Prospective assessment of canine thyroid cancer-part I: nodal metastatic rate and impact of nodal immunohistochemistry in 70 dogs.

OBJECTIVE: To determine the rate of nodal metastasis in dogs with thyroid cancer and evaluate whether immunohistochemistry (IHC) identifies additional metastases beyond evaluation with H&E. ANIMALS: 70 prospectively enrolled client-owned dogs with thyroid cancer managed with thyroidectomy. METHODS: Dogs underwent thyroidectomy with concurrent elective bilateral medial retropharyngeal (MRP) ± deep cervical lymphadenectomy. Thyroid tumors and associated lymph nodes were reviewed by a single board-certified pathologist. Immunohistochemistry was used for all primary tumors (thyroid transcription factor-1 and calcitonin) to support a diagnosis of follicular or medullary carcinoma. Lymph nodes without evidence of metastasis after H&E review were labeled with the antibody associated with the wider uptake in the primary tumor. RESULTS: 77 thyroid cancers were resected from the 70 dogs enrolled, including 61 (79.2%) follicular, 8 (10.7%) medullary, and 7 (9.3%) mixed follicular/medullary carcinomas, with 1 (1.3%) carcinosarcoma. Twelve dogs had evidence of nodal metastasis following H&E review. Occult micrometastasis was identified in 1 dog following nodal IHC, resulting in documented metastasis in 13 of 70 (18.6%) dogs. Metastasis was more common with medullary (5/8) and follicular/medullary carcinoma (3/7) than follicular carcinoma (5/61). All MRP metastases were ipsilateral (7/77 [9.1%]), without contralateral MRP metastases (0/62). Fourteen of 41 (34.1%) deep cervical lymph nodes were metastatic. CLINICAL RELEVANCE: Nodal metastasis was uncommon for follicular carcinoma but was seen in > 50% of dogs with thyroid cancer involving a medullary component. Routine nodal IHC appears to be low yield for thyroid carcinoma. Extirpation of ipsilateral MRP and identifiable deep cervical lymph nodes is recommended with thyroidectomy until detailed preoperative risk stratification becomes available.

Ocular biomarkers: useful incidental findings by deep learning algorithms in fundus photographs.

BACKGROUND/OBJECTIVES: Artificial intelligence can assist with ocular image analysis for screening and diagnosis, but it is not yet capable of autonomous full-spectrum screening. Hypothetically, false-positive results may have unrealized screening potential arising from signals persisting despite training and/or ambiguous signals such as from biomarker overlap or high comorbidity. The study aimed to explore the potential to detect clinically useful incidental ocular biomarkers by screening fundus photographs of hypertensive adults using diabetic deep learning algorithms. SUBJECTS/METHODS: Patients referred for treatment-resistant hypertension were imaged at a hospital unit in Perth, Australia, between 2016 and 2022. The same 45° colour fundus photograph selected for each of the 433 participants imaged was processed by three deep learning algorithms. Two expert retinal specialists graded all false-positive results for diabetic retinopathy in non-diabetic participants. RESULTS: Of the 29 non-diabetic participants misclassified as positive for diabetic retinopathy, 28 (97%) had clinically useful retinal biomarkers. The models designed to screen for fewer diseases captured more incidental disease. All three algorithms showed a positive correlation between severity of hypertensive retinopathy and misclassified diabetic retinopathy. CONCLUSIONS: The results suggest that diabetic deep learning models may be responsive to hypertensive and other clinically useful retinal biomarkers within an at-risk, hypertensive cohort. Observing that models trained for fewer diseases captured more incidental pathology increases confidence in signalling hypotheses aligned with using self-supervised learning to develop autonomous comprehensive screening. Meanwhile, non-referable and false-positive outputs of other deep learning screening models could be explored for immediate clinical use in other populations.

Perioperative Nivolumab in Resectable Lung Cancer.

BACKGROUND: Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes. METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety. RESULTS: At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group. CONCLUSIONS: Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.).

Utilization of older deceased donors for pediatric liver transplant may negatively impact long-term survival.

BACKGROUND: Multiple adult studies have investigated the role of older donors (ODs) in expanding the donor pool. However, the impact of donor age on pediatric liver transplantation (LT) has not been fully elucidated. METHODS: UNOS database was used to identify pediatric (≤18 years) LTs performed in the United States during 2002-22. Donors ≥40 years at donation were classified as older donors (ODs). Propensity analysis was performed with 1:1 matching for potentially confounding variables. RESULTS: A total of 10,024 pediatric liver transplantation (PLT) patients met inclusion criteria; 669 received liver grafts from ODs. Candidates receiving OD liver grafts were more likely to be transplanted for acute liver failure, have higher Model End-Stage Liver Disease/Pediatric End-Stage Liver Disease (MELD/PELD) scores at LT, listed as Status 1/1A at LT, and be in the intensive care unit (ICU) at time of LT (all p < 0.001). Kaplan-Meier (KM) analyses showed that recipients of OD grafts had worse patient and graft survival (p < 0.001) compared to recipients of younger donor (YD) grafts. KM analyses performed on candidates matched for acuity at LT revealed inferior patient and graft survival in recipients of deceased donor grafts (p < 0.001), but not living donor grafts (p > 0.1) from ODs. Cox regression analysis demonstrated that living donor LT, diagnosis of biliary atresia and first liver transplant were favorable predictors of recipient outcomes, whereas ICU stay before LT and transplantation during 2002-12 were unfavorable. CONCLUSION: Livers from ODs were used for candidates with higher acuity. Pediatric recipients of livers from ODs had worse outcome compared to YDs; however, living donor LT from ODs had the least negative impact on recipient outcomes.

Neonatal blood pressure by birth weight, gestational age, and postnatal age: a systematic review.

BACKGROUND: Blood pressure is a vital hemodynamic marker during the neonatal period. However, normative values are often derived from small observational studies. Understanding the normative range would help to identify ideal thresholds for intervention to treat hypotension or hypertension. Therefore, the aim of this study was to assess observed blood pressure values in neonates who have not received any blood-pressure modifying treatments from birth to three months postnatal age and whether these vary according to birth weight, gestational age and postnatal age. METHODS: This was a systematic review. A literature search was conducted in MEDLINE, PubMed, Embase, Cochrane Library, and CINAHL from 1946 to 2017 on blood pressure in neonates from birth to 3 months of age (PROSPERO ID CRD42018092886). Unpublished data were included where appropriate. RESULTS: Of 3,587 non-duplicate publications identified, 30 were included (one unpublished study). Twelve studies contained data grouped by birth weight, while 23 contained data grouped by gestational age. Study and clinical heterogeneity precluded meta-analyses thus results are presented by subgroup. A consistent blood pressure rise was associated with increasing birth weight, gestational age, and postnatal age. In addition, blood pressure seemed to rise more rapidly in the most preterm and low birth weight neonates. CONCLUSION: Despite blood pressure increasing with birth weight, gestational age, and postnatal age, there was marked blood pressure variability observed throughout. To better define hypotension and hypertension, future studies should develop consistent approaches for factors related to blood pressure variability, including the method and timing of measurement as well as statistical control of relevant patient characteristics.

Outcome in dogs with invasive adrenal gland tumors that did not pursue adrenalectomy.

OBJECTIVE: To report the survival times in dogs diagnosed with adrenal tumors with vascular or soft tissue invasion that did not undergo adrenalectomy. ANIMALS: Retrospective case series of 32 client-owned dogs. METHODS: The medical records of a referral veterinary hospital were reviewed to identify dogs that were diagnosed with an invasive adrenal mass and did not undergo adrenalectomy between January 2013 and December 2022. Data collected included signalment, examination findings, and diagnostic results from the initial presentation. Descriptive statistics were calculated to summarize dog signalment information, and Kaplan-Meier survival analysis was performed for calculation of median survival time. RESULTS: Most dogs (n = 28) had vascular invasion, primarily into the caudal vena cava. Surgery was offered but not pursued due to perceived risk of sudden death (n = 5), risk of hemorrhage (4), or concurrent diagnosis of disseminated intravascular coagulation (1). Only 1 dog pursued stereotactic body radiation therapy, and 1 was prescribed toceranib phosphate (Palladia). Of these 32 dogs, 30 (93.8%) died or were euthanized and 2 (6.2%) dogs survived. The median follow-up time was 49 days (range, 0 to 1,910 days). The median survival time was 50 days (95% CI, 4 to 194 days). The most common cause of death or euthanasia was hemoabdomen (n = 8). CLINICAL RELEVANCE: Nonsurgical management of invasive adrenal tumors was associated with short survival times in this case series.

Long-Term Blood Pressure Reductions Following Catheter-Based Renal Denervation: A Systematic Review and Meta-Analysis.

BACKGROUND: Renal denervation is a recognized adjunct therapy for hypertension with clinically significant blood pressure (BP)-lowering effects. Long-term follow-up data are critical to ascertain durability of the effect and safety. Aside from the 36-month follow-up data available from randomized control trials, recent cohort analyses extended follow-up out to 10 years. We sought to analyze study-level data and quantify the ambulatory BP reduction of renal denervation across contemporary randomized sham-controlled trials and available long-term follow-up data up to 10 years from observational studies. METHODS: A systematic review was performed with data from 4 observational studies with follow-up out to 10 years and 2 randomized controlled trials meeting search and inclusion criteria with follow-up data out to 36 months. Study-level data were extracted and compared statistically. RESULTS: In 2 contemporary randomized controlled trials with 36-month follow-up, an average sham-adjusted ambulatory systolic BP reduction of -12.7±4.5 mm Hg from baseline was observed (P=0.05). Likewise, a -14.8±3.4 mm Hg ambulatory systolic BP reduction was found across observational studies with a mean long-term follow-up of 7.7±2.8 years (range, 3.5-9.4 years; P=0.0051). The observed reduction in estimated glomerular filtration rate across the long-term follow-up was in line with the predicted age-related decline. Antihypertensive drug burden was similar at baseline and follow-up. CONCLUSIONS: Renal denervation is associated with a significant and clinically meaningful reduction in ambulatory systolic BP in both contemporary randomized sham-controlled trials up to 36 months and observational cohort studies up to 10 years without adverse consequences on renal function.

Comparing anti-tumor and anti-self immunity in a patient with melanoma receiving immune checkpoint blockade.

BACKGROUND: Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. METHODS: Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. RESULTS: While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. CONCLUSIONS: This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Race/Ethnicity and Incidence of Pelvic Organ Prolapse in Midlife Women: The Study of Women's Health Across the Nation.

Background: Pelvic organ prolapse (POP) affects a considerable proportion of women. Limited information exists regarding the incidence of POP as women transition through menopause. Using data from the Study of Women's Health Across the Nation (SWAN), this diverse community-based longitudinal cohort study assessed the incidence of symptomatic POP and risk by race/ethnicity. Methods: Self-reported POP was ascertained by questionnaire at 11 approximately annual SWAN visits over a median of 13.3 years of follow-up. We estimated probabilities for reporting POP using interval-censored Kaplan-Meier survival plots. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using interval-censored Cox proportional hazards models. Results: The estimated cumulative probability of POP increased linearly from 2.1% at age 45 to 10.1% by age 65 (4.0% per decade). At age 65, the probability was 4.2%, 4.8%, 8.9%, 9.7%, and 33.9% for Japanese, Chinese, Black, White, and Hispanic women, respectively. Compared with White women, the unadjusted HR for POP was 3.09 (95% CI = 2.18-4.39), 0.96 (0.71-1.31), 0.43 (0.22-0.85), and 0.48 (0.26-0.88) for Hispanic, Black, Chinese, and Japanese women, respectively. After adjustment for financial strain and vaginal birth, the low hazards among Chinese and Japanese women and the high hazard for Hispanic women remained significant. Conclusion: Incidence of symptomatic POP increased as women aged through midlife. Risks varied by race and ethnicity and were not accounted for by population differences in socioeconomic life contexts or the probability of having had a vaginal birth. Although not associated with menopause, health providers should incorporate screening for and information about POP when treating menopausal symptoms and health needs of midlife women. Research on pathophysiological factors associated with increasing POP in midlife is warranted.

Therapeutic Inertia With Initial Low-Dose Quadruple Combination Therapy for Hypertension: Results From the QUARTET Trial.

BACKGROUND: Low-dose combinations are a promising intervention for improving blood pressure (BP) control but their effects on therapeutic inertia are uncertain. METHODS: Analysis of 591 patients randomized to an ultra-low-dose quadruple pill or initial monotherapy. The episode of therapeutic inertia was defined as a patient visit with a BP of >140/90 mm Hg without intensification of antihypertensive treatment. We compared the frequency of therapeutic inertia episodes between Quadpill and initial monotherapy as a proportion of the total population (intention-to-treat analysis with the denominator being all participants randomized) and as a proportion of people with uncontrolled BP (with the denominator being participants with uncontrolled BP). RESULTS: Therapeutic inertia occurred in fewer participants randomized to Quadpill compared with monotherapy. For example, among the 390 participants with a 6-month follow-up, therapeutic inertia according to unattended BP was 21/192 (11%) versus 45/192 (23%), P=0.002. There were similar rates of therapeutic inertia among those with uncontrolled unattended BP in each group (all P>0.4). Consistent observations were seen with the use of attended office BP measures. The major determinants of not intensifying treatment during follow-up were BP readings that were close to target and large improvements in BP compared with the previous visit. CONCLUSIONS: Among all treated individuals, low-dose Quadpill reduced the number of therapeutic inertia episodes compared with initial monotherapy. After the first follow-up visit, most high BP values did not lead to treatment intensification in both groups. Education is needed about the importance of treatment intensification despite a significant improvement in BP or BP being close to target. REGISTRATION: URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12616001144404; Unique identifier: ACTRN12616001144404.

Ambulatory blood pressure after 12 weeks of quadruple combination of quarter doses of blood pressure medication vs. standard medication.

BACKGROUND: A combination of four ultra-low-dose blood pressure (BP) medications lowered office BP more effectively than initial monotherapy in the QUARTET trial. The effects on average ambulatory BP changes at 12 weeks have not yet been reported in detail. METHODS: Adults with hypertension who were untreated or on monotherapy were eligible for participation. Overall, 591 participants were randomized to either the quadpill (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) or monotherapy control (irbesartan 150 mg). The difference in 24-h, daytime, and night-time systolic and diastolic ambulatory BP at 12 weeks along further metrics were predefined secondary outcomes. RESULTS: Of 576 participants, 289 were randomized to the quadpill group and 287 to the monotherapy group. At 12 weeks, mean 24-h ambulatory SBP and DBP were 7.7 [95% confidence interval (95% CI) 9.6-5.8] and 5.3 (95% CI: 6.5-4.1) mmHg lower in the quadpill vs. monotherapy group ( P  < 0.001 for both). Similar reductions in the quadpill group were observed for daytime (8.1/5.7 mmHg lower) and night-time (6.3/4.0 mmHg lower) BP at 12 weeks (all P  < 0.001) compared to monotherapy. The rate of BP control (24-h average BP < 130/80 mmHg) at 12 weeks was higher in the quadpill group (77 vs. 50%; P  < 0.001). The reduction in BP load was also more pronounced with the quadpill. CONCLUSION: A quadruple quarter-dose combination compared with monotherapy resulted in greater ambulatory BP lowering across the entire 24-h period with higher ambulatory BP control rates and reduced BP variability at 12 weeks. These findings further substantiate the efficacy of an ultra-low-dose quadpill-based BP lowering strategy.

Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers.

PURPOSE: Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS: Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS: Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION: In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.

Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma.

Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.

Trends in blood pressure changes and hypertension prevalence in Australian adults before and during the COVID-19 pandemic.

Efforts to limit the impact of the coronavirus disease (COVID-19) pandemic led to the implementation of public health measures and reallocation of health resources. To investigate trends in blood pressure (BP), hypertension and BMI in the Australian population during the COVID-19 pandemic, data from publicly accessible health stations were analyzed. Average BP and BMI measured by the SiSU Health Station network in Australia in over 1.6 million health screenings were compared between the years 2018 and 2021. Additionally, paired trajectories for BP and BMI development before and during the COVID-19 pandemic were calculated. Comparisons between pre-COVID years and post-COVID years of 2018 versus 2020, 2019 versus 2020, 2018 versus 2021, and 2019 versus 2021 showed increases in average adjusted systolic BP of 2.0, 1.7, 2.6, and 2.3 mmHg, respectively. Paired analysis of longitudinal data showed an overall increase in the trajectory of systolic BP of 3.2 mmHg between pre- and post-COVID years. The prevalence of hypertension in users of the health stations increased by approximately 25% in the years 2020-2021. Similar trends were seen for BMI. Data from public Australian health stations indicated a strong trend toward higher BP during the COVID-19 pandemic. At the population level, BP increments have been shown to markedly increase cardiovascular disease risk. Anti-pandemic measures need to be carefully evaluated in terms of secondary public health effects and health support systems extended to effectively target cardiovascular risk.

Salt sensitivity risk derived from nocturnal dipping and 24-h heart rate predicts long-term blood pressure reduction following renal denervation.

BACKGROUND: Renal denervation (RDN) has been consistently shown in recent sham-controlled clinical trials to reduce blood pressure (BP). Salt sensitivity is a critical factor in hypertension pathogenesis, but cumbersome to assess by gold-standard methodology. Twenty-four-hour average heart rate (HR) and mean arterial pressure (MAP) dipping, taken by ambulatory blood pressure monitoring (ABPM), stratifies patients into high, moderate, and low salt sensitivity index (SSI) risk categories. OBJECTIVES: We aimed to assess whether ABPM-derived SSI risk could predict the systolic blood pressure reduction at long-term follow-up in a real-world RDN patient cohort. METHODS: Sixty participants had repeat ABPM as part of a renal denervation long-term follow-up. Average time since RDN was 8.9 ±â€Š1.2 years. Based on baseline ABPM, participants were stratified into low (HR < 70 bpm and MAP dipping > 10%), moderate (HR ≥70 bpm or MAP dipping ≤ 10%), and high (HR ≥ 70 bpm and MAP dipping ≤ 10%) SSI risk groups, respectively. RESULTS: One-way ANOVA indicated a significant treatment effect ( P  = 0.03) between low ( n  = 15), moderate ( n  = 35), and high ( n  = 10) SSI risk with systolic BP reduction of 9.6 ±â€Š3.7 mmHg, 8.4 ±â€Š3.5 mmHg, and 28.2 ±â€Š9.6 mmHg, respectively. Baseline BP was not significantly different between SSI Risk groups ( P  = 0.18). High SSI risk independently correlated with systolic BP reduction ( P  = 0.02). CONCLUSIONS: Our investigation indicates that SSI risk may be a simple and accessible measure for predicting the BP response to RDN. However, the influence of pharmacological therapy on these participants is an important extraneous variable requiring testing in prospective or drug naive RDN cohorts.

Patient-Reported Outcomes to Describe Global Health and Family Relationships in Pediatric Weight Management.

Background: Patient-reported outcomes (PROs) can assess chronic health. The study aims were to pilot a survey through the PEDSnet Healthy Weight Network (HWN), collecting PROs in tertiary care pediatric weight management programs (PWMP) in the United States, and demonstrate that a 50% enrollment rate was feasible; describe PROs in this population; and explore the relationship between child/family characteristics and PROs. Methods: Participants included 12- to 18-year-old patients and parents of 5- to 18-year-olds receiving care at PWMP in eight HWN sites. Patient-Reported Outcomes Measurement Information System (PROMIS®) measures assessed global health (GH), fatigue, stress, and family relationships (FR). T-score cut points defined poor GH or FR or severe fatigue or stress. Generalized estimating equations explored relationships between patient/family characteristics and PROMIS measures. Results: Overall, 63% of eligible parents and 52% of eligible children enrolled. Seven sites achieved the goal enrollment for parents and four for children. Participants included 1447 children. By self-report, 44.6% reported poor GH, 8.6% poor FR, 9.3% severe fatigue, and 7.6% severe stress. Multiple-parent household was associated with lower odds of poor GH by parent proxy report [adjusted odds ratio (aOR) 0.69, 95% confidence interval (CI) 0.55-0.88] and poor FR by self-report (aOR 0.36, 95% CI 0.17-0.74). Parents were significantly more likely to report that the child had poor GH and poor FR when a child had multiple households. Conclusions: PROs were feasibly assessed across the HWN, although implementation varied by site. Nearly half of the children seeking care in PWMP reported poor GH, and family context may play a role. Future work may build on this pilot to show how PROs can inform clinical care in PWMP.

Taming resistant hypertension: The promise of novel pharmacologic approaches and renal denervation.

Resistant hypertension is associated with an exceedingly high cardiovascular risk and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline-recommended therapy. While spironolactone is widely considered as the preferable fourth-line drug, its broad application is limited by its side effect profile, especially off-target steroid receptor-mediated effects and hyperkalaemia in at-risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist, aprocitentan, the aldosterone synthase inhibitor, baxdrostat and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter-based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This review will summarise the recently published evidence on novel antihypertensive drugs and renal denervation in the context of resistant hypertension.

Association between pathologic response and survival after neoadjuvant therapy in lung cancer.

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0-100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0-5%, >5-30%, >30-80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528 .

Immune microenvironment of basal cell carcinoma and tumor regression following combined PD-1/LAG-3 blockade.

Systemic treatment options for patients with locally advanced or metastatic basal cell carcinoma (BCC) are limited, particularly when tumors are refractory to anti-programmed cell death protein-1 (PD-1). A better understanding of immune checkpoint expression within the BCC tumor microenvironment may inform combinatorial treatment strategies to optimize response rates. CD3, PD-1, programmed death ligand-1 (PD-L1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3)+ cell densities within the tumor microenvironment of 34 archival, histologically aggressive BCCs were assessed. Tumor infiltrating lymphocyte (TIL) expression of PD-1, PD-L1, and LAG-3, and to a lesser degree TIM-3, correlated with increasing CD3+ T-cell densities (Pearson's r=0.89, 0.72, 0.87, and 0.63, respectively). 100% of BCCs (34/34) demonstrated LAG-3 and PD-1 expression in >1% TIL; and the correlation between PD-1 and LAG-3 densities was high (Pearson's r=0.89). LAG-3 was expressed at ~50% of the level of PD-1. Additionally, we present a patient with locally-advanced BCC who experienced stable disease during and after 45 weeks of first-line anti-PD-1 (nivolumab), followed by a partial response after the addition of anti-LAG-3 (relatlimab). Longitudinal biopsies throughout the treatment course showed a graduated increase in LAG-3 expression after anti-PD-1 therapy, lending support for coordinated immunosuppression and suggesting LAG-3 as a co-target for combination therapy to augment the clinical impact of anti-PD-(L)1.