Lower Neutrophil Counts Research Articles

Increased formation of neutrophil extracellular traps induced by autophagy and identification of autophagy-related biomarkers in systemic lupus erythematosus.

Abnormal death of neutrophils and the subsequent ineffective clearance of cell fragments result in production of autoantigens that can lead to systemic lupus erythematosus (SLE). Excessive formation of neutrophil extracellular traps (NETs) can trigger the synthesis of pro-inflammatory cytokines such as type I interferons, leading to tissue damage and immune dysfunction in SLE patients. In this study, we found that a decrease in neutrophil counts in the peripheral blood was correlated with clinical parameters in SLE patients. Patients with low neutrophil counts had high renal activity index and chronicity index scores. NET formation and neutrophil autophagy in SLE patients were increased. The autophagy inhibitor hydroxychloroquine was shown to restrict NET formation. Using comprehensive bioinformatics analysis, we found that the expression of the autophagy-related gene, hypoxia-inducible factor 1A (HIF1A), was enhanced in peripheral neutrophils and in the renal glomeruli in SLE patients. Targeting HIF1A could be a potential therapeutic approach for SLE.

Anti-Inflammatory Potential of Pteropodine in Rodents.

Pteropodine (PT) is a component of some plants with potentially useful pharmacological activities for humans. This compound has biomedical properties related to the modulation of the immune system, nervous system, and inflammatory processes. This study addresses the anti-inflammatory and antioxidant capacity of pteropodin in a murine model of arthritis and induced edema of the mouse ear. To evaluate the anti-inflammatory activity, we used the reversed passive Arthus reaction (RPAR), which includes the rat paw edema test, the rat pleurisy test, and a mouse ear edema model. The antioxidant effect of PT was evaluated by determining the myeloperoxidase enzyme activity. PT showed an anti-inflammatory effect in the different specific and non-specific tests. We found a 51, 66 and 70% inhibitory effect of 10, 20 and 40 mg/kg of PT, respectively, in the rat paw edema test. In the pleurisy assay, 40 mg/kg of PT induced a low neutrophil count (up to 36%) when compared to the negative control group, and 20 mg/kg of PT increased the content of lymphocytes by up to 28% and the pleural exudate volume decreased by 52% when compared to the negative control group, respectively. We also found an 81.4% inflammatory inhibition of the edema ear with 0.04 mg/ear of PT, and a significant myeloperoxidase enzyme inhibition by the three doses of PT tested. We conclude that PT exerted a potent anti-inflammatory effect in the acute inflammation model in rodents.

Beneficial effects of alpha-1 antitrypsin therapy in a mouse model of colitis-associated colon cancer

BackgroundIt is widely accepted that chronic inflammatory bowel diseases significantly higher a risk for colorectal cancer development. Among different types of treatments for patients with colon cancer, novel protein-based therapeutic strategies are considered.AIMTo explore the effect of human plasma alpha-1 antitrypsin (AAT) protein in the chemically induced mouse model of colorectal cancer.MethodsBALB/c mice with azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated colorectal cancer (CAC), we intraperitoneally treated with commercial preparation of human plasma AAT (4 mg per mouse). Effects of this therapy were evaluated histologically, and by immunohistochemical and gene expression assays.ResultsWhen compared with non-treated controls, AOM/DSS mice receiving AAT therapy exhibited significantly longer colons, and less anal bleeding. Concurrently, AAT-treated mice had significantly fewer polyps, and lower numbers of large colon tumors. Immunohistochemical examinations of colon tissues showed significantly lower neutrophil counts, more granzyme B-positive but fewer MMP9 (gelatinase B)-positive cancer cells and lower numbers of apoptotic cells in mice receiving AAT therapy. The expression levels of IL4 were significantly higher while TNFA was slightly reduced in tumor tissues of AOM/DSS mice treated with AAT than in AOM/DSS mice.ConclusionHuman AAT is an acute phase protein with a broad-protease inhibitory and immunomodulatory activities used as a therapeutic for emphysema patients with inherited AAT deficiency. Our results are consistent with previous findings and support an idea that AAT alone and/or in combination with available anti-cancer therapies may represent a new personalized approach for patients with colitis-induced colon cancer.

The Prognostic Role of Preoperative Hematological and Inflammatory Indices in Canine Appendicular Osteosarcoma.

Hematological indices play a prognostic role in human osteosarcoma (OSA), but data are limited in dogs. The aim of this retrospective multicentric cohort study was to investigate the prognostic significance of pre-operative hematological/inflammatory indices in a cohort of client-owned dogs with appendicular OSA receiving standardized treatment. Cut-offs associated with progression-free survival (PFS) for pre-operative hematological values/ratios were established using the minimal p-value approach. Historical prognostic factors were also assessed. Statistical analyses were performed for the whole population and after the exclusion of sighthounds. Fifty-nine dogs were included (13 were sighthounds). Multivariable analysis revealed that a low neutrophil count (<4.37 × 109/L, HR0.28, CI 95% 0.13-0.61, p = 0.001), a high red blood cell count (≥7.91, HR3.5, CI 95% 1.56-7.9, p = 0.002), and a proximal humerus location (HR3.0, CI 95% 1.48-6.1, p = 0.002) were associated with shorter PFS. In the sighthound-only population, only OSA location was significantly associated with PFS in univariable analysis. When sighthounds were excluded, a low neutrophil count, a low monocyte count, and a proximal humerus location were associated with shorter PFS, in multivariable analysis. Neutrophil count and possibly monocyte and red blood cell counts can be useful prognostic markers in canine OSA treated with amputation and adjuvant carboplatin. However, not all indices are appropriate in sighthounds.

Real-World Predictors of Severe Neutropenia Associated with Palbociclib and Endocrine Therapy for Metastatic Breast Cancer in Japanese Patients.

Therapy for patients of metastatic breast cancer based on palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has been approved in Japan. However, the risk factors for palbociclib-induced severe neutropenia in Japanese patients are rarely reported. Hence, the present study is aimed to identify the risk factors for adverse events requiring palbociclib dose reduction or discontinuation, and to identify the factors necessary to identify a more stable strategy for treatment continuation. This retrospective cohort analysis included patients with advanced breast cancer treated with 125 mg/d palbociclib. We demonstrated that severe neutropenia required significant dose reduction or therapy cessation. Most (77%) of the patients had severe neutropenia within the three courses. Risk factors for grade 3 or higher included low neutrophil counts (< 3250 /µL) before treatment [odds ratio (OR) = 9.10, 95% confidence interval (CI) (2.80-29.41), p < 0.001] and high age-adjusted Charlson comorbidity index (> 9) [OR = 1.64, 95% CI (1.09-2.48), p = 0.018]. Thus, low baseline neutrophil counts and high values for Age-adjusted Charlson comorbidity index are prospective predictive markers for palbociclib-induced severe neutropenia.

Importance of Demographic and Clinical Features in Evaluating the Severity of COVID-19 in Hospitalized Patients: A Serbian Retrospective Study in the First Pandemic Year.

The aim of this study is to determine the demographic and initial clinical characteristics of patients with COVID-19 and their importance in evaluating the severity of the disease. A retrospective study included patients suffering from COVID-19 who were hospitalized at The Department of Infectious Disease of the Clinical Hospital Center Pristina-Gracanica from the beginning of the pandemic until the end of 2020. We compared the symptoms of the disease, radiographic findings of pneumonia, laboratory parameters, duration of symptoms before admission, the difference in the need for certain therapies, and the presence of comorbidities between non-severe and severe groups of patients. Patients with a severe disease were statistically significantly older. Hypertension was significantly associated with severe clinical conditions. Radiographic findings of bilateral pneumonia on admission were much more frequent among the severe group, and these patients' need for oxygen support was significantly higher. Lower neutrophil and higher lymphocyte counts were statistically significant in the non-severe group. Biochemical parameters at admission also showed statistical significance between the examined groups. Based on our research, we can conclude that a complete overview of the patient, including demographic and laboratory parameters as perhaps the most significant attributes, can help doctors in the timely clinical assessment of patients and, thus, in the timely application of adequate therapeutic protocols in the treatment of COVID-19.

Leukopenia in autosomal dominant polycystic kidney disease: a single-center cohort of kidney transplant candidates with post-transplantation follow-up.

Autosomal dominant polycystic kidney disease (ADPKD) has occasionally been associated with lower peripheral white blood cell (WBC) counts. This study aimed to investigate the peripheral blood cell counts in a large cohort of kidney transplant recipients before and after kidney transplantation and its potential impact on post-transplant outcomes. This was a retrospective study with long-term follow-up data of 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals, of whom 392 had ADPKD. In total, 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals were included, of whom 392 had ADPKD. Both pre- and post-transplantation, ADPKD patients had significantly lower total WBC counts, and more specifically lower neutrophil, lymphocyte and eosinophil counts compared with the non-ADPKD patients. This observation was independent of potential confounders such as level of inflammation, smoking habit, vitamins and pre-transplant medication. Overall survival and kidney transplant survival were significantly better in ADPKD vs non-ADPKD transplant recipients and a longer time to first infection was observed. However, no association between blood cell counts and outcome differences was found. In conclusion, this large single-center study reports a strong and independent association between ADPKD and lower peripheral WBC counts both before and after kidney transplantation. Considering the role of inflammation in disease progression, further investigation into the role of WBC in ADPKD is needed.

Prevalence of neutropenia in US residents: a population based analysis of NHANES 2011–2018

AimsNeutrophils play a pivotal in immunity and inflammation. We aim to investigate the prevalence of neutropenia in the United States.MethodsIn this cross-sectional study, participants from the National Health and Nutrition Examination Survey (NHANES) (2011–2018) were enrolled. Demographic information, hematologic measurements, smoking status of all participants were collected for all participants. All statistical analyses were performed utilizing the NHANES survey weights. Covariate-adjusted linear regression was used to compare hematologic indices in different population grouped by age, sex, ethnicity, and smoking. We also employed multivariate-logistic regression to estimate the weighted odds ratio with a 95% confidence interval and predict the neutropenia risk among.Results32,102 participants from NHANES survey were included, represented 286.6 million multiracial population in the United States. Black participants had lower mean leukocyte count (mean difference (MD): 0.71 × 109/L; P < 0.001) and lower neutrophil count (MD: 0.83 × 109/L; P < 0.001) compared with white participants after adjusting for age and sex. Furthermore, t a notable observation was the significant downward shift in the distribution curves of leukocyte count and neutrophil count among black participants. Smokers had a higher mean leukocyte count (MD: 1.10 × 109 cells/L; P < 0.001) and a higher mean neutrophil count (MD: 0.75 × 109 cells/L; P < 0.001) comparing with nonsmokers. The estimated prevalence of neutropenia was 1.24% (95% CI: 1.11 − 1.37%), which corresponds to approximately 35.5 million individuals in the United States. The prevalence of neutropenia in black participants was significantly higher than other races. Results of logistic regression analysis showed that black individuals, male individuals, and children younger than 5 years had a higher risk of neutropenia.ConclusionsNeutropenia is more common in the general population than we thought, especially in black individuals and children. More attention should be paid to neutropenia.

Pharmacodynamic Model-Based Safety Management of Eribulin-Induced Myelosuppression in Patients With Breast Cancer.

Neutropenia is a major dose-limiting toxicity of cancer chemotherapy. Semimechanistic mathematical models have been applied to describe the time course of neutrophil counts. The objectives of this study were to develop a mathematical model describing changes in neutrophil counts during eribulin treatment, to apply the empirical Bayes method to predict the probability of developing neutropenia ≥ grade 3 during eribulin treatment in each patient, and to propose the implementation of this mathematical tool in clinical practice for individual safety management. The present model analysis and subsequent external evaluation were performed using the data of 481 patients with breast cancer, previously obtained from a postmarketing surveillance (training set) and a phase 2 clinical study (validation set). The model we previously reported (Kawamura et al 2018) was modified to improve its predictive capability. The individual time course of neutrophil changes during the treatment period was predicted by the empirical Bayes method using the observed neutrophil counts at baseline and the first measurement after the first eribulin dose. To evaluate the predictability of this method, the predicted neutrophil counts were compared with those of the observed values. The developed model provided good individual predictions, as indicated by the goodness-of-fit plots between the predicted and observed neutrophil counts, especially for a lower neutrophil count range. Days required to reach the nadir after the dose were also well-predicted. The sensitivity, specificity, and accuracy of the prediction of neutropenia grade ≥3 were 76%, 53%, and 71%, respectively. We developed a mathematical method for predicting and managing the risk of neutropenia during eribulin treatment. This method is generally applicable to other cases of chemotherapy-induced neutropenia and can be a new practical tool for individual safety management.

Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors.

Glycogen storage disease type Ib (GSD1b) is due to a defect in the glucose-6-phosphate transporter (G6PT) of the endoplasmic reticulum, which is encoded by the SLC37A4 gene. This transporter allows the glucose-6-phosphate that is made in the cytosol to cross the endoplasmic reticulum (ER) membrane and be hydrolyzed by glucose-6-phosphatase (G6PC1), a membrane enzyme whose catalytic site faces the lumen of the ER. Logically, G6PT deficiency causes the same metabolic symptoms (hepatorenal glycogenosis, lactic acidosis, hypoglycemia) as deficiency in G6PC1 (GSD1a). Unlike GSD1a, GSD1b is accompanied by low neutrophil counts and impaired neutrophil function, which is also observed, independently of any metabolic problem, in G6PC3 deficiency. Neutrophil dysfunction is, in both diseases, due to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), a potent inhibitor of hexokinases, which is slowly formed in the cells from 1,5-anhydroglucitol (1,5-AG), a glucose analog that is normally present in blood. Healthy neutrophils prevent the accumulation of 1,5-AG6P due to its hydrolysis by G6PC3 following transport into the ER by G6PT. An understanding of this mechanism has led to a treatment aimed at lowering the concentration of 1,5-AG in blood by treating patients with inhibitors of SGLT2, which inhibits renal glucose reabsorption. The enhanced urinary excretion of glucose inhibits the 1,5-AG transporter, SGLT5, causing a substantial decrease in the concentration of this polyol in blood, an increase in neutrophil counts and function and a remarkable improvement in neutropenia-associated clinical signs and symptoms.

Associations between short-term exposure to ambient air pollution and lung function in adults.

Evidence of the acute effects of high-level air pollution on small airway function and systemic inflammation in adults is scarce. To examined the associations of short-term (i.e., daily) exposure to multiple air pollutants with lung function and inflammatory markers. We assessed short-term (daily) effects of air pollutants, including particulate matter with aerodynamic diameter less than 2.5 μm (PM2.5) and 10 μm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2) and carbon monoxide (CO), on lung function and peripheral immune cell counts over various lag times using generalized linear regression models. A total of 4764 adults were included from the general community-dwelling population in Shanghai, China. Exposure to air pollutants and lung function were negatively correlated. Decline in FEF between 25% and 75% of vital capacity (FEF25-75%) were found associated with PM2.5, SO2, and CO, and decline in forced expiratory volume in 3 s (FEV3) to forced vital capacity (FVC) ratio were associated with all examined pollutants, indicating obstruction in small airways. Obstructed airflow in large and middle airways as indicated by decline in FEV1/FVC were also associated with all pollutants. In subgroup analysis, significant negative associations between the five pollutants and SAD parameters were found only in males but not in females. The difference in the associations of SO2 with FEF75% between males and females achieved statistical significance. Additionally, all examined pollutants were significantly associated with lower peripheral neutrophil count. Acute exposure to air pollutants were associated with airflow-limitation. Both small airways and proximal airways were affected. Acute exposure to air pollutants were accompanied with a lower neutrophil count.

A Case of X-Linked Moesin-Associated Immune Deficiency in a Pediatric Patient

BackgroundX-Linked Moesin-Associated Immune Deficiency (X-MAID) is a rare severe combined immunodeficiency (SCID) subtype that can present at any age due to its variability. Depending on severity, patients demonstrate failure to thrive, recurrent bacterial and viral infections, and increased susceptibility to varicella zoster. It has been characterized by marked lymphopenia with hypogammaglobulinemia and impaired T-cell migration and proliferation. Case PresentationThis is a report of a Cuban 7-year-old male with poor weight gain and facial dysmorphia. He had a history of recurrent bacterial gastrointestinal infections and pneumonia beginning at 4 months of age. He additionally had 4–6 upper respiratory tract and ear infections annually. While still living in Cuba, he was admitted for a profound EBV infection in the setting of significant leukopenia. A bone marrow biopsy confirmed no malignancy. After he moved to the United States, his laboratory work-up revealed marked leukopenia with low absolute neutrophil and lymphocyte count with low T and B cells, very low immunoglobulin levels IgG, IgA, and IgM, and poor vaccination responses to streptococcus pneumonia, varicella zoster, and SARS-CoV-2. Genetic testing revealed a missense pathogenic variant c.511C>T (p.Arg171Trp) in the moesin (MSN) gene associated with X-MAID. He was managed with Bactrim and acyclovir prophylaxis, and immunoglobulin replacement therapy, and considered for hematopoietic stem cell transplantation. DiscussionDiagnosis of X-MAID should be considered in patients with recurrent infections and profound lymphopenia. As with SCID, early diagnosis and intervention is of utmost importance to prevent morbidity and mortality. This case demonstrates the importance of genetic testing in identifying this disease as it may prompt an immunologist to consider HSCT if conservative management is suboptimal. In the current literature, HSCT appears promising, but the long-term outcomes have yet to be described.

Preventive Effect of Edaravone Against Ischemia-Reperfusion Injury in Rat Epigastric Island Flaps: An Experimental Study

Objective Ischemia-reperfusion (I/R) injury is tissue damage occurring when blood returns to a tissue after an ischemic phase. Reperfusion initiates a cascade of acute inflammatory processes that end in cell death, tissue malfunction, and necrosis. Edaravone (3-methy-1-pheny1-2-pyrazolin-5-one) is a powerful and unique synthetic radical scavenger. In this research, the effects of edaravone on I/R damage were investigated. Material and Methods: 16 adult male Sprague–Dawley rats were utilized. Eight rats were allocated at random into two groups. Group 1 (the control group) experienced ischemia and reperfusion of an abdominal skin flap for 10 hours without therapy. Group 2 (treatment group) received an intraperitoneal injection of 3 mg/kg edaravone 10 hours prior to ischemia and reperfusion in an abdominal skin flap. Using planimetry, flaps were examined at intervals of 1, 3, 7, and 10 days. Then, flaps were removed for biochemical (measurement of tissue glutathione [GSH], tissue protein, lipid peroxidation [MDA], and nitric oxide [NO] levels) and histopathological (measurement of tissue glutathione [GSH], tissue protein, lipid peroxidation [MDA], and nitric oxide [NO] levels) Results: We found no significant changes (p &amp;gt; 0.05) between groups 1 and 2 in terms of NO, MDA, GSH, or planimetric analyses. Group 2 had a lower neutrophil count than group 1, however the difference was not statistically significant (p &amp;gt; 0.05). Conclusion Edaravone is a very effective antioxidant. Nevertheless, our research indicates that it may not influence I/R damage in a skin flap model.

E028 Seronegative arthritis in the context of CHIP: is this a new entity that needs further investigation?

Abstract Background/Aims We describe a seronegative, non-erosive arthritis in the context of clonal haematopoiesis of indeterminant potential (CHIP), the premalignant stage of most myeloid malignancies and myelodysplastic syndromes (MDS). The use of targeted next-generation sequencing (NGS) has helped the clinician to identify the high risk individuals who are at an increased risk of haematological malignancies. Patients presenting with persistent neutropenia and inflammatory arthritis in addition to bone marrow examination, these genomic sequencing should be considered to identify clonal cytopenia and the risk for progression to myeloid malignancies. Methods A 70-year-old man referred to rheumatology clinic with pain and swelling in the small joints of the hands along with shoulder, hip and knee pains. There were few psoriatic patches but no typical features of psoriatic arthropathy. Clinically he had evidence of synovitis in the MCP joints, high inflammatory markers (CRP 157) and a low neutrophil count. Bone marrow examination at time of initial review was reported as completely normal as there was no evidence of MDS and the neutropenia was attributed to his underlying autoimmune condition. His X-rays showed no evidence of erosions and USS scan confirmed synovitis in the MCP joints. He was RF and anti-CCP negative and the diagnosis of suspected seronegative RA was considered. He was initially treated with steroids and hydroxychloroquine but the symptoms relapsed while tapering dose of steroids. A year later, adalimumab was introduced to manage the inflammatory arthritis. He did not show much response to it and golimumab was started, to which he responded very well. He was maintaining excellent clinical remission for 3 years however the neutropenia worsened. He was referred back to haematology for further investigations. Results The neutrophil counts had been fluctuating between 0.3 and 0.9 while receiving golimumab. Slight improvement in the count was noted after taking a 6-month break from biologics. However, this improvement was very transient. A repeat BM biopsy including myeloid next-generation genomic sequencing which diagnosed a high-risk CHIP/clinical cytopenia of unknown significance (CCUS) (mutation profile: IDH 1 R132 (12%VAF), IDH2 R140 (36% VAF), SRSF2 P95 (47% VAF) with no morphological evidence of MDS. Since this is a premalignant condition and there is a significant risk of developing AML, a decision was taken to stop golimumab and start rituximab. The neutrophil count has increased from 0.36 to 1.89 after starting the rituximab and the inflammatory arthritis remains in remission. Conclusion This case highlights low threshold of suspicion of CHIP in patients presenting with features of inflammatory arthritis and neutropenia and/or other cytopenias. Thus, detailed bone marrow sampling including targeted myeloid NGS panels should be undertaken to exclude CHIP or CCUS. This will potentially help us to guide treatment. Disclosure S. Mohamed: None. T. McKerrell: None. D. Makkuni: None.

Clinical observation of neutralizing antibody DXP-604 for treatment critical COVID-19 patients infected with SARS-CoV-2 Delta variant.

From January to March 2022, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta (B.1.617.2) infection was prevalent in Yuzhou and Zhengzhou. DXP-604 is a broad-spectrum antiviral monoclonal antibody, which has excellent viral neutralization ability in vitro and a long half-life in vivo, with good biosafety and tolerability. Preliminary results showed that DXP-604 can accelerate recovery from Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 Delta variant in hospitalized patients with mild to moderate clinical symptoms. However, the efficacy of DXP-604 has not been fully studied in high-risk severe patients. Here, we prospectively enrolled 27 high-risk patients, two groups were divided, in addition to receiving standard of care (SOC), 14 of them additionally received the neutralizing antibody DXP-604 therapy, and another 13 intensive care unit (ICU) patients simultaneously underwent SOC as a control group matched for age, gender, and clinical type. The results revealed lower C-reactive protein, interleukin-6, lactic dehydrogenase and neutrophil counts, and higher lymphocyte and monocyte counts from Day 3 post-DXP-604 treatment compared with SOC treatment. Besides, thoracic CT images showed improvements in lesion areas and degrees, along with changes in blood inflammatory factors. Moreover, DXP-604 reduced the invasive mechanical ventilation and mortality of high-risk SARS-CoV-2 infected patients. The ongoing clinical trials of DXP-604 neutralizing antibody will clarify its utility as a new attractive countermeasure for high-risk COVID-19.

New Perspectives on Primary Prophylaxis of Invasive Fungal Infection in Children Undergoing Hematopoietic Stem Cell Transplantation: A 10-Year Retrospective Cohort Study

Allogenic hematopoietic stem cell transplantation (a-HCT) remains a therapeutic treatment for many pediatric hematological diseases. The occurrence of invasive fungal infections (IFIs) is a complication for which ECIL-8 recommends primary antifungal prophylaxis. In this study, we evaluated the impact of our local strategy of not systematically administering primary antifungal prophylaxis in children undergoing a-HCT on the occurrence and mortality of IFIs. We performed a retrospective monocentric study from 2010 to 2020. We retained all proven and probable IFIs diagnosed during the first year post a-HCT. 308 patients were included. Eighteen patients developed twenty IFIs (thirteen proven, seven probable) (6.5%) among which aspergillosis (n = 10, 50%) and candidosis (n = 7, 35%) were the most frequently diagnosed infections. Only 2% of children died because of an IFI, which represents 14% of all deaths. Multivariate analysis found that age > 10 years (OR: 0.29), the use of a therapeutic antiviral treatment (OR: 2.71) and a low neutrophil count reconstitution (OR: 0.93) were significantly associated with the risk of IFI occurrence. There was also a trend of malignant underlying disease and status ≥ CR2 but it was not retained in multivariate analysis. IFI occurrence was not higher in our cohort than what is reported in the literature with the use of systematic antifungal prophylaxis, with a good survival rate nonetheless. Thus, a prophylaxis could be considered for children with a high risk of IFI such as those aged over 10 years.

TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

LBA17 Background: TALAPRO-2 (NCT03395197) is the first phase 3 study to combine the poly(ADP-ribose) polymerase inhibitor TALA with the androgen receptor inhibitor ENZA. Pts unselected for genetic alterations in DNA damage repair pathways, directly or indirectly involved with homologous recombination repair (HRR), received either TALA + ENZA or PBO + ENZA as 1L treatment for mCRPC. Methods: Pts randomized 1:1 to TALA 0.5 mg or PBO (all pts received ENZA 160 mg daily) were stratified by prior abiraterone or docetaxel for castration-sensitive PC and HRR gene alteration status. Key eligibility criteria: mildly or asymptomatic mCRPC with disease progression at study entry, ECOG PS ≤1, ongoing androgen deprivation therapy, no prior life-prolonging therapy for CRPC. Primary endpoint: imaging-based progression-free survival (ibPFS) by BICR per RECIST 1.1 and PCWG3. Results: 402 pts were randomized to receive TALA + ENZA and 403 PBO + ENZA. Of these 805 pts, enrollment was informed by tumor tissue for 804 (99.9%), by tumor tissue and blood for 114 (14.2%), and by blood only for 1 (0.1%). Median ibPFS by BICR was significantly improved in the TALA + ENZA vs PBO + ENZA arm (not reached vs 21.9 months, respectively; HR, 0.63; 95% CI, 0.51–0.78; P&lt; 0.001). ibPFS was significantly improved in HRR-deficient (HR, 0.46; 95% CI, 0.30–0.70; P&lt; 0.001), HRR-non-deficient or unknown (HR, 0.70; 95% CI, 0.54–0.89; P= 0.004), and HRR-non-deficient pts by tumor tissue testing (HR, 0.66; 95% CI, 0.49–0.91; P= 0.009) in the TALA + ENZA vs PBO + ENZA arm. Overall survival data are immature; 30.6% (TALA) and 32.0% (PBO) pts had died; HR (0.89 [95% CI, 0.69–1.14; P= 0.35]) favored the TALA + ENZA arm. Objective response rates, PSA response ≥50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy significantly favored the TALA + ENZA vs PBO + ENZA arm. In pts, 71.9% (TALA + ENZA) and 40.6% (PBO + ENZA) had grade 3-4 treatment-emergent adverse events (TEAEs). The most common grade ≥3 TEAEs were anemia, low neutrophil, and low platelet counts (TALA + ENZA), and hypertension, anemia, and fatigue (PBO + ENZA). TEAEs led to discontinuation of TALA in 19.1% of pts (vs PBO in 12.2%). Discontinuation rates of ENZA were 10.8% in the TALA + ENZA vs 11.0% in PBO + ENZA arm. Median time to definitive clinically meaningful deterioration in global health status/quality of life (GHS/QoL) was significantly longer with TALA + ENZA vs PBO + ENZA (30.8 vs 25.0 months, respectively; HR, 0.78; 95% CI, 0.62–0.99; P= 0.04). Conclusions: TALA + ENZA demonstrated statistically significant and clinically meaningful improvement in ibPFS over standard of care ENZA as 1L treatment in pts with mCRPC regardless of HRR status, while delaying time to worsening in GHS/QoL. There were no new safety signals; toxicity was generally manageable. Clinical trial information: NCT03395197 .

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Factors associated with mortality from gram-negative bacterial infections in children with cancer

Background/objectivesGram-negative bacteria (GNB) infection in children with cancer is an undesirable consequence of high intensity treatment. Our objective was to identify the prevalence of GNB infection in children with cancer, sensitivity patterns, mortality rates and factors associated with mortality. Design/methodsWe retrospectively analysed clinical and microbiological data of all newly diagnosed paediatric (0–18 years) cancer patients in Max Super Speciality Hospital, Saket and Patparganj in New Delhi who had GNB growths in their blood cultures from March 2013 to April 2019. Bacterial sensitivity to various antimicrobial agents was determined. Outcome of interest was death from GNB infection. ResultsA total of 1170 blood cultures were obtained from 485 children (range 0–28/child, median 1/child). Of these 213 (18.2%) were positive with 108 (50.7%) gram-positive bacteria, 87 (40.8%) with GNB and 18 (8.5%) with fungal. Sensitivity to piperacillin/tazobactam, amikacin, meropenem and colistin was observed in 38.4%, 57.6%, 51.5% and 95.3% of the GNB isolates, respectively. Sensitivity to our first line combination of piperacilin/tazobactam plus amikacin was observed in 72.7% of Pseudomonas species, 71.4% Acinetobacter species, 66.7% Enterobacter cloacae, 60% Klebsiella species and 42.1% of E coli. There were 9 deaths (mortality rate 18%). There was no significant difference in mortality by age group, gender, country, hospital, cancer type and type of GNB. Factors significantly associated with mortality were low neutrophil count and resistance to first line antibiotics. ConclusionGNB Infection in children with cancer in India is characterized by high antibiotic resistance. Multidrug resistance and neutropenia are associated with increased risk of mortality.

Late-term cardiac magnetic resonance imaging in multisystem inflammatory syndrome in children

Background. Cardiac involvement in multisystem inflammatory syndrome in children may have a spectrum ranging from mild disease to severe heart failure due to fulminant myocarditis. Cardiac involvement usually resolves after clinical recovery. However, the adverse effects of myocarditis on cardiac function after recovery are not fully known. This study aims to investigate cardiac involvement by performing cardiac magnetic resonance imaging (MRI) after the acute and recovery periods. Methods. 21 patients with clinical and laboratory signs of myocarditis, including left ventricular systolic dysfunction, mitral regurgitation, elevated troponin T, elevated N-terminal pro-B-type natriuretic peptide and electrocardiographic changes, who had given consent for cardiac MRI, underwent cardiac MRI after completion of the acute and recovery phases. Results. When compared to 16 patients with normal cardiac MRI, five patients with cardiac fibrosis on MRI were older, had greater body mass indexes, lower leucocyte counts, lower neutrophil counts, higher blood urea nitrogen levels and higher creatinine levels. Cardiac fibrosis on MRI was located in the posterior right ventricle insertion point and in mid ventricular septum. Conclusions. Adolescence and obesity appear as risk factors for the development of fibrosis as a late-term sequela of myocarditis. Furthermore, future studies reporting the follow-up data of patients with fibrosis are necessary to predict and manage adverse outcomes.