PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance.

Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.

Author Correction: PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Osteoporosis and fracture risk assessment in adults with ischaemic stroke.

PURPOSE: To study the prevalence of osteoporosis, falls and fractures in adults with ischaemic stroke. METHODS: Observational cohort study of adults aged ≥ 50 years admitted with ischaemic stroke over a 12-month period were invited to participate in a telephone interview one-year post-stroke to ascertain falls and fracture. A Fracture Risk After Ischaemic Stroke (FRAC-stroke) score was calculated. RESULTS: Of the 1267 patients admitted to the stroke unit between 1 January 2020 and 31 December 2020, 624 had a modified Rankin Score documented. Of these, 316 adults ≥ 50 years had ischaemic stroke and 131 consented to a telephone interview. Mean age was 72.4 ± 10.7 years and 36.6% were female. 34 patients (25.9%) had a FRAC-stroke score of ≥ 15, equating to ≥ 5% risk of fracture in the year following stroke. Eleven (8.4%) patients (6 female) had a minimal trauma fracture in the 12 months post-stroke. There was a significant difference in patients experiencing falls pre- and post-stroke (19.8% vs 31.3%, p = 0.04). FRAC-stroke score was higher in those who had a fracture post stroke compared those who did not (20.4 vs 8.9, p < 0.001). Receiver operating characteristic analysis found an area under the curve of 0.867 for FRAC-stroke score (95% CI 0.785-0.949, p < 0.005). The optimal cutoff value for FRAC-stroke score predicting fracture was 12 with a sensitivity of 90.9% and specificity of 70%. CONCLUSION: The FRAC-stroke score is a simple clinical tool that can be used to identify patients at high risk of fracture post-stroke who would most benefit from osteoporosis therapy. Stroke is a risk factor for fracture due to immobilisation, vitamin D deficiency and increased falls risk. This study found that a simple bedside tool, the FRAC-stroke score, can predict fracture after ischaemic stroke. This will allow clinicians to plan treatment of osteoporosis prior to discharge from a stroke unit.

T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

Knee Injuries in the Elite American Football Player: A Descriptive Pictorial Imaging and Mechanism of Injury Review.

ABSTRACT: Musculoskeletal injuries are common in American football, with an incidence ranging from approximately 10 to 35 per 1000 playing hours. Injuries occur more commonly in games than in practice. Although several studies have analyzed specific injury types in football, this review aims to describe the most common knee injuries sustained by American football players and to review the existing literature pertaining to the radiologic findings used in the diagnosis of these injuries.

Patients with end-stage kidney disease have markedly abnormal cortical hip parameters by dual-energy X-ray absorptiometry.

BACKGROUND: Patients with end-stage kidney disease (ESKD) have higher fracture rates and post-fracture mortality than the general population, but bone mineral density by dual-energy X-ray absorptiometry (DXA) is less predictive of fracture in this patient group. Bone biopsy and high-resolution imaging indicate that cortical thickness (CT) is reduced and cortical porosity is increased in ESKD. The aim of this study was to assess cortical parameters using DXA in patients with ESKD. It was hypothesized that these parameters would show deterioration and be associated with fracture. METHODS: Using advanced hip analysis, normal age-related ranges were determined from 752 female and 861 male femur scans and were compared with scans of 226 patients with ESKD at the time of transplantation. RESULTS: Compared with controls, female patients had lower mean±SD CT (mms) at the femoral neck (FN) (2.59 ± 1.42 versus 5.23 ± 1.85), calcar (3.46 ± 1.07 versus 5.09 ± 1.30) and shaft (4.42 ± 1.21 versus 7.44 ± 2.07; P < 0.001 for each), and buckling ratios were higher (8.21 ± 4.6 versus 3.63 ± 1.42; P < 0.001), indicating greater FN instability. All findings were similar for men. Prevalent fracture was documented in 28.8% of patients; 12.4% vertebral only, 8.4% non-vertebral only and 8% vertebral plus non-vertebral. In adjusted models, each 1 SD reduction in FN CT and increase in the buckling ratio was associated with a respective 1.73 (1.22-2.46)- and 1.82 (1.49-2.86)-fold increase in the risk of prevalent vertebral fracture. CONCLUSIONS: In patients with ESKD, DXA-derived cortical parameters are markedly abnormal compared with age- and sex-matched controls. These parameters should be assessed for incident fracture prediction and targeting treatment.

Bortezomib use and outcomes for the treatment of multiple myeloma.

BACKGROUND: The public subsidy in Australia of bortezomib (Velcade) for untreated non-transplant multiple myeloma patients was based on the VISTA trial. AIMS: To ascertain the health outcomes of bortezomib in 'real world' transplant-ineligible elderly patients, compared to trial data. METHODS: Patient and treatment data were extracted from an oncology information system, laboratory information system and medical chart audits for three Queensland public hospitals. RESULTS: We identified 74 patients; the median age was 75 years. Our cohort comprised 47% patients who were International Staging System stage III, 45% at stage II and 8% at stage I. Patients who had comorbidities, such as cardiac disease (41%), pulmonary disease (14%), diabetes (22%), peripheral neuropathy (14%) and other comorbidities (41%) at baseline were included. The common regimens prescribed were VMP, CVD and VD, and most patients (n = 73) received bortezomib on a once-weekly or twice-a-week basis. The overall response rate was 81%. Half (53%) of the patients did not complete their planned therapy due to toxicity (30%), suboptimal response or disease progression (15%), or death on treatment (8%). Overall survival was 40.7 months and progression free survival was 17.7 months. CONCLUSIONS: Our patients were older, had worse disease characteristics and more comorbidities than patients in the VISTA trial. While response rates were similar, survival outcomes appeared worse. Bortezomib-based treatment in the real world setting still carries a high risk of toxicity in the elderly population.

Analysis of Differentially Expressed MicroRNAs and Circulating Tumor Cells as Predictive Biomarkers of Platinum Chemoresistance in Primary Ovarian Carcinomas: A Prospective Study.

LESSON LEARNED: Circulating tumor cells, microRNA markers, or other biomarkers merit examination as part of correlative scientific analyses in prospective clinical trials. BACKGROUND: Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma; however, no biomarkers of ovarian carcinoma chemoresistance have been validated. We performed a prospective trial designed to identify tumor-based predictive biomarkers of platinum resistance. METHODS: Tumor specimens were collected from 29 women with newly diagnosed histopathologically proven primary ovarian carcinoma. Of these, 23 women had specimens accessible for assessment and outcome data available regarding chemosensitive versus chemoresistance status via review of the medical record. Tumor slices were stained with antibodies against two microRNAs (miRNAs 29b and 199a) differentially expressed in chemoresistant ovarian cancer cell lines. Additionally, blood samples obtained at the time of diagnosis were analyzed for the presence of circulating tumor cells (CTCs). RESULTS: The average age of the patients was 64 years, and 82.6% had high-grade epithelial carcinomas. The baseline median CA-125 was 464 (range 32-2,782). No statistically significant differences were observed in miR29b or 199a expression in platinum-resistant/refractory versus platinum-sensitive tumors. Furthermore, the presence of CTCs was not found to be statistically significantly predictive of eventual platinum resistance. CONCLUSION: Our analysis showed no differences in miR29b and 199a expression, and differences in baseline CTCs in women with newly diagnosed ovarian tumors were not statistically significant.

Longitudinal changes in bone density in adolescents and young adults with cerebral palsy: A case for early intervention.

CONTEXT: Cerebral palsy (CP) is a motor disorder affecting movement, muscle tone and posture due to damage to the foetal or infant brain. The subsequent lack of ambulation, nutritional deficiencies, anticonvulsant use and hormonal deficiencies have been implicated in the low bone mass associated with this condition. OBJECTIVE: To assess changes in areal bone mineral density (aBMD) during adolescence and young adulthood in individuals with CP. The effect of ambulation, nutrition, hypogonadism on longitudinal changes in aBMD is also examined. DESIGN: Retrospective longitudinal study. SETTING AND PARTICIPANTS: Forty-five subjects with CP who had longitudinal dual-energy X-ray absorptiometry (DXA) scans at a single tertiary hospital between 2006 and 2018. RESULTS: Mean age at first DXA was 19.4 years (range: 10-36 years), 57.8% were male and 80% were nonambulatory. The mean Z-scores at baseline were <-2.0 at all sites - lumbar spine (LS), femoral neck (FN), total hip (TH) and total body (TB). The median change in aBMD was +1.2%-1.9% per year in all subjects but in those <20 years of age, the median change was 4%-8% per year. Z-scores across all sites remained stable over time. Reduced functional state as measured by the gross motor functional classification scale (GMFCS) had a small negative effect on aBMD over time. CONCLUSION: In adolescents with CP, low bone mass was evident from the baseline DXA. However, significant bone accrual occurred during the second decade, followed by bone maintenance in young adulthood. Future studies should focus on optimizing bone health from early childhood.

Sex hormone-binding globulin is a biomarker associated with nonvertebral fracture in men on dialysis therapy.

Gonadal hormones impact bone health and higher values of sex hormone-binding globulin (SHBG) have been independently associated with fracture risk in men without chronic kidney disease. People with chronic kidney disease have a greatly increased fracture risk, and gonadal dysfunction is common in men receiving dialysis treatment. Nevertheless, in these men the effect of gonadal steroids and SHBG on bone mineral density (BMD) and fracture risk is unknown. Here we investigate relationships between gonadal steroids, SHBG, BMD and fracture in men on long-term dialysis therapy, awaiting kidney or simultaneous pancreas kidney transplantation. Results of serum biochemistry, SHBG, gonadal steroids (total testosterone, calculated free testosterone and estradiol), BMD by dual-energy X-ray absorptiometry and thoracolumbar X-rays were obtained. Multivariable regression models were used to examine associations between SHBG, gonadal steroids, BMD and fracture of 321 men with a mean age of 47 years. Diabetes mellitus was present in 45% and their median dialysis vintage was 24 months. Prior fractures occurred in 42%, 18% had vertebral fracture on lateral spine X-ray, 17% had non-vertebral fragility fracture within 10 years and 7% had both. After adjustment for age, body mass index and dialysis vintage, higher SHBG levels were significantly associated with nonvertebral fractures [odds ratio 1.81 (1.30-2.53)] and remained significant after adjustment for BMD. Calculated free testosterone and estradiol values were not associated with fracture. Prevalent fracture rates were high in relatively young men on dialysis awaiting transplantation. Thus, SHBG is a novel biomarker associated with fracture, which warrants investigation in prospective studies.

Increased prevalence of fracture and hypoglycaemia in young adults with concomitant type 1 diabetes mellitus and coeliac disease.

BACKGROUND: Both Type 1 diabetes mellitus (T1DM) and coeliac disease (CD) are independently associated with reduced bone mineral density (BMD) and increased fracture risk. Whilst poorer glycaemic control and increased microvascular complications have been described, the literature examining bone health and fractures in adults with concomitant T1DM and CD (T1DM + CD) is limited. OBJECTIVE: To evaluate fracture prevalence and explore associations with glycaemic control, hypoglycaemia and microvascular disease in T1DM + CD compared with T1DM alone. METHODS: We conducted a retrospective cross-sectional study of young adults with T1DM, who attended diabetes clinics at a large tertiary referral centre between August 2016 and February 2017. Clinical information, radiological and biochemistry results were extracted from medical records. Patients with comorbid chronic kidney disease, glucocorticoid use, hypogonadism and untreated hyperthyroidism were excluded. RESULTS: A total of 346 patients with T1DM alone (median age 23 years) and 49 patients with T1DM + CD (median age 24 years) were included. Median age, gender distribution, BMI, haemoglobin A1c, daily insulin dose and serum 25-hydroxyvitamin D levels were similar between groups. Higher adjusted fracture risk was observed in T1DM + CD compared with T1DM (12.2% vs 3.5%; OR 3.50, 95% CI 1.01-12.12, P = .01), yet BMD was only measured in 6% of patients. The adjusted risk of hypoglycaemia ≥2/week was greater for T1DM + CD (55% vs 38%, OR 3.28, 95% CI 1.61-6.69, P = .001); however, this was not independently associated with fractures. Replete vitamin D (≥ 50 nmol/L) was associated with less hypoglycaemia (OR 0.48, 95% CI 0.29-0.80; P = .005), but not with fractures. CONCLUSIONS: Coeliac disease status was independently associated with increased fracture prevalence in young adults with T1DM. Recurrent hypoglycaemia was also increased in T1DM + CD, although hypoglycaemia was not independently associated with fractures. Prospective studies are required to determine the long-term impacts of CD on bone health and glycaemic control in patients with T1DM.

Genetic basis for clinical response to CTLA-4 blockade in melanoma.

BACKGROUND: Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells. METHODS: We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients. RESULTS: Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab. CONCLUSIONS: These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.).

Serum phosphorus levels and fracture following renal transplantation.

PURPOSE: Increased fracture rates are observed in renal transplant recipients (RTRs) compared with the general population. Risk factors include age, diabetes, dialysis vintage, immunosuppression and mineral and bone disorders.1 Low serum phosphorus levels occur post-transplantation; however, its relationship with fracture risk has not been evaluated. The purpose of this study was to evaluate risk factors for fracture in RTRs at a single tertiary referral centre. METHODS: A retrospective cross-sectional analysis of 146 patients (75 M, 71 F) who had been referred for dual energy X-ray densitometry (DXA) post-renal transplantation was performed. Aetiology of end stage kidney disease (ESKD), duration of dialysis, parathyroidectomy history, immunosuppression regimen, bone mineral density (BMD), biochemistry and fractures were documented. Statistical analyses included univariable and multivariable regression. RESULTS: The mean age of patients was 54 years and mean time post-transplantation 6.7 years. A total of 79 fractures occurred in 52 patients (35%), with 40 fractures occurring post-transplantation. Ankle/foot fractures were most common (48%). Lower serum phosphorus levels and declining femoral neck (FN) T-score and were associated with fractures in both univariable and multivariable regression analyses after adjusting for age, gender, weight, estimated glomerular filtration rate and pre-transplant history of fracture (P=.011 and P=.042 respectively). The relationship between serum phosphorus and fracture remained significant independent of FN T-score, parathyroid hormone levels, parathyroidectomy status and prednisolone use. CONCLUSION: Fracture was common post-renal transplantation. Lower serum phosphorus levels and declining FN T-scores were associated with fractures. The mechanism of this previously unreported observation requires further evaluation in prospective studies.

A transwell assay that excludes exosomes for assessment of tunneling nanotube-mediated intercellular communication.

BACKGROUND: Tunneling nanotubes (TNTs) are naturally-occurring filamentous actin-based membranous extensions that form across a wide spectrum of mammalian cell types to facilitate long-range intercellular communication. Valid assays are needed to accurately assess the downstream effects of TNT-mediated transfer of cellular signals in vitro. We recently reported a modified transwell assay system designed to test the effects of intercellular transfer of a therapeutic oncolytic virus, and viral-activated drugs, between cells via TNTs. The objective of the current study was to demonstrate validation of this in vitro approach as a new method for effectively excluding diffusible forms of long- and close-range intercellular transfer of intracytoplasmic cargo, including exosomes/microvesicles and gap junctions in order to isolate TNT-selective cell communication. METHODS: We designed several steps to effectively reduce or eliminate diffusion and long-range transfer via these extracellular vesicles, and used Nanoparticle Tracking Analysis to quantify exosomes following implementation of these steps. RESULTS: The experimental approach outlined here effectively reduced exosome trafficking by >95%; further use of heparin to block exosome uptake by putative recipient cells further impeded transfer of these extracellular vesicles. CONCLUSIONS: This validated assay incorporates several steps that can be taken to quantifiably control for extracellular vesicles in order to perform studies focused on TNT-selective communication.

Urolithiasis is prevalent and associated with reduced bone mineral density in ß-thalassaemia major.

Asymptomatic urolithiasis is common and of mixed composition in patients with ß-thalassaemia major. Twenty-seven subjects were imaged using dual-energy computer tomography to determine the presence and composition of urolithiasis. The prevalence of urolithiasis was 59% and affected patients generally had multiple stones, often with more than one component: struvite (33%), calcium oxalate (31%) and cystine (22%). Hypercalciuria was present in 78% of subjects and calcium-containing urolithiasis was associated with reduced femoral neck Z scores.

Tumor exosomes induce tunneling nanotubes in lipid raft-enriched regions of human mesothelioma cells.

Tunneling nanotubes (TnTs) are long, non-adherent, actin-based cellular extensions that act as conduits for transport of cellular cargo between connected cells. The mechanisms of nanotube formation and the effects of the tumor microenvironment and cellular signals on TnT formation are unknown. In the present study, we explored exosomes as potential mediators of TnT formation in mesothelioma and the potential relationship of lipid rafts to TnT formation. Mesothelioma cells co-cultured with exogenous mesothelioma-derived exosomes formed more TnTs than cells cultured without exosomes within 24-48 h; and this effect was most prominent in media conditions (low-serum, hyperglycemic medium) that support TnT formation (1.3-1.9-fold difference). Fluorescence and electron microscopy confirmed the purity of isolated exosomes and revealed that they localized predominantly at the base of and within TnTs, in addition to the extracellular environment. Time-lapse microscopic imaging demonstrated uptake of tumor exosomes by TnTs, which facilitated intercellular transfer of these exosomes between connected cells. Mesothelioma cells connected via TnTs were also significantly enriched for lipid rafts at nearly a 2-fold higher number compared with cells not connected by TnTs. Our findings provide supportive evidence of exosomes as potential chemotactic stimuli for TnT formation, and also lipid raft formation as a potential biomarker for TnT-forming cells.

Systemic Immunological Changes After Yttrium-90 Radioembolization: A Pilot Prospective Observational Study-Clinical Insights.

PURPOSE: To prospectively investigate levels of circulating cytokines, changes in frequencies of various immune cell subsets and expression of proliferation and checkpoint molecules on T cells in the peripheral blood after yttrium-90 radioembolization (TARE) of colorectal cancer liver metastases (CLM). MATERIALS AND METHODS: We prospectively collected, isolated, and froze peripheral blood mononuclear cells (PBMC) and plasma samples from 15 patients immediately before, immediately after, 3 and 6 weeks post-TARE of CLM. Plasma samples were assessed for various cytokines using a multiplex immunoassay platform. PBMC samples were analyzed in a monocyte/dendritic cell (DC)/B cell flow panel and a T cell activation/exhaustion flow phenotyping panel. We compared the levels at the respective time points using Wilcoxon signed rank test. RESULTS: IFN-g significantly decreased immediately after (mean 1.62 vs. 3.02 at baseline, p = 0.04) and increased at 6 weeks compared to the immediately post-TARE nadir (mean 9.42 vs. 1.62, p = 0.04). IL-10 decreased at 3 weeks (mean 0.36 vs. 1.75, p = 0.025) post-TARE compared to baseline. Increased CD3+T cells (mean 78.24 vs. 60.8, p = 0.002) and decreased CTLA-4+CD4+T cells (mean 2.58 vs. 4.41, p = 0.033) were observed at 3 weeks compared to baseline. Increased Ki-67+ proliferating CD8+T cells at 3 and 6 weeks (mean 7.28 and 9.06, respectively, vs. 3.93 at baseline, p = 0.02 and 0.03) were recorded. CONCLUSION: A shift toward a favorable antitumoral cytokinic and immune cells response was observed after TARE. Significant changes were in specialized immune cells subsets playing important roles in the activation of the immune system. These results support trials combining TARE with immunotherapy for patients with CLM.

A pilot study proposing an algorithm for pubertal induction in cerebral palsy.

OBJECTIVES: To explore delayed puberty in cerebral palsy (CP) and to test the acceptability of an interventional puberty induction algorithm. METHODS: A two phase cohort study in children and adolescents diagnosed with CP who have delayed puberty. Phase 1: Retrospective review of clinical records and interviews with patients who have been treated with sex-steroids and Phase 2: Prospective interventional trial of pubertal induction with a proposed algorithm of transdermal testosterone (males) or oestrogen (females). Phase 1 examined experiences with sex-steroid treatment. Phase 2 collected data on height adjusted bone mineral density (BMAD), fractures, adverse effects, mobility and quality of life over two years during the induction. RESULTS: Phase 1, treatment was well tolerated in 11/20 treated with sex-steroids; phase 2, using the proposed induction algorithm, 7/10 treated reached Tanner stage 3 by nine months. One participant reached Tanner stage 5 in 24 months. Mean change in BMAD Z-scores was +0.27 % (SD 0.002) in those who could be scanned by dual-energy X-ray absorptiometry (DXA). CONCLUSIONS: Delayed puberty may be diagnosed late. Treatment was beneficial and well tolerated, suggesting all patients with severe pubertal delay or arrest should be considered for sex hormone supplementation.

Biomarkers associated with pulmonary exacerbations in a randomized trial of nintedanib for radiation pneumonitis.

BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP. MATERIALS AND METHODS: We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes. RESULTS: Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-ß1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036). CONCLUSION: We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.