Tools for telehealth: A correlational analysis of app-based hearing testing.

Objective: Telehealth evaluation of hearing is rapidly evolving; however, the lack of consensus on the most accurate remote hearing test application has made hearing evaluation complicated. The objective of this study was to evaluate the correlation between the pure tone audiometry results obtained from app-based hearing testing programs and a traditional audiogram. Methods: A prospective within-subject and between-subject study design was used to correlate audiogram results between app-based hearing programs and a traditional audiogram. All participants completed a traditional audiogram, 1 commercial app-based test (ShoeBox), 2 consumer app-based tests (EarTrumpet and Hearing Test and Ear Age Test [HTEAT]), and a Hearing Handicap Inventory screening version (HHI-S). Testing was conducted in an acoustically controlled environment (traditional) and a quiet room (app-based hearing tests). Results: A total of 39 participants were enrolled in the study (21 with normal hearing and 18 with hearing loss). In patients with normal hearing, only the commercial hearing testing app (ShoeBox) had a statistically significant pure tone average correlation in both ears with traditional audiometry (Right ear-r = 0.7, p = .005, Left ear-r = 0.66, p = .001). Both consumer and commercial apps had statistically significant correlations with both ears in patients with hearing loss (ranging from r = 0.62 to r = 0.9). Regarding accuracy within 10 dB of the pure tone average of the traditional audiogram of all tested ears, the commercial app-based test was accurate in 94% for all ears (normal and hearing loss), while consumer app-based tests were between 14% and 36% for all ears. The HHI-S indicated no hearing impairment in 95% of those with normal hearing and indicated hearing impairment in 89% of those with hearing loss. Conclusion: Commercial-grade app-based pure tone audiometry demonstrates overall strong correlation and accuracy with traditional audiometry. The HHI-S assessment remains a valid and useful tool to predict normal hearing and hearing impairment. Level of Evidence: 2.

A Multicenter Evaluation of Treatment-Associated Changes in Body Composition in Men with Germ Cell Tumors (GCT) of the Testis: Implications for Adverse Events and Complications.

OBJECTIVES: To characterize changes in body composition following cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and quantify associations between body composition metrics and chemotherapy-associated adverse events (AEs) and post-retroperitoneal lymph node dissection (RPLND) complications. MATERIALS AND METHODS: This retrospective multi-center study included 216 men with GCT treated with cytotoxic chemotherapy and/or RPLND (2005-2020). We measured body composition including skeletal muscle (SMI), visceral adipose (VAI,), subcutaneous adipose (SAI), and fat mass (FMI) indices on computed tomography. We quantified chemotherapy-associated changes in body composition and evaluated associations between body composition and incidence of grade 3+ AEs and post-RPLND complications on multivariable logistic regression analyses. RESULTS: 182 men received a median of 3 cycles of cisplatin-based chemotherapy. Following chemotherapy, median change in SMI was -6% (p=<0.0001), while VAI, SAI, and FMI increased by +13% (p=<0.0001), +11% (p=<0.0001), and +6% (p=<0.0001), respectively. 79 patients (43%) experienced at least one grade 3+ AE. A decrease in SMI following chemotherapy was associated with increased risk of grade 3+ AEs (p=0.047). 103 men with a median age of 28.5 years (IQR 23-35.5) underwent RPLND of whom 22 (21.3%) experienced at least one grade 3+ post-RPLND complication. No baseline body composition metrics were associated with post-RPLND complications. CONCLUSIONS: In men with GCT of the testis, chemotherapy was associated with 6% loss of lean muscle mass and gains in adiposity. Lower skeletal muscle was associated with a higher incidence of chemotherapy-associated AEs. Body composition was not associated with the incidence of post-RPLND complications.

Brain capillary obstruction during neurotoxicity in a mouse model of anti-CD19 chimeric antigen receptor T-cell therapy.

Immunotherapy for haematologic malignancies with CD19-directed chimeric antigen receptor T cells has been highly successful at eradicating cancer but is associated with acute neurotoxicity in ∼40% of patients. This neurotoxicity correlates with systemic cytokine release syndrome, endothelial activation and disruption of endothelial integrity, but it remains unclear how these mechanisms interact and how they lead to neurologic dysfunction. We hypothesized that dysfunction of the neurovascular unit is a key step in the development of neurotoxicity. To recapitulate the interaction of the intact immune system with the blood-brain barrier, we first developed an immunocompetent mouse model of chimeric antigen receptor T-cell treatment-associated neurotoxicity. We treated wild-type mice with cyclophosphamide lymphodepletion followed by escalating doses of murine CD19-directed chimeric antigen receptor T cells. Within 3-5 days after chimeric antigen receptor T-cell infusion, these mice developed systemic cytokine release and abnormal behaviour as measured by daily neurologic screening exams and open-field testing. Histologic examination revealed widespread brain haemorrhages, diffuse extravascular immunoglobulin deposition, loss of capillary pericyte coverage and increased prevalence of string capillaries. To measure any associated changes in cerebral microvascular blood flow, we performed in vivo two-photon imaging through thinned-skull cranial windows. Unexpectedly, we found that 11.9% of cortical capillaries were plugged by Day 6 after chimeric antigen receptor T-cell treatment, compared to 1.1% in controls treated with mock transduced T cells. The capillary plugs comprised CD45+ leucocytes, a subset of which were CD3+ T cells. Plugging of this severity is expected to compromise cerebral perfusion. Indeed, we found widely distributed patchy hypoxia by hypoxyprobe immunolabelling. Increased serum levels of soluble ICAM-1 and VCAM-1 support a putative mechanism of increased leucocyte-endothelial adhesion. These data reveal that brain capillary obstruction may cause sufficient microvascular compromise to explain the clinical phenotype of chimeric antigen receptor T-cell neurotoxicity. The translational impact of this finding is strengthened by the fact that our mouse model closely approximates the kinetics and histologic findings of the chimeric antigen receptor T-cell neurotoxicity syndrome seen in human patients. This new link between systemic immune activation and neurovascular unit injury may be amenable to therapeutic intervention.

Changes in skeletal muscle and adipose tissue during cytotoxic chemotherapy for testicular germ cell carcinoma and associations with adverse events.

OBJECTIVES: To quantify changes in body composition during cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and evaluate associations between change in skeletal muscle and adipose tissue and chemotherapy-associated adverse events. MATERIALS AND METHODS: This retrospective single-institution study evaluated men with GCT treated with cytotoxic chemotherapy from 2005 to 2018. We measured skeletal muscle index (SMI [cm2/m2]), skeletal muscle density (SMD [Hounsfield Units (HU)]), skeletal muscle gauge (SMG [cm²*HU/m²]), fat mass index (FMI [kg/m2]), visceral adipose index (VAI [cm2/m2]), and subcutaneous adipose index (SAI [cm2/m2]) on axial computed tomography images at the level of the third lumbar vertebra within 75 days before and after chemotherapy. Chemotherapy-associated adverse events (AE) were graded based on the Common Terminology Criteria for Adverse Events (CTCAE v5.0.) Changes in body composition were quantified. Predictors of change in body composition were evaluated with multivariable linear regression. Associations between baseline or change in body composition and AEs were estimated with multivariable logistic regression adjusting for age, comorbidity, performance status, stage, and number/type of chemotherapy cycles. RESULTS: 141 patients (median age, 30 years [IQR 25-39]) including 86 patients (61%) with non-seminomatous GCT were included. Patients received a median of 3 cycles of cisplatin-based chemotherapy, and 124 patients (88%) completed planned chemotherapy. Median observed changes in SMI, SMD, and SMG were -6% (P<0.0001), -2% (P=0.07), and -7% (P<0.0001), respectively, while FMI increased 5.3% (P<0.0001). Overall, 120 patients (85%) experienced at least one AE including one or more ≥grade 3 AE in 57 patients (48%). Decrease in SMI (OR: 0.89, P=0.02), decrease in SMG (OR: 0.88, P=0.01,) and post-chemotherapy SMG (OR: 0.94, P=0.05) were independently associated with higher incidence of AEs, while pre-chemotherapy skeletal muscle parameters and post-chemotherapy SMI and SMD were not associated with AEs (P>0.05 for all). Preoperative adipose tissue or change in adiposity was not associated with incidence of AEs. CONCLUSIONS: In men with GCT receiving cytotoxic chemotherapy, a decrease in skeletal muscle mass and quality during chemotherapy were associated with a higher incidence of chemotherapy-associated AEs. Adipose tissue was not associated with the incidence of AEs.