Durable benefit from poly(ADP-ribose) polymerase inhibitors in metastatic prostate cancer in routine practice: biomarker associations and implications for optimal clinical next-generation sequencing testing.

BACKGROUND: Controlled trials have consistently demonstrated the efficacy of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1 or BRCA2 alterations (BRCAalt). However, the reported efficacy of PARPi for alterations in other homologous recombination repair (HRR) genes is less consistent. We sought to evaluate the routine practice effectiveness of PARPi between and within these groups. DESIGN: Patient-level data from a deidentified nationwide (USA-based) cancer clinico-genomic database between January 2011 and September 2023 were extracted. Patients with mCRPC and comprehensive genomic profiling by liquid biopsy [circulating tumor DNA (ctDNA)] or tissue (tumor) biopsy and who received single-agent PARPi were included and grouped by BRCAalt, ATMalt, other HRR, or no HRR. We further subcategorized BRCAalt into homozygous loss (BRCAloss) and all other deleterious BRCAalt (otherBRCAalt). RESULTS: A total of 445 patients met inclusion criteria: 214 with tumor and 231 with ctDNA. BRCAalt had more favorable outcomes to PARPi compared with ATM, other HRR, and no HRR groups. Within the BRCAalt subgroup, compared with other BRCAalt, BRCAloss had a more favorable time to next treatment (median 9 versus 19.4 months, P = 0.005), time to treatment discontinuation (median 8 versus 14 months, P = 0.006), and routine practice overall survival (median 14.7 versus 19.4 months, P = 0.016). Tumor BRCAloss prevalence (3.1%) was similar to ctDNA prevalence in liquid biopsy specimens with high tumor fraction (>20%). BRCAloss was not detected in orthogonal germline testing. CONCLUSIONS: PARPi routine practice effectiveness between groups mirrors prospective trials. Within the BRCAalt group, BRCAloss had the best outcomes. Unless the ctDNA tumor fraction is very high, somatic tissue testing (archival or metastatic) should be prioritized to identify patients who may benefit most from PARPi. When tissue testing is not clinically feasible, sufficient ctDNA tumor fraction levels for detection are enriched at clinical timepoints associated with tumor progression.

Randomized phase 2 dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma.

BACKGROUND: Belzutifan is a first-in-class HIF-2α inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed death receptor (or ligand)-1 (PD-[L]1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether belzutifan dose could be optimized is unclear. PATIENTS AND METHODS: The phase 2 LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after 1-3 prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1:1 to receive belzutifan 120 mg or 200 mg once daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 154 patients were enrolled (120 mg: n = 76; 200 mg: n = 78). Median follow-up was 20.1 months (range 14.8-28.4). ORR was 23.7% vs 23.1% for the 120 mg and 200 mg groups, respectively (P = 0.5312; -0.5% [95% CI, -14.0 to 12.9]. Median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS (HR 0.94 [95% CI 0.63-1.40]) or OS (medians not reached; HR 1.11 [95% CI, 0.65-1.90]). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group. CONCLUSION: The efficacy of belzutifan was similar between the 120-mg dose and the 200-mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.

Prognostic significance of absolute lymphocyte count in patients with metastatic renal cell carcinoma receiving first-line combination immunotherapies: results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared. RESULTS: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707). CONCLUSIONS: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era.

Elevated middle cerebral artery peak systolic velocity and risk of death in donor twin affected by twin-twin transfusion syndrome but not twin anemia-polycythemia sequence.

OBJECTIVES: To determine the association between elevated (> 1.5 multiples of the median (MoM)) middle cerebral artery (MCA) peak systolic velocity (PSV) and fetal demise of the donor twin in pregnancies complicated by twin-twin transfusion syndrome (TTTS) in the absence of twin anemia-polycythemia sequence (TAPS). Secondary objectives were to evaluate if donor or recipient MCA-PSV is associated with a risk for their corresponding fetal death, and to compare the proportion of donor fetuses with low MCA pulsatility index (PI) among donor twins with high MCA-PSV and those with normal MCA-PSV to evaluate the contribution of blood-flow redistribution to the fetal brain in donor twins with high MCA-PSV. METHODS: This prospective cohort study included TTTS cases that underwent laser surgery between 2011 and 2022 at a single center. TAPS cases were excluded from the study. Multivariable and Poisson regression analysis were performed to explore the association between isolated elevated donor MCA-PSV and fetal demise, adjusted for TTTS stage, selective fetal growth restriction (sFGR) and other confounders. RESULTS: Of 660 TTTS cases, donor MCA-PSV was not recorded in 48 (7.3%) cases. Of the remaining 612 patients, nine (1.5%) were lost to follow-up and 96 TAPS cases were excluded; thus, 507 cases were included in the study. High donor MCA-PSV was seen in 6.5% (33/507) of cases and was an independent risk factor for donor fetal demise (adjusted relative risk (aRR), 4.52 (95% CI, 2.72-7.50)), after adjusting for confounders. Regression analysis restricted to each Quintero TTTS stage demonstrated that high donor MCA-PSV was an independent risk factor for fetal demise of the donor in Quintero Stage II (aRR, 14.21 (95% CI, 1.09-186.2)) and Quintero Stage III (aRR, 3.41 (95% CI, 1.82-6.41)). Donor MCA-PSV in MoM was associated with fetal demise of the donor (area under the receiver-operating-characteristics curve (AUC), 0.69; P < 0.001), but recipient MCA-PSV in MoM was not associated with fetal demise of the recipient (AUC, 0.54; P = 0.44). A higher proportion of donor twins in the group with high MCA-PSV had a low MCA-PI compared to the group with normal MCA-PSV (33.3% vs 15.5%; P = 0.016). CONCLUSIONS: Elevated donor MCA-PSV without TAPS prior to laser surgery for TTTS is associated with a 4-fold increased risk for donor fetal demise, adjusted for sFGR, TTTS stage and other confounders. Doppler evaluation of donor MCA-PSV prior to laser surgery may help stratify TTTS staging to evaluate the risk of donor fetal demise. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Management of large placental chorioangioma: two-port laser approach for fetal intervention.

OBJECTIVES: There is a paucity of literature providing evidence-based guidelines for the management of large placental chorioangioma (≥ 4 cm in diameter). The objectives of this study were to compare outcomes between patients managed expectantly and those undergoing in-utero intervention and to describe the different in-utero techniques used for cessation of blood flow to the tumor and the associated outcome. METHODS: This was a retrospective cohort study of 34 patients referred for the management of large placental chorioangioma in a single center between January 2011 and December 2022, who were managed expectantly or underwent in-utero intervention. In-utero intervention was performed when the fetus developed any signs of impending compromise, including high combined cardiac output (CCO), worsening polyhydramnios or abnormal fetal Doppler velocimetry findings. Interventions included radiofrequency ablation (RFA), interstitial laser ablation (ILA) and single-port or two-port fetoscopic laser photocoagulation (FLP). Treatment selection was dependent on the proximity of the tumor to the umbilical cord insertion (UCI) and placental location. The two-port technique was performed in patients with a chorioangioma with large feeding vessels (≥ 3 mm) located in the posterior placenta, in which one port was used for occlusion using bipolar forceps and the other port was used for laser photocoagulation of the feeding vessels downstream. The single-port technique was used for chorioangioma with small feeding vessels (< 3 mm) located in the posterior placenta. ILA or RFA was performed in cases with an anterior placenta. Supportive treatments, including amnioreduction and intrauterine transfusion (IUT), were performed for worsening polyhydramnios and suspected fetal anemia based on middle cerebral artery Doppler flow studies, respectively. Comparative statistical analysis between cases undergoing expectant management vs in-utero intervention was performed. Descriptive details were provided for patients who underwent in-utero intervention. RESULTS: Thirty-four cases of large chorioangioma were evaluated, of which 25 (73.5%) were managed expectantly and nine (26.5%) underwent intervention. The frequency of polyhydramnios was significantly higher in the intervention group compared with the expectant-management group (66.7% vs 8.0%, P < 0.001). The live-birth rate among expectantly managed cases with large chorioangioma was significantly higher compared with that in cases that underwent in-utero intervention (96.0% vs 62.5%, P = 0.01). In the intervention group, preoperative CCO was elevated in all cases with available information and preoperative hydrops was present in 33.3% (3/9) of cases. One patient experienced fetal demise following IUT prior to planned FLP. Among the remaining eight patients, four underwent two-port FLP, two underwent single-port FLP, one underwent ILA and one underwent both ILA and RFA. All three cases in which hydrops was present at the time of intervention resulted in fetal demise. CONCLUSIONS: In-utero interventions aimed at cessation of blood flow in the feeding vessels are a therapeutic option for the management of cases with large chorioangioma. The two-port percutaneous technique appears to improve the efficiency of FLP when a large chorioangioma with large feeding vessels is located in the posterior placenta. We propose that in-utero interventions for large chorioangioma should be initiated prior to the development of fetal hydrops. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Prognostic significance of soft tissue deposits in head and neck squamous cell carcinoma: a systematic review and meta-analysis.

Soft tissue deposits, also known as tumour deposits (TDs), have not been studied well in head and neck squamous cell carcinoma (HNSCC) and are not included in any of the staging systems or treatment guidelines. The aim of this systematic review was to determine the prevalence and prognostic implications of TDs in patients with HNSCC. This systematic review of the literature was conducted following the PRISMA guidelines. The PubMed, Embase, and Scopus electronic databases were searched for relevant studies, from inception to August 2022. Although 14 studies qualified for inclusion, only eight were finally included in the review due to the considerable overlap of patients in several studies. Data from 7127 patients were analysed. The pooled prevalence of TDs was 21% (95% confidence interval (CI) 9-33%). The presence of TDs was adversely associated with overall survival and disease-free survival, with hazard ratios of 2.08 (95% CI 1.60-2.70) and 2.56 (95% CI 1.97-3.32), respectively. TDs are detected in a significant number of patients with HNSCC and adversely affect survival. Longitudinal prospective studies are needed to evaluate the prognostic implications of TDs in HNSCC for their potential role in cancer staging and adjuvant treatment planning.

Microencapsulated and Lyophilized Lactobacillus acidophilus Improved Gut Health and Immune Status of Preruminant Calves.

The present study was conducted to study the effect of microencapsulated, lyophilized, or fermented milk using Lactobacillus acidophilus NCDC15 as a probiotic to improve gut health, growth, nutrient utilization, and immunity status of young crossbred calves. The viable culture of L. acidophilus was used for preparation of different probiotic forms/products. To compare the efficacy of probiotic products, twenty crossbred calves (3-day old) were divided into four groups (n = 5), control (C), fed only milk and basal diet, and treatment groups, supplemented with microencapsulated, fermented, and lyophilized probiotic at 108 colony-forming units, respectively. Probiotic-supplemented groups showed reduction in faecal score, faecal pH, and ammonia concentration as compared to control indicating decreased diarrheal incidence. There was an increase (P < 0.05) in the concentration of faecal lactate and butyrate in the probiotic-supplemented groups. The faecal count (log10 (CFU)/g of fresh faeces) of lactobacilli and bifidobacteria was higher (P < 0.05), whereas faecal coliforms and clostridia count were reduced (P < 0.001) in all the probiotic fed groups as compared to control. The cell-mediated immunity was improved (P < 0.05) in the microencapsulated and fermented probiotic groups. However, there was no effect on the nutrient utilization, average daily gain, and blood biochemical profile. Therefore, it is concluded that the fermented, microencapsulated and lyophilized probiotic products were superior in improving the gut health in terms of its microbiota and metabolites and cell-mediated immunity response in calves, irrespective of form of probiotic. The increased population of Lactobacillus and Bifidobacterium decreased the colonization of the gut by pathogens such as Escherichia coli and Clostridium by exclusion and production of organic acids in the intestine. This decreased the diarrhoeal incidence (1.3 vs 1.8) and days in diarrhoea (3.9 vs 5.8) in calves in probiotic fed groups as compared to control.

Can Early Thyroid Profiling Help Avert Spontaneous Abortions/Early Pregnancy Loss: A Retrospective Study.

Presence of thyroid autoantibodies in euthyroid women can result in various complications such as miscarriages and pre-eclampsia. Women who are hypothyroid have an increased risk of anaemia, infertility, and preterm birth. Spontaneous miscarriages have been reported in association with women with antithyroid antibodies. This can be utilised as a supplementary marker for the mother's immune system failure. The goal of this study was to compare the thyroid profiles of pregnant women who had a normal delivery to those who had a high-risk obstetric history, and to see if early thyroid profiling can help prevent poor pregnancy outcomes. In conclusion, our analysis has demonstrated that women with abnormal values of T4, T3, anti-thyroid peroxidase (TPO), and TSH were associated with fetal demise when compared to women with normal values of T4, T3, anti-TPO, and TSH. Anti-TPO levels were shown to be elevated in women with a poor obstetric history, making early thyroid profiling improve outcomes in pregnancy. Hypothyroidism with increased TSH and anti-TPO levels may have a negative impact on obstetric history, resulting in the loss of an early pregnancy.

Predictors of Metabolic Complications in Obese Indian Children and Adolescents.

OBJECTIVE: To identify predictors of metabolic complications in obese Indian children and adolescents. METHODS: This cross-sectional study included 282 obese children and adolescents [188 boys, mean (SD) age of 11.7 (3.1) y, body mass index standard deviation score (BMI SDS) 2.4 (0.6)] who underwent metabolic work-up (oral glucose tolerance test, SGPT, lipid profile) and adiposity assessment (waist circumference and Dual energy X-ray absorptiometry). RESULTS: One hundred and fifteen subjects (40.8%) had no metabolic complication (metabolic healthy obesity) with similar prevalence across BMI SDS categories (38.8% for BMI SDS below 2, 42.1% for 2-3 and 40.4% for those above 3). Normal birth weight (odds ratio 3.2, 95% confidence interval 1.0-10.1, p = 0.04), negative family history of type 2 diabetes (odds ratio 1.81, 95% confidence interval 1.0-3.3, p = 0.04) and younger age [11.3 (3.1) y as against 12.1 (3.1) y, p = 0.03] were associated with metabolically healthy obesity. No difference in BMI SDS [2.4 (0.6) as against 2.4 (0.6), p = 0.7], waist circumference SDS [2.0 (0.7) as against 2.2 (0.9), p = 0.07], waist to height ratio [0.6 (0.05) as against 0.6 (0.05), p = 0.1], DXA derived fat percentage [48.6 (5.4)% as against 47.8% (5.2), p = 0.2], android to gynoid ratio [1.05 (0.1) as against 1.06 (0.1), p = 0.08] and fat mass index [13.8 (3.5) as against 13.8 (3.3), p = 0.9] was observed in the two groups. CONCLUSIONS: A substantial proportion of obese children and adolescents do not develop metabolic complications. Birth weight and family history of type 2 diabetes are the only predictors of complications. Further exploration is needed to identify interventional targets.

Insights into Metatranscriptome, and CAZymes of Buffalo Rumen Supplemented with Blend of Essential Oils.

The aim of this study was to investigate the rumen microbial diversity and functionality in buffaloes fed with a blend of essential oils (BEO) using LSD switch over design. The BEO consisting of blend of Trachyspermum copticum (Ajwain) oil, Cymbopogon citratus (lemon grass) oil and Syzygium aromaticum (clove bud) oleoresin mixed in equal proportion, was fed at the rate of 0, 0.75 and 1.5 ml/100 kg of body weight in 0 (control), 0.75 and 1.5 groups, respectively. The metatranscriptomic libraries of the rumen microbiome were represented by 7 domains, 84 phyla, 64 archeal genera and 663 bacterial genera with Bacteroidetes and Firmicutes constituting 80% of phyla abundance irrespective of feeding regime. Methanogenic archaea was represented by 22 phyla with Methanobrevibacter as the major genus. BEO feeding reduced the abundance of Methanococcus and Thermoplasma (P < 0.05) at all levels. The results revealed that the feeding of BEO shifted the archeal and bacterial population at very low magnitude. The study explored the vast diversity of buffalo rumen bacteria and archaea, and the diverse wealth of rumen enzymes (CAZymes), which revealed that a major part of CAZymes comes from the less known rumen microbes indicating alternative paths of fiber degradation along with the very well known ones.

Celiac Disease in Indian Children and Adolescents with Type 1 Diabetes.

To estimate the time trend and prevalence of celiac disease in 208 children with type 1 diabetes by retrospective case review. Tissue transglutaminase (TTG IgA) levels were done within the first six months of diagnosis and annually on follow-up. Celiac disease was diagnosed in 35 (16.8%; 3 before diagnosis, 18 at initial screening and 14 on follow-up). 14 subjects with negative TTG serology at presentation, developed celiac disease after 3.9 (2.9) years (range 1.4 - 12.6 years, 85.7% within 5 years). Celiac disease is common in Indian children and adolescents with type I diabetes, developing in most within five years of diagnosis.

Factors Associated With Cerebral Edema at Admission in Indian Children with Diabetic Ketoacidosis.

OBJECTIVE: To evaluate the time course and predictors of cerebral edema in diabetic ketoacidosis (DKA). METHODS: Review of hospital records of 107 episodes of DKA between January 2013 to March 2019. RESULTS: Cerebral edema was identified in 26 (24.3%; 22 at presentation and 4 during treatment). Cerebral edema at presentation was associated with lower (<10 mmHg) arterial carbon dioxide (OR 3.6, 95% CI 1.0,12.7; P=0.04), prior fluid treatment (OR 4.7, 95% CI 1.8,12.7; P=0.001) and new onset diabetes (OR 3.5, 95% CI 1.1,11.1; P=0.03). Prior fluid was the only significant predictor on multivariate analysis (P=0.013). Cerebral edema resulted in a longer ICU stay [4.1 (2.3) vs 1.8 (0.9) d; P<0.001]. CONCLUSIONS: Cerebral edema at admission is common in Indian children with DKA and should be suspected with severe metabolic acidosis and inappropriate prior fluid treatment.

Low caloric intake and high fluid intake during the first week of life are associated with the severity of bronchopulmonary dysplasia in extremely low birth weight infants.

OBJECTIVE: To study whether there is an association between nutritional intake during the first week of life and severity of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. METHODS: In a retrospective cohort study, medical records of all ELBW infants admitted to our Neonatal Intensive Care Unit (2010-2017) were reviewed for infants' demographics, clinical characteristics, nutritional intake during their first week of life, and BPD risk factors. RESULTS: During the study period 226 infants were identified of whom 67% (151/226) had moderate-severe BPD and the rest served as controls. Overall infants with moderate-severe BPD were younger, smaller, and spent more time on mechanical ventilation than their controls [(mean±standard deviation) 24.7±1.7 vs. 26.8±2.0 weeks gestational age (p < 0.001); 678±154 vs. 837±129 grams (p < 0.001); and 37.9±23.6 vs. 13.7±15.3 days (p < 0.001) respectively]. During the first week of life, the average caloric, carbohydrate, protein and lipid intakes were significantly lower, and the average fluid intake was significantly higher in the moderate-severe BPD than the control group. After adjustment for confounders, fluid intake, and days on mechanical ventilation were significantly associated with moderate-severe BPD with an odds ratio [OR (95% confidence interval)] of 1.03 (1.01-1.04), and 1.05 (1.03-1.07) respectively. Daily caloric intake was associated with an increased risk for moderate-severe BPD [OR: 0.94 (0.91-0.97)]. CONCLUSION: Low caloric intake, and high fluid intake during the first week of life are associated with the severity of BPD in ELBW infants.