Effect of Androgen-Androgen Receptor Directed Therapy on COVID-19 Outcome in Prostate Cancer Patients.

TMPRSS2 is utilized by SARS-CoV-2 for cellular entry. Androgen-Androgen receptor directed therapy (A/ARDT) downregulates expression of TMPRSS2. We hypothesized A/ARDT might protect prostate cancer (PCa) patients from poor COVID-19 outcome. A retrospective analysis of PCa patients with COVID-19 infection was performed. 146 PCa cases were identified, 17% were on A/ARDT. Hospitalization rates were same 52% (OR = 0.99, 0.41-2.24). Mean hospitalization was 9.2 (Range: 1-25) and 14.9 (Range: 2-47) days in A/ARDT and non-A/ARDT groups, respectively. While definitive conclusions cannot be made regarding outcome differences between groups due to lack of statistical significance, these data generate hypothesis that A/ARDT might shorten hospitalization stay.

Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

BACKGROUND: Memory CD8+ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer's disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8+ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity. RESULTS: We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing. CONCLUSIONS: We report differential expression of "normal" aging genes associated with IL-7Rαlow EM CD8+ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8+ T cells, in AD.

Defining Clinical and Immunological Predictors of Poor Immune Responses to COVID-19 mRNA Vaccines in Patients with Primary Antibody Deficiency.

Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4+ T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4+ T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19+ B-cells, switched memory B-cells, naïve CD8+ T-cells, and a higher frequency of EM CD8+ T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity.

Emerging Role of PARP Inhibitors in Metastatic Prostate Cancer.

PURPOSE OF REVIEW: We highlight the clinical development of Poly (ADP-Ribose) polymerase (PARP) inhibitors in prostate cancer. RECENT FINDINGS: Approximately 10 to 30% of metastatic prostate cancer patients carry germline or somatic mutations in DNA repair pathways. BRCA2 is the most commonly mutated gene in DNA damage repair pathways. Because of its critical function in homologous recombination repair (HRR) machinery, deleterious BRCA2 mutation enables synthetic lethality to a PARP inhibitor. Olaparib demonstrated clinical benefit in patients with deleterious mutations in HRR-related genes and most clearly in patients with BRCA2 mutations. Olaparib received the US FDA approval or mCRPC patients with a qualifying HRR gene mutation in May 2020. Rucaparib received an accelerated FDA approval for patients with BRCA1- or BRCA2-mutated mCRPC based on 43% objective response rate in a phase II study. To expand the application of a PARP inhibitor, several trials have evaluated various combination strategies with an androgen receptor signaling inhibitor, immunotherapy, radium-223, and others. While no PARP inhibitor combination regimen has been approved, promising data from a PARP inhibitor and an ASI combination have been reported. PARP inhibitor represents a standard treatment for patient with mCRPC with germline or somatic mutations in BRCA2 and other HRR pathway genes.

A distinct association of inflammatory molecules with outcomes of COVID-19 in younger versus older adults.

Aging can alter immunity affecting host defense. COVID-19 has the most devastating clinical outcomes in older adults, raising the implication of immune aging in determining its severity and mortality. We investigated biological predictors for clinical outcomes in a dataset of 13,642 ambulatory and hospitalized adult COVID-19 patients, including younger (age < 65, n = 566) and older (age ≥ 65, n = 717) subjects, with in-depth analyses of inflammatory molecules, cytokines and comorbidities. Disease severity and mortality in younger and older adults were associated with discrete immune mechanisms, including predominant T cell activation in younger adults, as measured by increased soluble IL-2 receptor alpha, and increased IL-10 in older adults although both groups also had shared inflammatory processes, including acute phase reactants, contributing to clinical outcomes. These observations suggest that progression to severe disease and death in COVID-19 may proceed by different immunologic mechanisms in younger versus older subjects and introduce the possibility of age-based immune directed therapies.

Comparison of different locking plate fixation methods in lateral malleolus fractures.

BACKGROUND: Several fixation methods may be used for displaced lateral malleolar fractures. We aimed to compare clinical and radiologic outcomes associated with use of locking one third tubular plate vs. anatomical distal fibula locking plate in lateral malleolar fractures. METHODS: A total of 62 orthopedic patients operated for lateral malleolus fracture were included in this retrospective study. Patients were divided into two groups regarding the plate used for fixation as locking one third tubular plate (group I; n=37) and locking anatomical distal fibula plate (group II; n=25). Data on Danis-Weber ankle fracture classification (Type A, Type B), duration of follow up, clinical outcome [ankle range of motion (ROM), American Orthopaedic Foot & Ankle Society (AOFAS) score], radiological outcomes (adequacy of reduction, loss of alignment), time to fracture healing and complications were recorded in study groups. RESULTS: No significant difference was noted between groups in terms of AOFAS score [87.0 (73-100) vs. 85.0 (71-100), respectively (p=0.339)] and no patients had severe restriction in sagittal and hindfoot motion in both groups. The two groups showed similar healing time [9.0 (7-13) weeks vs. 10.0 (8-13) weeks, respectively (p=0.355)] and complication rate [0.0% vs. 4.0%, respectively (p=0.403)]. CONCLUSIONS: This study revealed no significant difference between use of locking one third tubular plate and locking anatomical distal fibula plate in lateral malleolar fixation, in terms of clinical and radiological outcomes, complication rates and fracture healing time.

Femoral shortening osteotomy in total hip arthroplasty for severe dysplasia: a comparison of two fixation techniques.

PURPOSE: The purpose of this study was to compare two distinct fixation methods for a total hip replacement performed via transverse femoral shortening osteotomy for patients with severe hip dysplasia. METHODS: In this retrospective study we compared two fixation methods for total hip replacement of 78 hips in 76 patients exhibiting Crowe type IV developmental hip dysplasia (DDH). The hip replacements were performed via a transverse femoral shortening osteotomy and carried out between September 2009 and December 2013. Group I patients underwent fixation of the shortened femoral segment via a cable attached to the osteotomied segment, and group II patients underwent fixation with a plate and screw. We compared the two techniques based on operating time, osteotomy site union time, Harris hip score, hip loosening signs, and overall clinical outcomes. RESULTS: The mean operating time for groups I and II was determined to be 116.5 ± 12.8 min and 137.7 ± 14 min, respectively (p < 0.05), while the average union time was 113 ± 51 days for group I and 152 ± 37 days for group II (p < 0.05). Fixation of the femur with a cable (group I) is therefore faster and results in more rapid union time when compared to plate osteosynthesis at the osteotomy site (group II). We observed only one non-union in group I compared with three in group II (p = 0.49). Harris hip scores at the final patient follow-up were 82.8 ± 7.8 and 80.8 ± 6.7 for groups I and II, respectively (p = 0.23). Thus, notably no significant differences were observed between the groups with regard to clinical outcomes such as the Harris hip score or loosening of the replacement components. CONCLUSION: Fixation of the removed femoral segment with a cable provided adequate rotational stability and decreased the operating time, leading to early union at the osteotomy site.

Minimally Invasive Plate Osteosynthesis of Distal Tibia and Fibular Fractures Through a Single Distal Anterolateral Incision.

Treating distal tibia fractures is often challenging given the extent of soft tissue damage around the fracture and the risk of infection and other complications with internal fixation and the accompanying incisions. Minimally invasive plate osteosynthesis minimizes these complications and can be performed through a single incision. From April 2009 to January 2011, we treated 20 patients who had both tibial and fibular distal fractures through a distal anterolateral approach with this technique. The mean follow-up period was 15.5 (range 12 to 26) months. The mean interval to bony union was 21 (range 18 to 25) weeks. A 5° varus deformity was found in 1 patient. Another patient, who had a history of alcohol consumption and smoking, developed wound necrosis that was treated successfully with debridement and without skin grafting. The mean American Orthopaedic Foot and Ankle Society score for all patients was 91.8 (range 84 to 97). The anterolateral, minimally invasive plate osteosynthesis technique is a useful method for treating distal tibial and fibular fractures at the same level, with a low complication rate.

The potential effect of anatomic relationship between the femur and the tibia on medial meniscus tears.

BACKGROUND: The anatomic and the kinematical relationships between the femur and the tibia have been previously examined in both normal and diseased knees. However, less attention has been directed to the effect of these relationships on the meniscal diseases. Therefore, we aimed to investigate the impact of femorotibial incongruence on both lateral and medial meniscal tears. MATERIALS AND METHODS: A total of 100 images obtained from MRI of 100 patients (39 males and 61 females) were included in the study. Diameters of the medial and the lateral femoral condyles, thicknesses of the menisci, and diameters of the medial and the lateral tibial articular surfaces were measured. RESULTS: The medial meniscus tear was detected in 40 (40 %) patients. However, no lateral meniscus tear was found. Significant relationships were found between the diameters of the posterior medial femoral condyle and the medial tibial superior articular surface and between the diameters of the posterior lateral femoral condyle and the lateral tibial superior articular surface. The mean values for the diameter of the medial condyle of the femur, the lateral condyle of the femur, the medial superior articular surface of the tibia, and the lateral superior articular surface of the tibia were found to be significantly higher in cases with meniscus tear compared to cases without meniscus tear. However, no significant difference was present regarding the thicknesses of the medial and the lateral menisci. A positive relationship between the diameter of the posterior medial femoral condyle and the tibial medial superior articular surface was found in cases with (n = 40) (r (2) = 0.208, p = 0.003) and without tear (n = 60) (r (2) = 0.182, p = 0.001). In addition, a significant positive relationship was found between the diameter of the posterior medial femoral condyle and the medial tibial superior articular surface in cases with and without tear. CONCLUSION: The impact of femorotibial incongruence on the medial meniscus tear is important for the understanding of the lesions.

Comparison of single and double incision leg fasciotomy in disaster settings-Experience from 2023 Türkiye earthquakes.

INTRODUCTION: Although there are studies comparing methods for leg fasciotomy in compartment syndrome after fractures, choice of single or double fasciotomies in disasters was not investigated. The aim of this study was to compare the efficacy of single and double incision leg fasciotomy in the setting of disaster. METHODS: Patients that have undergone fasciotomy after 2023 Kahramanmaras earthquakes were retrospectively analyzed. The cases were separated into two groups as single incision and double incision according to the method of the first fasciotomy. The number of debridements after each fasciotomy, muscle group excisions, completion time of treatment, presence of amputation, the method of closure (primary closure or graft/flap) and positive results of wound cultures were analyzed and compared between two groups. RESULTS: 62 legs of 52 patients (22 females, 30 males, age 36.9 ± 11.2 years) with compartment syndrome that have undergone fasciotomy after 2023 Kahramanmaras earthquakes were included in the study. Single-incision group included 27 legs and double incision group included 35 legs. Amputation was needed in 15 patients (%24.2), six in single incision group and nine in double incision group. (p = 0.75). Compartment excision (eight patients in single incision, nine patients in double incision groups, p = 0.81), number of debridements (median 4 in both groups, p = 0.55), wound closure time (median 17 days in single incision, 22 days in double incision groups, p = 0.52), graft or flap requirement (11 patients in single incision, 16 patients in double incision groups, p = 0.53), positive culture results (15 patients in single incision, 16 patients in double incision groups, p = 0.44) were not different statistically between two groups. CONCLUSION: Single and double incision fasciotomy methods are equally effective and safe in treatment of compartment syndrome of the leg in disaster situations. To our knowledge, this is the first study comparing outcomes of single and double incision fasciotomy in disaster settings.

IL-1 receptor 1 signaling shapes the development of viral antigen-specific CD4+ T cell responses following COVID-19 mRNA vaccination.

BACKGROUND: The innate immune cytokine interleukin (IL)-1 can affect T cell immunity, a critical factor in host defense. In a previous study, we identified a subset of human CD4+ T cells which express IL-1 receptor 1 (IL-1R1). However, the expression of such receptor by viral antigen-specific CD4+ T cells and its biological implication remain largely unexplored. This led us to investigate the implication of IL-1R1 in the development of viral antigen-specific CD4+ T cell responses in humans, including healthy individuals and patients with primary antibody deficiency (PAD), and animals. METHODS: We characterized CD4+ T cells specific for SARS-CoV-2 spike (S) protein, influenza virus, and cytomegalovirus utilizing multiplexed single cell RNA-seq, mass cytometry and flow cytometry followed by an animal study. FINDINGS: In healthy individuals, CD4+ T cells specific for viral antigens, including S protein, highly expressed IL-1R1. IL-1ß promoted interferon (IFN)-γ expression by S protein-stimulated CD4+ T cells, supporting the functional implication of IL-1R1. Following the 2nd dose of COVID-19 mRNA vaccines, S protein-specific CD4+ T cells with high levels of IL-1R1 increased, likely reflecting repetitive antigenic stimulation. The expression levels of IL-1R1 by such cells correlated with the development of serum anti-S protein IgG antibody. A similar finding of increased expression of IL-1R1 by S protein-specific CD4+ T cells was also observed in patients with PAD following COVID-19 mRNA vaccination although the expression levels of IL-1R1 by such cells did not correlate with the levels of serum anti-S protein IgG antibody. In mice immunized with COVID-19 mRNA vaccine, neutralizing IL-1R1 decreased IFN-γ expression by S protein-specific CD4+ T cells and the development of anti-S protein IgG antibody. INTERPRETATION: Our results demonstrate the significance of IL-1R1 expression in CD4+ T cells for the development of viral antigen-specific CD4+ T cell responses, contributing to humoral immunity. This provides an insight into the regulation of adaptive immune responses to viruses via the IL-1 and IL-1R1 interface. FUNDING: Moderna to HJP, National Institutes of Health (NIH) 1R01AG056728 and R01AG055362 to IK and KL2 TR001862 to JJS, Quest Diagnostics to IK and RB, and the Mathers Foundation to RB.

Single-Cell Next-Generation Sequencing to Monitor Hematopoietic Stem-Cell Transplantation: Current Applications and Future Perspectives.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are genetically complex and diverse diseases. Such complexity makes challenging the monitoring of response to treatment. Measurable residual disease (MRD) assessment is a powerful tool for monitoring response and guiding therapeutic interventions. This is accomplished through targeted next-generation sequencing (NGS), as well as polymerase chain reaction and multiparameter flow cytometry, to detect genomic aberrations at a previously challenging leukemic cell concentration. A major shortcoming of NGS techniques is the inability to discriminate nonleukemic clonal hematopoiesis. In addition, risk assessment and prognostication become more complicated after hematopoietic stem-cell transplantation (HSCT) due to genotypic drift. To address this, newer sequencing techniques have been developed, leading to more prospective and randomized clinical trials aiming to demonstrate the prognostic utility of single-cell next-generation sequencing in predicting patient outcomes following HSCT. This review discusses the use of single-cell DNA genomics in MRD assessment for AML/MDS, with an emphasis on the HSCT time period, including the challenges with current technologies. We also touch on the potential benefits of single-cell RNA sequencing and analysis of accessible chromatin, which generate high-dimensional data at the cellular resolution for investigational purposes, but not currently used in the clinical setting.

Toxicity Profile of Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapies in Multiple Myeloma: Pathogenesis, Prevention and Management.

Multiple myeloma is the second-most common hematologic malignancy in adults worldwide. Despite ongoing advancement in therapeutic modalities, it remains an incurable disease with a 5-year survival rate of approximately 50%. The recent development and introduction of anti-BCMA immunotherapies into clinical practice, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies, has radically shifted the treatment paradigm. However, despite the promising potential of these therapies for broader application, frequent and significant adverse effects have been reported, both in short- and in long-term settings, requiring increasing awareness and vigilance in the treating team, close monitoring, and prompt interventions with a multidisciplinary approach. In this review, we will discuss the toxicities associated with CAR-T cell and bispecific antibody therapies, focusing on results from major clinical studies and real-world observations. In addition, we will emphasize on effective strategies for prevention, monitoring and management, and provide expert recommendations.

Aging gene signature of IL-7 receptor alpha low effector memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

CD45RA+ effector memory (EM) CD8+ T cell expansion was reported in Alzheimer's disease (AD). Such cells are IL-7 receptor alpha (IL-7Rα)low EM CD8+ T cells, which expand with age and have a unique aging gene signature (i.e., IL-7Rαlow aging genes). Here we investigated whether IL-7Rαlow aging genes and previously reported AD and memory (ADM) genes overlapped with clinical significance in AD patients. RT-qPCR analysis of 40 genes, including 29 ADM, 9 top IL-7Ralow aging and 2 control genes, showed 8 differentially expressed genes between AD and cognitively normal groups; five (62.5%) of which were top IL-7Rαlow aging genes. Over-representation analysis revealed that these genes were highly present in molecular and biological pathways associated with AD. Distinct expression levels of these genes were associated with neuropsychological testing performance in 3 subgroups of dementia participants. Our findings support the possible implication of the IL-7Rαlow aging gene signature with AD.

Randomized Trial of Olaparib With or Without Cediranib for Metastatic Castration-Resistant Prostate Cancer: The Results From National Cancer Institute 9984.

PURPOSE: Cediranib, a pan-vascular endothelial growth factor receptor inhibitor, suppresses expression of homologous recombination repair (HRR) genes and increases sensitivity to poly-(ADP-ribose) polymerase inhibition in preclinical models. We investigated whether cediranib combined with olaparib improves the clinical outcomes of patients with prostate cancer. METHODS: Patients with progressive metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned 1:1 to arm A: cediranib 30 mg once daily plus olaparib 200 mg twice daily or arm B: olaparib 300 mg twice daily alone. The primary end point was radiographic progression-free survival (rPFS) in the intention-to-treat patients. The secondary end points were rPFS in patients with HRR-deficient and HRR-proficient mCRPC. RESULTS: In the intention-to-treat set of 90 patients, median rPFS was 8.5 (95% CI, 5.4 to 12.0) and 4.0 (95% CI, 3.2 to 8.5) months in arms A and B, respectively. Cediranib/olaparib significantly improved rPFS versus olaparib alone (hazard ratio [HR], 0.617; 95% CI, 0.392 to 0.969; P = .0359). Descriptive analyses showed a median rPFS of 10.6 (95% CI, 5.9 to not assessed [NA]) and 3.8 (95% CI, 2.33 to NA) months (HR, 0.64; 95% CI, 0.272 to 1.504) among patients with HRR-deficient mCRPC, and 13.8 (95% CI, 3.3 to NA) and 11.3 (95% CI, 3.8 to NA) months (HR, 0.98; 95% CI, 0.321 to 2.988) among patients with BRCA2-mutated mCRPC in arms A and B, respectively. The incidence of grades 3-4 adverse events was 61% and 18% in arms A and B, respectively. CONCLUSION: Cediranib combined with olaparib improved rPFS compared with olaparib alone in men with mCRPC. This combination was associated with an increased incidence of grades 3-4 adverse events. BRCA2-mutated subgroups treated with olaparib with or without cediranib were associated with a numerically longer median rPFS.

T Cell Response to Influenza Vaccination Remains Intact in Adults with Congenital Heart Disease Who Underwent Early Thymectomy.

Introduction: T cells developed in the thymus play a key role in vaccine immunity. Thymectomy occurs during infant congenital heart surgery and results in an altered T cell distribution. We investigated if adults with congenital heart disease (ACHD) who underwent early thymectomy have a diminished response to influenza vaccination. Methods: Blood samples from ACHD with early thymectomy ≤ 1 year of age (ACHD-ET; n = 12), no thymectomy (ACHD-NT; n = 8), and healthy controls (HC; n = 14) were collected prior to and 4 weeks after influenza vaccination. Flow cytometric analysis of T cell subsets and vaccine-specific cytokine expressing CD4+ T cells as well as hemagglutination inhibition (HI) assays were completed. Results: The mean age of the cohort was 34 ± 10.6 years and similar in all groups. The mean frequencies of naïve CD4+ and CD8+ T cells were lower in ACHD-ET than in HC (32.7% vs. 46.5%, p = 0.027 and 37.2% vs. 57.4%, p = 0.032, respectively). There was a rise in the frequency of memory CD4+ and CD8+ T cells in the ACHD-ET group. The ACHD-NT had no statistical difference from either group. The frequencies of influenza-specific memory CD4+ T cells expressing IFN-γ and TNF-α were increased after vaccination across all groups (p < 0.05). Conclusions: ACHD-ET have fewer naïve T cells, suggesting immunosenescence. Despite this, they show an adequate T Cell response to vaccination in young adulthood. Our findings support routine vaccination is effective in this population, but research into older ACHD is necessary.

Prolonged Complete Response of Early Stage Primary Adenocarcinoma of the Lung to Nivolumab Monotherapy.

Immune checkpoint inhibitors are currently employed for the treatment of various malignancies, including advanced melanoma and non-small cell lung cancer. As more patients are treated with checkpoint inhibitors, situations will arise in which early-stage disease may be subjected, intentionally or unintentionally, to these agents. This is especially relevant for patients presenting with multiple primary malignant tumors (MPMTs). Here we report the case of a patient presenting synchronously with metastatic melanoma to multiple regional lymph nodes and stage I lung adenocarcinoma with high Programmed-Death Ligand 1 (PD-L1) expression. Given the high-risk nature of his melanoma, he was treated with nivolumab monotherapy, and had a durable response of both malignancies to a PD-1 inhibitor. He remains disease-free, off therapy sixteen months after completing a 19-month course of treatment. This highlights the complexity of treating patients with MPMTs in the era of effective immunotherapy and raises the possibility of treating primary lung cancer with systemic immunotherapy in situations in which surgery is not feasible due to comorbidities or other circumstances.