A Pilot Study of the CD38 Antagonist Daratumumab in Patients with Metastatic Renal Cell Carcinoma or Muscle-Invasive Bladder Cancer.

PURPOSE: We performed a pilot study of daratumumab (an mAb directed against CD38) in muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: Patients with MIBC underwent baseline transurethral resection of the bladder tumor followed by four weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent baseline and sequential biopsies after eight weekly doses. The primary endpoint was safety. The secondary endpoints were pathologic complete response rate for the MIBC cohort and objective response rate and progression-free survival for the mRCC cohort. Exploratory analyses included immune monitoring and overall survival. A Bayesian sequential monitoring design for toxicity was used for excessive toxicity. RESULTS: In both the MIBC (n = 8) and mRCC (n = 8) cohorts, no toxicity events were encountered. In the MIBC cohort, one patient experienced pathologic complete response rate. In the mRCC cohort, no objective responses were reported, and the median progression-free survival was 1.5 months (95% confidence interval, 1.1-1.8 months). Immune monitoring found significant reductions in NK cells in circulation in both cohorts after treatment. In the tissue analysis, IHC found evidence of diminished CD38 presence in mRCC with treatment, whereas the baseline levels in MIBC were low. CONCLUSION: Treatment with daratumumab was safe. No signal of efficacy was detected in mRCC, and conclusions on the activity in MIBC were limited. Evidence of daratumumab targeting CD38 was detected in circulating immune cells and within the tumor microenvironment of mRCC and MIBC. SIGNIFICANCE: In this prospective clinical trial of daratumumab, treatment in patients with MIBC and mRCC was safe. Limited efficacy was observed. Treatment with daratumumab resulted in CD38-expressing immune cell subsets to be targeted both in circulation and within the tumor microenvironment.

Trends of Buprenorphine Prescribing for Opioid Dependence Before, and During the Early and Later Part of the COVID-19: A Study from a Large Publicly-Funded Opioid Agonist Treatment Services in India.

BACKGROUND: The COVID-19 pandemic has affected the availability and access to medications for opioid dependence (OD). We examined the monthly trends in new buprenorphine/naloxone (BNX) treatment episodes, number of clinical visits for BNX, BNX dispensed per person, and BNX prescription over 56-month, which included pre-pandemic, during early, and later part of pandemic (Jan 2017 - Aug 2022). METHODS: Research data were collected from the pharmacy database of a large publicly funded treatment center in India. A flexible, low-threshold service was adopted in April 2020 in response to the lockdown implemented on 25 March 2020. Change Point analyses were performed to examine monthly trends visually and statistically. We used Autoregressive integrated moving averages to forecast trends from April to Aug 2020 and March to August 2022, using Jan 2017 to March 2020 and March 2020 to February 2022 as training datasets. RESULTS: 993 patients were started on BNX treatment, 40452 BNX clinic attendances were made, 1401393 BNX tablets were dispensed, and 6795 new patients with OD were registered. The observed data for clinic attendance for BNX was significantly lower than the projected estimates in April -Aug 2020; however, observed new treatment episodes and monthly BNX prescriptions were within the 95% projected estimates; BNX dispensed per person was significantly more than the projected estimate. In contrast, observed BNX prescription trends surpassed the upper limit of 95% CI in March-Aug 2022. CONCLUSION: A low-threshold and flexible treatment service could mitigate the unintended consequences of pandemic-induced restrictions.

Molecular Pathways and Cellular Subsets Associated with Adverse Clinical Outcomes in Overlapping Immune-Related Myocarditis and Myositis.

Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d, which were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results provide insight into the myeloid subsets present in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. See related Spotlight by Fankhauser et al., p. 954.

A Modular Trial of Androgen Signaling Inhibitor Combinations Testing a Risk-Adapted Strategy in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers. PATIENTS AND METHODS: In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone, and apalutamide (AAPA; module 1) and then allocated to modules 2 or 3 based on satisfactory (≥50% PSA decline from baseline and <5 circulating tumor cell/7.5 mL) versus unsatisfactory status. Men in the former were randomly assigned to continue AAPA alone (module 2A) or with ipilimumab (module 2B). Men in the latter group had carboplatin + cabazitaxel added to AAPA (module 3). Optional baseline biopsies were subjected to correlative studies. RESULTS: Median overall survival (from allocation) was 46.4 [95% confidence interval (CI), 39.2-68.2], 41.4 (95% CI, 33.3-49.9), and 18.7 (95% CI, 14.3-26.3) months in modules 2A (n = 64), 2B (n = 64), and 3 (n = 59), respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pretreatment metastatic biopsies. The aggressive-variant prostate cancer molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with unsatisfactory status. Exploratory analyses suggested that secreted phosphoprotein 1-positive and insulin-like growth factor-binding protein 2-positive macrophages, druggable myeloid cell markers, and germline pathogenic mutations were enriched in the unsatisfactory group. CONCLUSIONS: Adding ipilimumab to AAPA did not improve outcomes in men with androgen-responsive metastatic castration-resistant prostate cancer. Despite the addition of carboplatin + cabazitaxel, men in the unsatisfactory group had shortened survivals. Adaptive designs can enrich for biologically and clinically relevant disease subgroups to contribute to the development of marker-informed, risk-adapted therapy strategies in men with prostate cancer.

Review of plant-based milk analogue: its preparation, nutritional, physicochemical, and organoleptic properties.

In recent years, the market demand for plant-based milk analogues has been rising because of health concerns with bovine milk, like lactose intolerance and hypercholesteremia. Another reason is the lifestyle changes like adopting veganism. This review aims to offer a layout of the manufacturing process and discuss the different properties of plant-based milk analogues. The health benefits offered by the plant-based milk analogues and measures taken to eliminate the existing limitations are also discussed. Sensory profile and stability of plant-based milk analogues which add to the quality of the product were also taken into account and reviewed. The current review's objective is to present a comprehensive, scientifically comparable overview of the preparation procedures, nutritional content, and sensory characteristics of plant-based milk analogues. This is done while keeping in mind the potential of plant-based milk substitutes and associated challenges.

Genetic and phenotypic landscape of pediatric-onset epilepsy in 142 Indian families: Counseling and therapeutic implications.

The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022). Of these, 95% (60/63) of the families exhibited syndromes with developmental epileptic encephalopathy or progressive neurological deterioration. A definitive molecular diagnosis was achieved in 74 of 142 (52%) families. Infantile-onset epilepsy was noted in 81% of these families (61/74). Fifty-five monogenic, four chromosomal, and one imprinting disorder were identified in 74 families. The genetic variants included 65 (96%) single-nucleotide variants/small insertion-deletions, 1 (2%) copy-number variant, and 1 (2%) triplet-repeat expansion in 53 epilepsy-associated genes causing monogenic disorders. Of these, 35 (52%) variants were novel. Therapeutic implications were noted in 51% of families (38/74) with definitive diagnosis. Forty-one out of 66 families with monogenic disorders exhibited autosomal recessive and inherited autosomal dominant disorders with high risk of recurrence.

The post-operative tonsillectomy (POPT) study: A multi-centre prospective paediatric cohort study.

OBJECTIVES: Tonsillectomy is the most common operation performed by otolaryngologists in the UK, despite this we have a poor understanding of the post-operative recovery. We aimed to investigate post-operative bleeding and pain following paediatric tonsillectomy using a patient diary. DESIGN: Prospective observational cohort study. SETTING: Multi-centre study involving 12 secondary and tertiary otolaryngology units across the North of England. Patients were recruited from 1st March 2020 to 30th June 2022. Multilevel ordered logistic regression model statistics were performed. PARTICIPANTS: Children (≥4 years, ≤16 years) undergoing tonsillectomy (with or without adenoidectomy) for benign pathology. MAIN OUTCOME MEASURES: Frequency and severity of post-operative bleeding. Intensity and pattern of post-operative pain. RESULTS: In total 297 children were recruited, with 91 (30.6%) diaries eligible for analysis. Post-operative bleeding occurred in 44% of children. Most frequently blood in the saliva was reported (82.9%). Increasing age significantly increased bleeding odds by 17% per year (p = .001). Bleeding frequency decreased with higher surgeon grade (p = .003) and when performing intracapsular coblation tonsillectomy (p = .02) compared with other techniques. Lower age and intracapsular coblation tonsillectomy, against other techniques, significantly reduced rates of pain post-operatively (p < .0001 and p = .0008). CONCLUSION: A high level of low-level post-operative bleeding was observed. Pain scores remained high for 5 days post-operatively then gradually reduce to normal by day 13. Intracapsular coblation tonsillectomy appears to be superior to all other techniques in terms of reducing post-operative bleeding and pain. These findings should be used to guide patients in the consent process to inform them of the expected nature of post-surgical recovery.

Comprehensive phenotyping of fetuses with trisomy 18: a perinatal center experience.

Trisomy 18 is the second most common aneuploidy after trisomy 21. It presents with varying degrees of heterogeneous clinical phenotypes involving multiple organ systems, with a high mortality rate. Clinical assessment of fetal trisomy 18 is always challenging. In this study, we describe the phenotypes of the fetuses with trisomy 18 from a perinatal cohort. We reviewed fetuses with trisomy 18 in referrals for perinatal autopsy over the period of 15 years. A detailed phenotyping of the fetuses with trisomy 18 was executed by perinatal autopsy. Appropriate fetal tissues were obtained to perform genomic testing. We observed trisomy 18 in 16 fetuses (2%) in our cohort of 784 fetal/neonatal losses and a perinatal autopsy was performed on all of them. Abnormal facial profile was the most frequent anomaly (10/16, 62%) followed by anomalies of the extremities (9/16, 56%), and cardiac defects (6/16, 37%). We also observed esophageal atresia, diaphragmatic hernia, and neural tube defect. The study represents one of the largest cohorts of trisomy 18 from a perinatal center from a developing country and highlights the clinical heterogeneity attributed to trisomy 18. We also report a recurrence of trisomy 18 in a family.

Diagnostic validity of premenstrual dysphoric disorder: revisited.

The World Health Organization (WHO) and American Psychiatric Association (APA) have recognised premenstrual dysphoric disorder (PMDD) as an independent diagnostic entity, legitimising the distress and socio-occupational impairment experienced by affected women. However, the biological validity of this diagnosis remains inexplicit. This illness has also been criticised for a feminist-led, sympathetic reaction to the modern cultural challenges of urban, literate, employed, high-functioning women. This article systematically reviews existing literature on PMDD using the criteria established by Robins and Guze for the validity of a psychiatric diagnosis (clinical description, laboratory study, exclusion of other disorders, follow-up study, and family study). Despite the early recognition of premenstrual syndrome (PMS) in the 1950s, the research has encountered challenges due to two groups of proponents viewing it with psychologising bias and medicalising bias. PMDD is currently understood as the most severe form of PMS, characterised by the presence of psychological features. Recent evidence suggests that PMDD perhaps has neurodevelopmental underpinnings (attention deficit hyperactive disorder, adverse childhood experiences) affecting the fronto-limbic circuit that regulates the emotions. In addition, the affected individuals exhibit an increased sensitivity to gonadal hormonal fluctuations as observed during premenstrual, pregnancy, and perimenopausal phases of life. The prevalence is comparable between high-income countries and low- and middle-income countries (LAMIC), refuting the notion that it mostly affects modern women. Instead, a greater prevalence is observed in LAMIC. Despite the fact that educated women possess knowledge regarding the importance of getting help, there is a prevalent issue of inadequate help-seeking behaviour. This can be attributed to the perception of seeking help as an isolating experience, which is influenced by profound internalised stigma and discrimination in the workplace. Future studies must aim to develop culturally validated assessment tools and more research to understand the life course of the illness, in addition to systematically examining for more biological validators (animal models, genetics, imaging, neurotransmitters).

De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.

The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.

Microstructure, hardness and wear behavior of ZrC particle reinforced AZ31 surface composites synthesized via friction stir processing.

Dry sliding wear behaviour of friction stir processed (FSP) AZ31 and AZ31/ZrC particles (5, 10, and 15 vol%) reinforced surface composite was investigated at different sliding speeds and loads. The samples were tested using a pin-on-disc apparatus with EN31 steel as the counter body to determine the role of FSP and ZrC reinforcement on the microstructure, hardness, and wear behaviour of AZ31. Base metal AZ31 alloy exhibits a hardness of 60 HV, whereas the 15 vol% ZrC-reinforced composites had the highest hardness of 108 HV. It was also identified that 15 vol% ZrC-reinforced composites exhibited lowest wear rate and friction coefficient under all testing conditions. Abrasion, delamination, oxidation, material softening, and plastic deformation are the primary wear mechanisms viewed from the wear tracks of the samples. Higher volume fraction of ZrC particles exhibited better wear resistance at all speeds and loads than AZ31 alloy. A wear map has been generated for different material compositions and wear conditions to identify the main wear mechanisms easily.

Non-thermal, energy efficient hydrodynamic cavitation for food processing, process intensification and extraction of natural bioactives: A review.

Hydrodynamic cavitation (HC) is the process of bubbles formation, expansion, and violent collapse, which results in the generation of high pressures in the order of 100-5000 bar and temperatures in the range of 727-9727 °C for just a fraction of seconds. Increasing consumer demand for high-quality foods with higher nutritive values and fresh-like sensory attributes, food processors, scientists, and process engineers are pushed to develop innovative and effective non-thermal methods as an alternative to conventional heat treatments. Hydrodynamic cavitation can play a significant role in non-thermal food processing as it has the potential to destroy microbes and reduce enzyme activity while retaining essential nutritional and physicochemical properties. As hydrodynamic cavitation occurs in a flowing liquid, there is a decrease in local pressure followed by its recovery; hence it can be used for liquid foods. It can also be used to create stable emulsions and homogenize food constituents. Moreover, this technology can extract food constituents such as polyphenols, essential oils, pigments, etc., via biomass pretreatment, cell disruption for selective enzyme release, waste valorization, and beer brewing. Other applications related to food production include water treatment, biodiesel, and biogas production. The present review discusses the application of HC in the preservation, processing, and quality improvement of food and other related applications. The reviewed examples in this paper demonstrate the potential of hydrodynamic cavitation with further expansion toward the scaling up, which looks at commercialization as a driving force.

Effectiveness of buprenorphine (naloxone) for opioid dependence does not differ across opioid categories: a retrospective cohort study from India.

We aimed to examine whether treatment retention, abstinence, and adherence to buprenorphine-naloxone (BNX) differ among individuals with opioid dependence (OD) across three common categories of opioids- heroin, opium, and low-potency pharmaceutical. In a retrospective cohort study, we analyzed outpatient treatment records from March 2020 through February 2022. Opioid category was determined by lifetime and current opioid use. We defined treatment retention as weeks of uninterrupted clinic attendance. Abstinence and BNX adherence were calculated by weeks of extra-medical opioid-negative and buprenorphine-positive urine screening from treatment initiation. Four-hundred-thirteen patients were eligible; 406 (98.3%) were included in the final analysis. Two-hundred-ninety (71.4%) patients were dependent on heroin; 66 (16.3%) were natural opioid dependent, and 50 (12.3%) were dependent on low-potency pharmaceutical opioids. BNX effectiveness in treatment retention, abstinence, and adherence did not differ in patients dependent on heroin, natural, and low-potency pharmaceutical opioids. Patients on ≥8 mg daily BNX had better retention and adherence than those on <8 mg daily. Patients from lower socioeconomic status (SES) had higher odds of retention, abstinence, and adherence than those from upper/middle SES. Treatment outcomes on BNX did not differ across opioid categories. However, BNX should be dosed adequately.

Kisspeptin neuron projections to oxytocin neurons are not necessary for parturition in the mouse.

Oxytocin is synthesized by hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) neurons and is released from the posterior pituitary gland to trigger uterine contractions during parturition. In rats, oxytocin neuron innervation by periventricular nucleus (PeN) kisspeptin neurons increases over pregnancy and intra-SON kisspeptin administration excites oxytocin neurons only in late pregnancy. To test the hypothesis that kisspeptin neurons excite oxytocin neurons to trigger uterine contractions during birth in C57/B6J mice, double-label immunohistochemistry for kisspeptin and oxytocin first confirmed that kisspeptin neurons project to the SON and PVN. Furthermore, kisspeptin fibers expressed synaptophysin and formed close appositions with oxytocin neurons in the mouse SON and PVN before and during pregnancy. Stereotaxic viral delivery of caspase-3 into the AVPV/PeN of Kiss-Cre mice before mating reduced kisspeptin expression in the AVPV, PeN, SON and PVN by > 90% but did not affect the duration of pregnancy or the timing of delivery of each pup during parturition. Therefore, it appears that AVPV/PeN kisspeptin neuron projections to oxytocin neurons are not necessary for parturition in the mouse.

Early and severe tricuspid valve dysplasia in a fetus with cardiospondylocarpofacial syndrome due to a variant c.616T>G p.(Tyr206Asp) in MAP3K7.

Cardiospondylocarpofacial syndrome (CSCF; MIM#157800) is a rare condition caused by monoallelic variants in the MAP3K7 gene. The characteristic features of CSCF include growth retardation, facial dysmorphism, carpal-tarsal fusion, dorsal spine synostosis, deafness, inner ear malformation, cardiac septal defect and valve dysplasia. We present here a 20-week-old fetus with cardiospondylocarpofacial syndrome arising from a de novo variant c.616T>G p.(Tyr206Asp) in the MAP3K7 (NM_145331.3) gene with early and severe tricuspid valve dysplasia as a prenatal manifestation. Fetal echocardiography revealed tricuspid regurgitation with valve prolapse. Fetus had facial dysmorphism and dilated right atrium and right ventricle with tricuspid valve dysplasia on perinatal evaluation. To the best of our knowledge, this is the first report mentioning the prenatal manifestation of cardiospondylocarpofacial syndrome.

Deep intronic mutation in CRTAP results in unstable isoforms of the protein to induce type I collagen aggregation in a lethal type of osteogenesis imperfecta type VII.

Genetic mutations are involved in Mendelian disorders. Unbuffered intronic mutations in gene variants can generate aberrant splice sites in mutant transcripts, resulting in mutant isoforms of proteins with modulated expression, stability, and function in diseased cells. Here, we identify a deep intronic variant, c.794_1403A>G, in CRTAP by genome sequencing of a male fetus with osteogenesis imperfecta (OI) type VII. The mutation introduces cryptic splice sites in intron-3 of CRTAP, resulting in two mature mutant transcripts with cryptic exons. While transcript-1 translates to a truncated isoform (277 amino acids) with thirteen C-terminal non-wild-type amino acids, transcript-2 translates to a wild-type protein sequence, except that this isoform contains an in-frame fusion of non-wild-type twenty-five amino acids in a tetratricopeptide repeat sequence. Both mutant isoforms of CRTAP are unstable due to the presence of a unique 'GWxxI' degron, which finally leads to loss of proline hydroxylation and aggregation of type I collagen. Although type I collagen aggregates undergo autophagy, the overall proteotoxicity resulted in death of the proband cells by senescence. In summary, we present a genetic disease pathomechanism by linking a novel deep intronic mutation in CRTAP to unstable mutant isoforms of the protein in lethal OI type VII.

Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial.

Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7-43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6-61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129 .).

Immune and pathologic responses in patients with localized prostate cancer who received daratumumab (anti-CD38) or edicotinib (CSF-1R inhibitor).

BACKGROUND: The prostate tumor microenvironment (TME) is immunosuppressive, with few effector T cells and enrichment of inhibitory immune populations, leading to limited responses to treatments such as immune checkpoint therapies (ICTs). The immune composition of the prostate TME differs across soft tissue and bone, the most common site of treatment-refractory metastasis. Understanding immunosuppressive mechanisms specific to prostate TMEs will enable rational immunotherapy strategies to generate effective antitumor immune responses. Daratumumab (anti-CD38 antibody) and edicotinib (colony-stimulating factor-1 receptor (CSF-1R) inhibitor) may alter the balance within the prostate TME to promote antitumor immune responses. HYPOTHESIS: Daratumumab or edicotinib will be safe and will alter the immune TME, leading to antitumor responses in localized prostate cancer. PATIENTS AND METHODS: In this presurgical study, patients with localized prostate cancer received 4 weekly doses of daratumumab or 4 weeks of daily edicotinib prior to radical prostatectomy (RP). Treated and untreated control (Gleason score ≥8 in prostate biopsy) prostatectomy specimens and patient-matched pre- and post-treatment peripheral blood mononuclear cells (PBMCs) and bone marrow samples were evaluated. The primary endpoint was incidence of adverse events (AEs). The secondary endpoint was pathologic complete remission (pCR) rate. RESULTS: Twenty-five patients were treated (daratumumab, n=15; edicotinib, n=10). All patients underwent RP without delays. Grade 3 treatment-related AEs with daratumumab occurred in 3 patients (12%), and no ≥grade 3 treatment-related AEs occurred with edicotinib. No changes in serum prostate-specific antigen (PSA) levels or pCRs were observed. Daratumumab led to a decreased frequency of CD38+ T cells, natural killer cells, and myeloid cells in prostate tumors, bone marrow, and PBMCs. There were no consistent changes in CSF-1R+ immune cells in prostate, bone marrow, or PBMCs with edicotinib. Neither treatment induced T cell infiltration into the prostate TME. CONCLUSIONS: Daratumumab and edicotinib treatment was safe and well-tolerated in patients with localized prostate cancer but did not induce pCRs. Decreases in CD38+ immune cells were observed in prostate tumors, bone marrow, and PBMCs with daratumumab, but changes in CSF-1R+ immune cells were not consistently observed with edicotinib. Neither myeloid-targeted agent alone was sufficient to generate antitumor responses in prostate cancer; thus, combinations with agents to induce T cell infiltration (eg, ICTs) will be needed to overcome the immunosuppressive prostate TME.

Transdiagnostic investigation into the relationship between mirror neuron system activity, echo-phenomena, and theory of mind in major psychoses.

The association between social cognition and putative mirror neuron system (MNS)-activity in major psychoses might be contingent upon frontal dysregulation. We used a transdiagnostic ecological approach to enrich a specific behavioral phenotype (echophenomena or hyper-imitative states) across clinical diagnoses (mania and schizophrenia) to compare behavioral and physiological markers of social cognition and frontal disinhibition. We examined 114 participants with schizophrenia (N = 53) and mania (N = 61) for the presence and severity of echo-phenomena (echopraxia, incidental, and induced echolalia) using an ecological paradigm to simulate real-life social communication. Symptom severity, frontal release reflexes, and theory of mind performance were also assessed. In a proportion of these participants with (N = 20) and without (N = 20) echo-phenomena, we compared motor resonance (motor evoked potential facilitation during action observation compared to static image viewing) and cortical silent period (CSP) as putative markers of MNS-activity and frontal disinhibition, respectively, using Transcranial Magnetic Stimulation. While the prevalence of echo-phenomena was similar between mania and schizophrenia, incidental echolalia was more severe in mania. Participants with echo-phenomena (compared to those without) had significantly greater motor resonance with singlepulse (not with paired-pulse) stimuli, poorer theory of mind scores, higher frontal release reflexes but similar CSP, and greater symptom severity. None of these parameters significantly differed between participants with mania and schizophrenia. We observed relatively better phenotypic and neurophysiological characterization of major psychoses by categorizing participants based on the presence of echophenomena than clinical diagnoses. Higher putative MNS-activity was associated with poorer theory of mind in a hyper-imitative behavioral state.