Citations

Immune escape is a prerequisite for tumor growth. We previously described a decline in intratumor activated cytotoxic T cells and T cell receptor (TCR) clonotype diversity in invasive breast carcinomas compared to ductal carcinoma in situ (DCIS), implying a central role of decreasing T cell responses in tumor progression. To determine potential associations between peripheral immunity and breast tumor progression, here, we assessed the peripheral blood TCR clonotype of 485 breast cancer patients diagnosed with either DCIS or de novo stage IV disease at younger (<45) or older (≥45) age. TCR clonotype diversity was significantly lower in older compared to younger breast cancer patients regardless of tumor stage at diagnosis. In the younger age group, TCR-α clonotype diversity was lower in patients diagnosed with de novo stage IV breast cancer compared to those diagnosed with DCIS. In the older age group, DCIS patients with higher TCR-α clonotype diversity were more likely to have a recurrence compared to those with lower diversity. Whole blood transcriptome profiles were distinct depending on the TCR-α Chao1 diversity score. There were more CD8 + T cells and a more active immune environment in DCIS tumors of young patients with higher peripheral blood TCR-α Chao1 diversity than in those with lower diversity. These results provide insights into the role that host immunity plays in breast cancer development across different age groups.

ABSTRACT Early COVID-19 convalescent plasma (CCP) transfusion to outpatients with COVID-19 decreases progression to hospitalization, but the mechanism of how CCP reduces severity is unknown. Among 882 COVID-19 participants transfused with CCP or control plasma in a randomized controlled trial, 21 cytokines and chemokines were measured using electrochemiluminescence assays. Wilcoxon rank sum tests were used to evaluate the difference between early (transfused within 5 days of symptom onset) CCP vs early control plasma and late (transfused 6–9 days after symptom onset) CCP vs late control plasma at each visit. Linear mixed-effect models were used to assess the difference in the slope of cytokine change. Median cytokine and chemokine levels were similar between the early CCP and early control groups pre-transfusion. At the day 14 visit, only the median IL-6 ( P = 0.014) and IL-16 ( P = 0.036) levels were lower in the early CCP group compared to the early control group, but these differences were not statistically significant after correcting for multiple comparisons (requiring P < 0.0024). IL-6 levels decreased significantly faster in the early CCP group from screening to the day 14 visit compared to the early control group ( P < 0.001). No difference was observed in the slope of cytokine change from screening to day 90 between early CCP and early control groups. Late control and late CCP arms showed similar cytokine and chemokine levels through study follow-up. One mechanism by which early CCP transfusion reduces hospitalization may be by decreasing IL-6 levels, as the reduction is associated with better recovery from COVID-19. IMPORTANCE This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Objective Tricuspid regurgitation (TR) is a prevalent valve disease associated with significant morbidity and mortality. We aimed to apply machine learning (ML) to assess risk stratification in patients with ≥moderate TR. Methods Patients with ≥moderate TR on echocardiogram between January 2005 and December 2016 were retrospectively included. We used 70% of data to train ML-based survival models including 27 clinical and echocardiographic features to predict mortality over a 3-year period on an independent test set (30%). To account for differences in baseline comorbidities, prediction was performed in groups stratified by increasing Charlson Comorbidity Index (CCI). Permutation feature importance was calculated using the best-performing model separately in these groups. Results Of 13 312 patients, mean age 72 ± 13 years and 7406 (55%) women, 7409 (56%) had moderate, 2646 (20%) had moderate–severe and 3257 (24%) had severe TR. The overall performance for 1-year mortality by 3 ML models was good, c-statistic 0.74–0.75. Interestingly, performance varied between CCI groups, (c-statistic = 0.774 in lowest CCI group and 0.661 in highest CCI group). The performance decreased over 3-year follow-up (average c-index 0.78). Furthermore, the top 10 features contributing to these predictions varied slightly with the CCI group, the top features included heart rate, right ventricular systolic pressure, blood pressure, diuretic use and age. Conclusions Machine learning of common clinical and echocardiographic features can evaluate mortality risk in patients with TR. Further refinement of models and validation in prospective studies are needed before incorporation into the clinical practice.

Patients with autosomal dominant polycystic kidney disease benefit from specialized care over their lifetimes, starting with diagnosis of the condition with ongoing discussion of both the renal course and extra-renal issues. Both renal and extra-renal issues may continue to cause major morbidity even after successful kidney transplant or initiation of RRT, and extra-renal disease aspects should always be considered as part of routine management. In this review, we will focus on updates in pain/depression screening, cardiac manifestations, liver and pancreatic cysts, kidney stone management, and genetic counseling. In some instances, we have shared our current clinical practice rather than an evidence-based guideline. We anticipate more standardization of care after the release of the Kidney Disease Improving Global Outcomes guidelines for management in autosomal dominant polycystic kidney disease later this year.

Background: Quadriceps muscle atrophy remains a limiting factor in returning to activity after anterior cruciate ligament reconstruction (ACLR). Blood flow restriction (BFR) therapy may accelerate quadriceps strengthening in the perioperative period. Purpose: To evaluate postoperative isometric quadriceps strength in patients who underwent ACLR with a perioperative BFR program. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Patients indicated for ACLR were randomized into 2 groups, BFR and control, at their initial clinic visit. All patients underwent 2 weeks of prehabilitation preoperatively, with the BFR group performing exercises with a pneumatic cuff set to 80% limb occlusion pressure placed over the proximal thigh. All patients also underwent a standardized postoperative 12-week physical therapy protocol, with the BFR group using pneumatic cuffs during exercise. Quadriceps strength was measured as peak and mean torque during seated leg extension and presented as quadriceps index (percentage vs healthy limb). Patient-reported outcomes (PROs), knee range of motion, and quadriceps circumference were also gathered at 6 weeks, 3 months, and 6 months postoperatively, and adverse effects were recorded. Results: Included were 46 patients, 22 in the BFR group (mean age, 25.4 ± 10.6 years) and 24 in the control group (mean age, 27.5 ± 12.0 years). At 6 weeks postoperatively, the BFR group demonstrated significantly greater strength compared with the controls (quadriceps index: 57% ± 24% vs 40% ± 18%; P = .029), and the BFR group had significantly better Patient-Reported Outcomes Measurement Information System–Physical Function (42.69 ± 5.64 vs 39.20 ± 5.51; P = .001) and International Knee Documentation Committee (58.22 ± 7.64 vs 47.05 ± 13.50; P = .011) scores. At 6 weeks postoperatively, controls demonstrated a significant drop in the peak torque generation of the operative versus nonoperative leg. There were no significant differences in strength or PROs at 3 or 6 months postoperatively. Three patients elected to drop out of the BFR group secondary to cuff intolerance during exercise; otherwise, no other severe adverse events were reported. Conclusion: Integrating BFR into perioperative physical therapy protocols led to improved strength and increased PROs at 6 weeks after ACLR. No differences in strength or PROs were found at 3 and 6 months between the 2 groups. Registration: NCT04374968 (ClinicalTrials.gov identifier).

Background: Rearranged during transfection ( RET ) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET -altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET -mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET -mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET -mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET -mutant MTC and prior C/V, 62 treatment-naïve patients with RET -mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4–68.5] in patients with RET -mutant MTC and prior C/V, 77.4% [95% CI: 65.0–87.1] in treatment-naïve patients with RET -mutant MTC, and 90.9% [95% CI: 70.8–98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET -mutant MTC and prior C/V, not reached in treatment-naïve patients with RET -mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET -altered thyroid cancer safety population ( N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET- altered thyroid cancer. Clinical Trial Registration: NCT03037385

Background Digital and mobile (mHealth) solutions are online or application-based services intended to support individuals with health needs. Despite evidence supporting the use of mHealth for patients with chronic pain, and the increasing desire of these types of solutions by both patients and providers, adoption of mHealth solutions remains limited. Implementation mapping can serve as a practical method to facilitate implementation and adoption of mHealth solutions within healthcare settings. Methods Implementation mapping was used to develop implementation strategies based on contextual determinants organized within the Consolidated Framework for Implementation Research (CFIR) for mHealth eLearning solutions across an integrated, multi-site healthcare system. We describe our experience identifying stakeholders, delineating implementation facilitators and barriers, defining implementation outcomes using RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework, outlining initial implementation strategies, and iterating on implementation strategies. Results A total of 30 implementation strategies were identified and implemented. Over the first year, primary and specialty care providers across all the clinical sites ( n = 70) placed 2559 orders for the mHealth solution. Most patients reported receiving the mHealth eLearning module (74%), and most patients felt that the tool improved their knowledge regarding their condition (82%) and their ability to provide self-care related to the condition (73%). Conclusion Practical applications of implementation science methods can help enable change within healthcare settings. Implementation mapping is an exercise that can engage stakeholders to facilitate the incorporation of new methods of care delivery, including mHealth solutions.