 3307 citations, 6 RCTs were included for PFS analysis, and 4 were included for OS analysis. The median follow-up ranged from 3.1 to 7.8 years. The pooled OS HR for HDT versus SDT consolidation in patients with standard-risk and high-risk cytogenetics was 0.90 (95% confidence interval [CI], 0.70-1.17; I2 = 0%) and 0.66 (95% CI, 0.45-0.97; I2 = 0%), respectively. The difference in HDT efficacy in terms of OS between standard-risk and high-risk patients was statistically significant in favor of the high-risk group (P for interaction = .03). The pooled PFS HR for HDT versus SDT was 0.65 (95% CI 0.56-0.76; I2 = 0%) versus 0.52 (95% CI, 0.33-0.83; I2 = 55%), respectively. The difference in HDT efficacy in terms of PFS between standard-risk and high-risk patients was not significant (P for interaction = .25). CONCLUSIONS: The magnitude of OS benefit with upfront HDT is cytogenetics-dependent. Patients with high-risk cytogenetics should preferably receive upfront rather than delayed HDT consolidation. LAY SUMMARY: Upfront autologous stem cell transplantation improves overall survival in patients with newly diagnosed myeloma harboring high-risk cytogenetics.

Adjuvant Tyrosine Kinase Inhibitors in Renal Cell Carcinoma: A Concluded Living Systematic Review and Meta-Analysis.

PURPOSE: Multiple large clinical trials have investigated adjuvant tyrosine kinase inhibitors (TKIs) to reduce the risk of cancer recurrence and progression to metastasis in high-risk renal cell carcinoma. We sought to maintain living and interactive evidence on this topic, until a high level of certainty is reached for key clinical outcomes such that further updates become unnecessary and unlikely to change clinical practice. METHODS: We created a living interactive evidence synthesis platform to maintain a continuously updated meta-analysis on TKI monotherapy in adjuvant renal cell carcinoma. We implemented an automated search strategy with weekly updates to identify randomized phase 2 and 3 clinical trials. Study selection, appraisal, and data extraction were done in duplicate. Cumulative meta-analysis was performed using Analyzer Module in Living Interactive Evidence platform. For each outcome (overall survival [OS], disease-free survival [DFS], and all-cause and treatment-related adverse events), we assessed certainty of evidence using GRADE approach and conducted trial sequential analysis. RESULTS: This final update includes five randomized trials including recently updated data from PROTECT trial. Meta-analysis shows that adjuvant TKI monotherapy offers no benefit in OS (hazard ratio, 1.01; 95% CI, 0.91 to 1.12, high certainty) or DFS (hazard ratio, 0.92; 95% CI, 0.86 to 1.00, high certainty) and significantly increases adverse event risk. Lack of benefit was consistent across subgroups including highest-risk patients (test for subgroup differences: P = .32). Optimal information size criteria were met, and there was high certainty of evidence for lack of DFS and OS benefit for adjuvant TKIs. CONCLUSION: There is no guidance on when to stop maintaining a living review. In this example, we used trial sequential analysis and high certainty of evidence (future clinical trials unlikely to change current conclusions) as a benchmark to conclude a living review in view of convincing evidence.

Wide Stromal Mapping Using an Anterior Segment Optical Coherence Tomography.

PURPOSE: To quantify and assess the reproducibility of the corneal stromal thickness profiles captured by the SD-OCT. Secondly, we correlated the zonal thicknesses to the age, gender and axial length. METHODS: We included 227 normal eyes of 227 patients with a maximum hypermetropia of +5 and myopia of -6 diopters (D). Subjects with an intraocular pressure exceeding 22 mm Hg, evidence of cataract formation, history of ophthalmic surgery or disease were excluded. Lastly, reproducibility was evaluated in a subset of 50 participants by means of an identical scan protocol repeated by 2 different OCT operators. RESULTS: Stromal values were consistently thicker in the peripheral cornea (p<0.001). Age was negatively correlated with approximately every sector of the stroma with notable exceptions of the center (r=0.117, p=0.088) and the superior inner (r=0.057, 0.409), middle (r=0.086, p=0.209) and outer locations (r=0.120, p=0.079). There was no statistical significance in most sectors when looking at the axial length, gender and K1/K2. This method was highly reproducible in terms of both the ICC and COV. CONCLUSION: Corneal stromal mapping is highly reproducible and shows a negative correlation to age. Additionally, the periphery of the stroma is consistently thicker to the center. Other variables like gender and axial length show no relationship to the corneal stroma.

Prevalence and Predictors of the Burnout Syndrome in Medical Students of Karachi, Pakistan.

Objectives Burnout is a psychophysiological syndrome, consisting of a triad of emotional and physical exhaustion, exhibition of impersonal attitude and loss of a sense of achievement for oneself. This study aimed to pinpoint its risk factors, measure its current prevalence in medical students of Karachi, Pakistan and accentuate the areas of focus to benefit the primary care-oriented community as a whole. Methods This cross-sectional study included responses from 600 medical students in Karachi (third to final year). A self-administered questionnaire using the Maslach Burnout Inventory-Human Services Survey (MBI-HSS), multi-dimensional mood state questionnaire and perceived stress scale was used, along with a section about burnout prevention assessment. Data were analyzed using SPSS version 24.0 (IBM Corp., Armonk, NY) and chi-square tests used to find significant associations. Results One-fifth (n=109, 18.2%) of our subjects were burned out. The syndrome was significantly observed in those who operated on insufficient sleep (p-value 0.028) and in those having anger management issues and non-dominating temperaments (p-value 0.05). Furthermore, it was statistically significant in those who gave up easily, in those who had no hobbies and had no time to exercise and pray (p-value <0.05). It was more prevalent in pupils of private medical colleges whereas two of its three constitutive factors, Emotional Exhaustion (p-value 0.03) and Personal Achievement (p-value <0.001) were significantly higher in pupils of public sector universities.  Conclusion The deleterious repercussions of burnout syndrome warrant the need for extensive efforts towards the propagation of its awareness.

Effect of Demographic Variables on the Regional Corneal Pachymetry.

PURPOSE: The measurement of corneal thickness by corneal pachymetry provides valuable information in the setting of corneal disease; however, spectral-domain optical coherence tomography (SD-OCT)-based assessment of different corneal sectors has been scarce in Pakistan. DESIGN: We aimed to obtain a whole-corneal thickness map using SD-OCT and to evaluate its correlation with age, sex, and axial length. METHODS: Our study included 214 subjects with healthy corneas; each eye was scanned with an SD-OCT covering a 9-mm diameter, and reproducibility was evaluated in a subset of 50 participants by means of an identical scan protocol repeated by 2 different OCT operators. RESULTS: Our analysis revealed corneal thickness to be thinnest inferotemporally whereas thickest in the superior and superonasal quadrants. No statistically significant differences could be detected between male and female participants with respect to corneal thickness, age, intraocular pressure, axial length, and refractive errors. However, we identified a significant negative correlation between age and corneal thickness in all corneal sections, excluding the inner and middle superior, inner superonasal, and inner and middle superotemporal quadrants. Conversely, the correlation between axial length and corneal thickness was found to be positive in the central region (P = 0.03, R = 0.149), the outer inferotemporal quadrant (P = 0.012, R = 0.171), throughout the temporal quadrant (P = 0.024, R = 0.154 for inner; P = 0.025, R = 0.153 for middle; P = 0.006, R = 0.186 for outer), and in the inner superotemporal quadrant (P = 0.018, R = 0.162). CONCLUSIONS: Different corneal sectors may interact heterogeneously with patient-related characteristics. This may provide incentive to evaluate whole-corneal thickness as a distinct parameter for clinical identification of disease processes.