Search

Purpose: Data on short courses of antibiotic therapy for Enterobacterales bacteremia in high-risk neutropenic patients are limited. The aim of the study was to describe and compare the frequency of bacteremia relapse, 30-day overall and infection-related mortality, Clostridiodes difficile infection and length of hospital stay since bacteremia among those who received antibiotic therapy for 7 or 14 days. Methods: This is a multicenter, prospective, observational cohort study in adult high-risk neutropenic patients with hematologic malignancies or hematopoietic stem cell transplant and monomicrobial Enterobacterales bacteremia. They received appropriate empirical antibiotic therapy, had a clinical response within 7 days, and infection source control. Clinical, epidemiological and outcomes variables were compared based on 7 or 14 days of AT. Results: Two hundred patients were included (100, 7-day antibiotic therapy; 100, 14-day antibiotic therapy). Escherichia coli was the pathogen most frequently isolated (47.5%), followed by Klebsiella sp. (40.5%). Among those patients that received 7-day vs. 14-day antibiotic course, a clinical source of bacteremia was found in 54% vs. 57% (p = 0.66), multidrug-resistant Enterobacterales isolates in 28% vs. 30% (p = 0.75), and 40% vs. 47% (p = 0.31) received combined empirical antibiotic therapy. Overall mortality was 3% vs. 1% (p = 0.62), in no case related to infection; bacteremia relapse was 7% vs. 2% (p = 0.17), and length of hospital stay since bacteremia had a median of 9 days (IQR: 7–15) vs. 14 days (IQR: 13–22) (p = < 0.001). Conclusions: These data suggest that seven-day antibiotic therapy might be adequate for patients with high-risk neutropenia and Enterobacterales bacteremia, who receive appropriate empirical therapy, with clinical response and infection source control. [ABSTRACT FROM AUTHOR]

Background: Trilaciclib, in comparison to placebo plus carboplatin, etoposide, ± atezolizumab (PEA), has shown significant reductions in incidence of severe neutropenia (SN) among patients with extensive-stage small cell lung cancer (ES-SCLC). Despite these findings, real-world utility remains limited. Methods: A single-center quasi-experimental study compared trilaciclib + PEA (PEAT) versus PEA in ES-SCLC patients. The study period ranged from April 1, 2021 to July 31, 2022, for the PEAT recipients and February 1, 2020, to February 28, 2021, for PEA recipients. The primary endpoint evaluated was incidence of SN after cycle 1 and during the treatment period. Secondary endpoints included measures related to myelopreservation and patient outcomes. Results: Among 34 PEAT and 44 PEA patients, baseline characteristics were similar, except for a higher median age (69 vs 64 years) and more males (64.7% vs 38.6%) in the PEAT cohort. The PEAT cohort exhibited a lower SN rate (3%) versus the PEA cohort (18%), with statistical significance demonstrated on multivariate analysis (p = 0.015). Additionally, the PEAT cohort also demonstrated significant reductions in red blood cell transfusion requirements (3% vs 23%; p = 0.02), grade 3–4 anemia (6% vs 25%; p = 0.03), and grade 3–4 thrombocytopenia (0% vs 11%, p = 0.045). Conclusion: Trilaciclib, in combination with PEA, demonstrated an improvement in the safety profile without compromising survival outcomes in ES-SCLC patients. These findings underscore the potential benefits of incorporating trilaciclib in real-world clinical settings for enhanced patient care. [ABSTRACT FROM AUTHOR]

Purpose: Haematology patients with high-risk neutropenia are prone to mucosal-barrier injury-associated laboratory-confirmed bloodstream infections (MBI-LCBI). We assessed risk factors for MBI-LCBI including candidaemia in neutropenic haematology patients with fever. Methods: This prospective observational study was performed in six dedicated haematology units in the Netherlands. Eligible haematology patients had neutropenia < 500/mL for ≥ 7 days and had fever. MBI-LCBIs were classified according to Centers for Disease Control (CDC) definitions and were followed until the end of neutropenia > 500/mL or discharge. Results: We included 416 patients from December 2014 until August 2019. We observed 63 MBI-LCBIs. Neither clinical mucositis scores nor the blood level of citrulline at fever onset was associated with MBI-LCBI. In the multivariable analysis, MASCC-score (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.05 to 1.29 per point decrease), intensive chemotherapy (OR 3·81, 95% CI 2.10 to 6.90) and Pichia kudriavzevii (formerly Candida krusei) colonisation (OR 5.40, 95% CI 1.75 to 16.7) were retained as risk factors for MBI-LCBI, while quinolone use seemed protective (OR 0.42, 95% CI 0.20 to 0.92). Citrulline level (OR 1.57, 95% CI 1.07 to 2.31 per µmol/L decrease), active chronic obstructive pulmonary disease (OR 15.4, 95% CI 1.61 to 14.7) and colonisation with fluconazole-resistant Candida (OR 8.54, 95% CI 1.51 to 48.4) were associated with candidaemia. Conclusion: In haematology patients with fever during neutropenia, hypocitrullinaemia at fever onset was associated with candidaemia, but not with bacterial MBI-LCBI. Patients with intensive chemotherapy with a low MASCC-score and colonisation with Pichia kudriavzevii had the highest risk of MBI-LCBI. Trial registration: ClinicalTrials.gov (NCT02149329) at 19-NOV-2014. [ABSTRACT FROM AUTHOR]

Background: This case explores the challenges encountered in managing treatment-resistant paranoid schizophrenia, focusing on the limitations of using clozapine due to the risk of neutropenia. The United Kingdom Clozapine Patient Monitoring Service (UK CPMS) and its eligibility criteria are discussed, highlighting the potential benefits of expanding access to clozapine for patients who could potentially benefit from this medication. The integration of clozapine genetic testing as a personalized approach is explored, emphasizing the importance of identifying patients with a favorable genetic profile for clozapine response. Methods: Case report. Results: The case presentation of Mr. X exemplifies the difficulties faced in managing treatment-resistant schizophrenia when access to clozapine is restricted, leading to persistent negative symptoms. Conclusion: The article underscores the importance of innovative solutions and personalized care to enhance the treatment outcomes for patients with treatment-resistant paranoid schizophrenia. It acknowledges that certain restrictions of clozapine use may limit the effective management of patients with this condition. [ABSTRACT FROM AUTHOR]

LCP1 encodes L-plastin, an actin-bundling protein primarily expressed in hematopoietic cells. In mouse and fish models, LCP1 deficiency has been shown to result in hematologic and immune defects. This study aimed to determine the nature of a human inborn error of immunity resulting from a novel genetic variant of LCP1. We performed genetic, protein, and cellular analysis of PBMCs from a kindred with apparent autosomal dominant immune deficiency. We identified a candidate causal mutation in LCP1 , which we evaluated by engineering the orthologous mutation in mice and Jurkat cells. A splice-site variant in LCP1 segregated with lymphopenia, neutropenia, and thrombocytopenia. The splicing defect resulted in at least 2 aberrant transcripts, producing an in-frame deletion of 24 nucleotides, and a frameshift deletion of exon 8. Cellular analysis of the kindred revealed a proportionate reduction of T and B cells and a mild expansion of transitional B cells. Similarly, mice carrying the orthologous genetic variant exhibited the same in-frame aberrant transcript, reduced expression Lcp1 and gene dose-dependent leukopenia, mild thrombocytopenia, and lymphopenia, with a significant reduction of T-cell populations. Functional analysis revealed that LCP1c740-1G>A confers a defect in platelet development and function with aberrant spreading on collagen. Immunologic analysis revealed defective actin organization in T cells, reduced migration of PBMCs from patients, splenocytes from mutant mice, and a mutant Jurkat cell line in response to CXCL12; impaired germinal center B-cell expansion after immunization; and reduced cytokinesis during T cell proliferation. We describe a unique human hematopoietic defect affecting neutrophils, lymphocytes, and platelets arising from partial LCP1 deficiency. [ABSTRACT FROM AUTHOR]

Background FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. Methods In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). Results One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. Conclusions A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting. [ABSTRACT FROM AUTHOR]

Background No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD. Methods In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period. Results All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated. Conclusion The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073). [ABSTRACT FROM AUTHOR]

Background: The management of febrile neutropenia (FN) in pediatric cancer patients has traditionally been conducted in a hospital setting. However, recent evidence has indicated that outpatient management of FN can be equally effective compared to inpatient care. Based on this evidence, we conducted a cost-minimization analysis (CMA) specifically focused on pediatric cancer patients in Mexico. Methods: A piggy-back study was conducted during the execution of a non-inferiority clinical trial that compared outpatient treatment to inpatient treatment for FN in children with cancer. A CMA was performed from a societal perspective using patient-level data. In the previous study, we observed that step-down oral outpatient management of low-risk FN was as safe and effective as inpatient intravenous management. Direct and indirect costs were collected prospectively. The costs were adjusted for inflation and converted to US dollars, with values standardized to July 2022 costs. Statistical analysis using bootstrap methods was employed to obtain robust estimations for decision-making within the Mexican public health care system. Results: A total of 117 FN episodes were analyzed, with 60 in the outpatient group and 57 in the inpatient group; however, complete cost data were available for only 115 FN episodes. The analysis revealed an average savings of $1,087 per FN episode managed on an outpatient basis, representing a significant 92% reduction in total cost per FN episode compared to inpatient treatment. Length of hospital stay and inpatient consultations emerged as the primary cost drivers within the inpatient care group. Conclusion: This CMA demonstrates that the step-down outpatient management approach is cost-saving when compared to inpatient management of FN in pediatric cancer patients. The mean difference observed between the treatment groups provides support for decision-making within the public health care system, as outpatient management of FN allows for substantial cost savings without compromising patient health. [ABSTRACT FROM AUTHOR]

ABSTRACT Neutropenia is a common chemotherapy‐associated adverse event (AE) in dogs and a significant cause of decreased relative dose intensity. Dose reductions (DRs) and treatment delays (TDs) are frequently applied to decrease the risk of further neutropenic events (NEs) and AEs, but there is no standardised approach. The two main objectives of this retrospective study were to determine: (1) the failure rate of a 10% DR to prevent a subsequent inadequate absolute neutrophil count (ANC), defined as a nadir ANC <0.75 × 109/L or pretreatment ANC <1.5 × 109/L; and (2) if the duration of TDs due to pretreatment neutropenia affects the occurrence of subsequent NEs. A total of 1056 chemotherapy treatments were recorded for 128 dogs that developed at least one NE. In 75 of 124 (60.5%, 95% CI: 51.2%–69%) evaluable NEs, a nadir ANC of ≥0.75 × 109/L and pretreatment ANC of ≥1.5 × 109/L were achieved after a single 10% chemotherapy DR, while a 10% DR failed to prevent a subsequent inadequate ANC in the remaining 49/124 (39.5%, 95% CI: 30.1%–48.3%). The only variable associated with failure was the drug prescribed. DR failure occurred in 22/39 (56.4%, 95% CI: 40.9%–70.6%) lomustine DRs, 14/27 (51.9%, 95% CI: 33.9%–69.2%) cyclophosphamide DRs, but only 2/22 (9.1%, 95% CI: 2.5%–27.8%) doxorubicin DRs and 2/24 (8.3%, 95% CI: 2.3%–25.8%) vincristine DRs. Seventy‐three evaluable TDs (mean: 5 days, SD ± 2.2 days) were prescribed. There was no association between TD duration and subsequent NEs (p = 0.11). [ABSTRACT FROM AUTHOR]

Mavorixafor (XOLREMDI™) is an oral, selective C-X-C chemokine receptor 4 (CXCR4) antagonist developed by X4 Pharmaceuticals that blocks the binding of C-X-C chemokine ligand 12 (also known as stromal derived factor-1) to CXCR4. In April 2024, it became the first therapy to be approved for WHIM syndrome (named by an acronym for its observed characteristics of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis) in the USA, where it is indicated for use in patients aged ≥ 12 years with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. Clinical development of mavorixafor is ongoing for chronic neutropenic disorders. This article summarizes the milestones in the development of mavorixafor leading to this first approval for use in patients aged ≥ 12 years with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. [ABSTRACT FROM AUTHOR]

Purpose: An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy. Methods: The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML. Results: Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8–46 days). Area under the concentration–time curve (AUC0–24) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC0–24 was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007). Conclusion: Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy. [ABSTRACT FROM AUTHOR]

Purpose. Endocrine therapy combined with cyclin‐dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) is the preferred treatment for hormone receptor‐positive (HR+)/human epidermal growth factor receptor 2‐negative (HER2–) metastatic breast cancer (MBC). However, there are currently no recommendations for therapeutic strategies after progression on CDK4/6i‐based treatment. This study aimed to examine the efficacy and safety of anlotinib plus chemotherapy in HR+/HER2– MBC after progression on CDK4/6 inhibitors. Methods. We collected data from 32 patients with HR+/HER2– MBC treated with anlotinib plus chemotherapy after progressing on CDK4/6i at Jiangsu Cancer Hospital from March 2020 to October 2023. The median follow‐up was 9.1 months (range, 2.0–19.7 months) as of the data cutoff date in October 2023. The primary endpoint was median progression‐free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and adverse events. Results. The median PFS (mPFS) of all patients was 7.6 months (95% confidence interval (CI), 5.75–9.45). There was no significant difference in mPFS between patients who responded to prior CDK4/6i treatment and those who did not (8.3 months vs. 6.8 months, p = 0.580). Besides, the ORR was 34.4% and DCR was 93.8%. The most frequently observed adverse events were anemia (50.0%), neutropenia (40.6%), thrombocytopenia (34.4%), and epistaxis (34.4%). Dose interruption or reductions due to adverse events occurred in 2 (6.3%) and 5 (15.6%) patients, respectively. Conclusions. The study preliminarily demonstrates that anlotinib combined with chemotherapy may be an optional recommendation for patients with HR+/HER2– metastatic breast cancer who have progressed after CDK4/6i. [ABSTRACT FROM AUTHOR]

Background: Neutropenia is a common complication in lung transplant recipients (LTRs). Filgrastim may be used to treat neutropenia in LTRs, but its consequences on acute cellular rejection (ACR) remain controversial. Objective: The purpose was to examine the association between filgrastim and incidence of ACR 6 months after filgrastim administration in LTRs. Secondary outcomes included burden of ACR, infections, chronic lung allograft dysfunction (CLAD), and survival. Methods: This was a matched cohort study of patients transplanted between January 2010 and October 2019. LTRs who received filgrastim for neutropenia were compared to a cohort who did not. LTRs were matched on transplant indication, sex, age, and time post-transplant and multivariable logistic regression models were used to evaluate the likelihood of ACR. Results: 212 patients were included in the analysis (106 in each group). 50 patients (47.2%) in the filgrastim group experienced ACR compared to 37 patients (34.9%) in the no filgrastim group (P =.070). In multivariable analysis, filgrastim use was not associated with ACR at 6 months (OR 1.409, 95% CI 0.772-2.571). Time to first ACR was shorter (P =.049) and 6-month ACR score was higher in the filgrastim group (.49 vs.33, P =.047). LTRs in the filgrastim group had higher incidence of bacterial pneumonia and 1-year mortality. Conclusions: Although not associated with increased likelihood of ACR at 6 months, our study found that filgrastim is associated with increased ACR burden and decreased time to ACR. This study can help inform clinicians of ACR risk after filgrastim use in LTRs. [ABSTRACT FROM AUTHOR]

The design of compounds selectively binding to specific isoforms of histone deacetylases (HDACs) is ongoing research to prevent adverse side effects. Two of the most studied isoforms are HDAC1 and HDAC6 which are important targets in various disease conditions. Here, various machine learning (ML) approaches were built and tested to predict the bioactivity and selectivity towards specific isoforms. The selectivities of compounds were precited using two different approaches: selectivity profiling and selectivity window approaches. The bioactivity models of HDAC1 and HDAC6 were used to determine the selectivities of compounds in the selectivity profiling approach. In the selectivity window approach, models were developed by directly training on the bioactivity differences of tested compounds against HDAC1 and HDAC6. In this study, firstly all available classification and regression ML algorithms in Python package were tested to find suitable algorithms. Five ML algorithms were selected based on their performances and algorithm differences. These models were compared to each other by using traditional evaluation metrics. Then, a consensus approach of the selected ML models was employed to compare the selectivity window and selectivity profiling approaches regarding their ability to distinguish HDAC1- and HDAC6-selective compounds from others. Here, the performances were also tested against an external set and it was seen that the selectivity window approach was performing slightly better in categorizing selective compounds than the selectivity profiling approach. The approaches presented in this study could be an important step to utilize for screening molecular libraries to discover selective inhibitors for targets. Discovering selective inhibitors for HDAC isoforms is critical to decrease side effects such as thrombocytopenia, neutropenia, cardiotoxicity etc. Machine learning (ML) methods could be employed to predict selectivity of inhibitors Here, selectivity window and selectivity profiling approaches were used along with various ML models for estimation of selectivity against HDAC1 and HDAC6 isoforms. [ABSTRACT FROM AUTHOR]

Background: Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity. Objective: To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel. Methods: We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild‐type ELANE/G6PC3 were referred for next‐generation sequencing. Results: Sixty‐five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman–Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte‐colony stimulating factor or due to myeloid transformation. Conclusions: The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow‐up. [ABSTRACT FROM AUTHOR]

Objectives: This paper critiques the haematological monitoring guidelines for clozapine. It describes the history of clozapine, as well as the pathophysiology and epidemiology of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA). The paper appraises the extant literature on mandatory clozapine haematological monitoring. Conclusion: Contemporary Australian protocols for clozapine haematological monitoring are not consistent with the current evidence base. CIN and CIA are rare occurrences, and the associated risk of death is low. Potential modifications to existing guidelines include changing neutrophil thresholds for patients with benign ethnic neutropenia and reducing the frequency or removing haematological monitoring after two years of clozapine treatment. [ABSTRACT FROM AUTHOR]

To reduce severe fluoropyrimidine-related toxicity, pharmacogenetic guidelines recommend a dose reduction for carriers of four high-risk variants in the DPYD gene (*2A, *13, c.2846A>T, HapB3). The polymorphism in the MIR27A gene has been shown to enhance the predictive value of these variants. Our study aimed to explore whether rs895819 in the MIR27A gene modifies the effect of five common DPYD variants: c.1129-5923C>G (rs75017182, HapB3), c.2194G>A (rs1801160, *6), c.1601G>A (rs1801158, *4), c.496A>G (rs2297595), and c.85T>C (rs1801265, *9A). The study included 370 Caucasian patients with gastrointestinal tumors who received fluoropyrimidine-containing chemotherapy. Genotyping was performed using high-resolution melting analysis. The DPYD*6 allele was associated with overall severe toxicity and neutropenia with an increased risk particularly pronounced in patients carrying the MIR27A variant. All carriers of DPYD*6 exhibited an association with asthenia regardless of their MIR27A status. The increased risk of neutropenia in patients with c.496G was only evident in those co-carrying the MIR27A variant. DPYD*4 was also significantly linked to neutropenia risk in co-carriers of the MIR27A variant. Thus, we have demonstrated the predictive value of the *6, *4, and c.496G alleles of the DPYD gene, considering the modifying effect of the MIR27A polymorphism. [ABSTRACT FROM AUTHOR]

Background Genotyping isolates of a specific pathogen may demonstrate unique patterns of antimicrobial resistance, virulence or outcomes. However, evidence for genotype–outcome association in Candida glabrata is scarce. We aimed to characterize the mycological and clinical relevance of genotypes on C. glabrata bloodstream infections (BSIs). Methods Non-duplicated C. glabrata blood isolates from hospitalized adults were genotyped by MLST, and further clustered by the unweighted pair group method with arithmetic averages (UPGMA). A clonal complex (CC) was defined by UPGMA similarities of >90%. Antifungal susceptibility testing was performed by a colorimetric microdilution method and interpreted following CLSI criteria. Results Of 48 blood isolates evaluated, 13 STs were identified. CC7 was the leading CC (n  = 14; 29.2%), including 13 ST7. The overall fluconazole and echinocandin resistance rates were 6.6% and 0%, respectively. No specific resistance patterns were associated with CC7 or other CCs. Charlson comorbidity index (adjusted OR, 1.49; 95% CI, 1.05–3.11) was the only predictor for CC7. By multivariable Cox regression analyses, CC7 was independently associated with 28 day mortality [adjusted HR (aHR), 3.28; 95% CI, 1.31–8.23], even after considering potential interaction with neutropenia (aHR, 3.41; 95% CI, 1.23–9.42; P for interaction, 0.24) or limited to 34 patients with monomicrobial BSIs (aHR, 2.85; 95% CI, 1.15–7.08). Also, the Kaplan–Meier estimate showed greater mortality with CC7 (P  = 0.003). Fluconazole resistance or echinocandin therapy had no significant impact on mortality. Conclusions Our data suggested comorbid patients were at risk of developing CC7 BSIs. Further, CC7 was independently associated with worse outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Chemotherapy for breast cancer can cause neutropenia, increasing the risk of febrile neutropenia (FN) and serious infections. The use of granulocyte colony-stimulating factors (G-CSF) as primary prophylaxis has been explored to mitigate these risks. To evaluate the efficacy and safety of primary G-CSF prophylaxis in patients with invasive breast cancer undergoing chemotherapy. Methods: A systematic literature review was conducted according to the "Minds Handbook for Clinical Practice Guideline Development" using PubMed, Ichushi-Web, and the Cochrane Library databases. Randomized controlled trials (RCTs) and cohort studies assessing using G-CSF as primary prophylaxis in invasive breast cancer were included. The primary outcomes were overall survival (OS) and FN incidence. Meta-analyses were performed for outcomes with sufficient data. Results: Eight RCTs were included in the qualitative analysis, and five RCTs were meta-analyzed for FN incidence. The meta-analysis showed a significant reduction in FN incidence with primary G-CSF prophylaxis (risk difference [RD] = 0.22, 95% CI: 0.01–0.43, p = 0.04). Evidence for improvement in OS with G-CSF was inconclusive. Four RCTs suggested a tendency for increased pain with G-CSF, but statistical significance was not reported. Conclusions: Primary prophylactic use of G-CSF is strongly recommended for breast cancer patients undergoing chemotherapy, as it has been shown to reduce the incidence of FN. While the impact on OS is unclear, the benefits of reducing FN are considered to outweigh the potential harm of increased pain. [ABSTRACT FROM AUTHOR]

To validate the efficacy and safety of withholding antimicrobial therapy in a new cohort of children with cancer and febrile neutropenia (FN) having a demonstrated viral respiratory tract infection. Prospective, multicenter, noninferiority, randomized study, approved by the ethical committee, in children presenting with FN at seven hospitals in Chile, evaluated at admission for diagnosis of bacterial and viral pathogens. Children who were positive for a respiratory virus, negative for a bacterial pathogen, and had a favourable evolution after 48–72 hours of antimicrobial therapy were randomized to either maintain or withhold antimicrobial therapy. The primary endpoint was the percentage of episodes with an uneventful resolution, whereas the secondary endpoints were days of fever, days of hospitalization, requirement of antimicrobial treatment readministration, sepsis, paediatric intensive care unit admission, and death. A total of 301 of 939 children with FN episodes recruited between March 2021 and December 2023 had a respiratory virus as a unique identified microorganism, of which 139 had a favourable evolution at 48–72 hours and were randomized, 70 to maintain and 69 to withdraw antimicrobial therapy. The median days of antimicrobial therapy was 5 (IQR 3–6) versus 3 (IQR 3–6) days (p < 0.001), with similar frequency of uneventful resolution 66/70 (94%) and 66/69 (96%); relative risk, 1.01; (95% CI, 0.93 to 1.09), absolute risk difference 0.01; (95% CI, −0.05 to 0.08) and similar number of days of fever and days of hospitalization. No cases of sepsis, paediatric intensive care unit admission, or death were reported. We validated the strategy of withdrawal antimicrobial therapy in children with FN and viral respiratory tract infection based on clinical and microbiological/molecular diagnostic criteria. This will enable advances in antimicrobial stewardship strategies with a possible future impact on antimicrobial resistance. [ABSTRACT FROM AUTHOR]

This study compared the effects of megestrol acetate (MA) prophylactic (p-MA) versus reactive (r-MA) use for critical body-weight loss (>5% from baseline) during concurrent chemoradiotherapy (CCRT) in patients with advanced pharyngolaryngeal squamous cell carcinoma (PLSCC). Patients receiving CCRT alone in two phase-II trials were included for analyses. Both the p-MA and r-MA cohorts received the same treatment protocol at the same institution, and the critical body-weight loss, survival, and adverse event profiles were compared. The mean (SD) weight loss was 5.1% (4.7%) in the p-MA cohort (n = 54) vs. 8.1% (4.6%) in the r-MA cohort (n = 50) (p =.001). The percentage of subjects with body-weight loss >5% was 42.6% in the p-MA cohort vs. 68.0% in the r-MA cohort (p =.011). Tube feeding was needed in 22.2% of p-MA vs. 62.0% of r-MA patients (p <.001). Less neutropenia (26.0% vs. 70.0% [p <.001]) and a shorter duration of grade 3-4 mucositis (2.4 ± 1.4 vs. 3.6 ± 2.0 wk [p =.009]) were observed with p-MA treatment. Disease-specific survival, locoregional control, or distant metastasis-free survival did not differ. Less competing mortality from secondary primary cancer resulted in a better overall survival trend in the p-MA cohort. p-MA may reduce body-weight loss and improve adverse event profiles during CCRT for patients with PLSCC. [ABSTRACT FROM AUTHOR]

Background: Mecapegfilgrastim, a long‐acting granulocyte‐colony stimulating factor has been approved for reducing the incidence of infection, particularly febrile neutropenia (FN), in China. Objective: We conducted a multicenter prospective observational study to examine the safety and effectiveness of mecapegfilgrastim in preventing neutropenia in gastrointestinal patients receiving the chemotherapy, including S‐1/capecitabine‐based regimens or the fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) regimens. Method: Five hundred and sixty‐one gastrointestinal patients from 40 sites across China, between May 2019 and November 2021, were included. The administration of mecapegfilgrastim was prescribed at the discretion of local physicians. Results: The most common adverse drug reactions (ADRs) of any grade for all patients was increased white blood cells (2.9%). Grade 3/4 ADRs were observed for anemia (0.2%), decreased white blood cells (0.2%), and decreased neutrophil count (0.2%). Among the 116 patients who received S‐1/capecitabine‐based chemotherapy throughout all cycles, ADRs of any grade included anemia (1.7%), myalgia (0.9%), and increased alanine aminotransferase (0.9%). No grade 3/4 ADRs were observed. In 414 cycles of patients who underwent S‐1/capecitabine‐based regimens, only one (0.2%) cycle experienced grade 4 neutropenia. In the FOLFIRINOX, FOLFOXIRI, and FOLFOX chemotherapy regimens, grade 4 neutropenia occurred in one (2.7%) of 37 cycles, four (4.7%) of 85 cycles, and two (1.2%) of 167 cycles, respectively. Conclusion: In a real‐world setting, mecapegfilgrastim has proven effective in preventing severe neutropenia in gastrointestinal patients following chemotherapy. This includes commonly used moderate or high‐risk FN regimens or regimens containing S1/capecitabine, all of which have demonstrated favorable efficacy and safety profiles. [ABSTRACT FROM AUTHOR]

Tunneled central venous catheters (CVCs) are the cornerstone of modern oncologic practice. Establishing best practices for catheter management in children with cancer is essential to optimize care, but few guidelines exist to guide placement and management. Objectives: To address four questions: 1) Does catheter composition influence the incidence of complications; 2) Is there a platelet count below which catheter placement poses an increased risk of complications; 3) Is there an absolute neutrophil count (ANC) below which catheter placement poses an increased risk of complications; and 4) Are there best practices for the management of a central line associated bloodstream infection (CLABSI)? Data Sources: English language articles in Ovid Medline, PubMed, Embase, Web of Science, and Cochrane Databases. Study Selection: Independently performed by 2 reviewers, disagreements resolved by a third reviewer. Data Extraction: Performed by 4 reviewers on forms designed by consensus, quality assessed by GRADE methodology. Data were extracted from 110 manuscripts. There was no significant difference in fracture rate, venous thrombosis, catheter occlusion or infection by catheter composition. Thrombocytopenia with minimum thresholds of 30,000–50,000 platelets/mcl was not associated with major hematoma. Limited evidence suggests a platelet count <30,000/mcL was associated with small increased risk of hematoma. While few studies found a significant increase in CLABSI in CVCs placed in neutropenic patients with ANC<500Kcells/dl, meta-analysis suggests a small increase in this population. Catheter removal remains recommended in complicated or persistent infections. Limited evidence supports antibiotic, ethanol, or hydrochloric lock therapy in definitive catheter salvage. No high-quality data were available to answer any of the proposed questions. Although over 15,000 tunneled catheters are placed annually in North America into children with cancer, there is a paucity of evidence to guide practice, suggesting multiple opportunities to improve care. III. This study was registered as PROSPERO 2019 CRD42019124077. • What is currently known about this topic? Despite the fact long term central venous catheters are the standard of care for the administration of chemotherapy, there is a paucity of information related to best practices for both line insertion and maintenance. • What new information is contained in this article? This is the first systematic review to address the current literature on both guidelines for catheter placement (including catheter composition and considerations of thrombocytopenia and neutropenia) as well as for catheter removal in the presence of a catheter-based infection. [ABSTRACT FROM AUTHOR]

Background We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ). Methods This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue. Results Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P  = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P  < .001) and grade 2/3 neuropathy (17% vs 7%; P  = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations. Conclusion FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation. CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944). [ABSTRACT FROM AUTHOR]

Copyright of Journal of Traditional Medical Complementary Therapies is the property of Turkiye Klinikleri and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted. [ABSTRACT FROM AUTHOR]

Purpose: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment. Methods: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30–35 mg/m2 twice daily on days 1–5) and irinotecan (150–165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose. Results: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease. Conclusion: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment. [ABSTRACT FROM AUTHOR]

This phase 1b study aimed to evaluate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of HR070803, a novel nanoliposomal formulation of irinotecan, in combination with 5-fluorouracil and leucovorin in patients with pretreated advanced solid tumors. This study consisted of dose-escalation and expansion stages. Dose escalation was performed with a traditional 3 + 3 design; patients received intravenous infusion of HR070803 from 60 to 80 mg/m2, followed by leucovorin (200 mg/m2) and 5-fluorouracil (2000 mg/m2) every 2 weeks. In the expansion stage, patients received treatments at selected tolerable dose. Fifteen patients received treatments at 60 mg/m2 (n = 12) and 80 mg/m2 (n = 3). DLTs occurred in 2 patients at 80 mg/m2 (grade 2 neutropenia that resulted in a dose delay of ≥ 7 days, n = 1; grade 3 febrile neutropenia, n = 1). The MTD was determined to be 60 mg/m2. The most frequent HR070803related adverse events included anorexia, leukopenia, neutropenia, nausea, fatigue, and diarrhea. SN-38, the active metabolite of irinotecan, exhibited lower maximum plasma concentrations and a prolonged terminal half-life when irinotecan was administered via nanoliposome compared to conventional injection. Overall, 4 patients achieved a partial response (confirmed, n = 2), and 9 had stable disease. The MTD of HR070803 was 60 mg/m2 when infused with 5-fluorouracil and leucovorin. Nanoliposomal encapsulation modified the pharmacokinetics of irinotecan and SN-38. HR070803 with 5-fluorouracil and leucovorin demonstrated a manageable safety profile and promising antitumor efficacy in advanced solid tumors. Trial registration: Clinicaltrials.gov, NCT05086848. Retrospectively registered on Oct. 12, 2021. [ABSTRACT FROM AUTHOR]

Copyright of Parodontologie: die Zeitschrift für die Praxis (Berlin, Germany) is the property of Quintessenz Verlags GmbH and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: High-intensity chemotherapy can cause life-threatening complications in pediatric patients. Therefore, this study investigated safety and efficacy of long-acting pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF; Jinyouli®) in children undergoing high-intensity chemotherapy. Methods: Treatment-naive patients received post-chemotherapy PEG-rhG-CSF as primary prophylaxis for two cycles. The primary endpoints were drug-related adverse events (AEs) and bone pain scores. Secondary endpoints included grade 3-4 neutropenia, duration of neutropenia recovery, absolute neutrophil count changes, febrile neutropenia (FN), reduced chemotherapy intensity, antibiotic usage, and AE severity. The cost-effectiveness of PEG-rhG-CSF was compared with that of rhG-CSF (Ruibai®). Results: Here, 307 and 288 patients underwent one and two PEG-rhG-CSF cycles, respectively. Ninety-one patients experienced drug-related AEs, primarily bone pain (12.7%). Moreover, Grade 3-4 neutropenia and FN were observed. Median FN durations were 3.0 days in both cycles. No drug-related delays were observed during chemotherapy. One patient experienced grade 4 neutropenia-induced reduction in chemotherapy intensity during cycle 2. In total, 138 patients received antibiotics. PEG-rhG-CSF exhibited superior costeffectiveness compared to rhG-CSF. Conclusion: Our findings indicate that PEG-rhG-CSF is safe, efficient, and costeffective in pediatric patients undergoing high-intensity chemotherapy, providing preliminary evidence warranting further randomized controlled trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Chemotoxicity in colorectal cancer (CRC) patients impacts treatment compliance, survival, and quality of life. While clinician-reported chemotoxicity predicts rehospitalization and survival, a comprehensive understanding is lacking. This systematic review and meta-analysis studied chemotoxicity in CRC patients. The study found that 45.7% of patients experienced overall moderate-to-severe toxicities, with gastrointestinal toxicity (22.9%) and neuropathy or neutropenia (17.9%) being the most common. Risk factors included malnutrition, frailty, impaired immune or hepato-renal functions, short telomere lengths, low gut lactobacillus levels, age, female sex, aggressive chemotherapy, and low quality of life. Age was linked to neutropenia and gastrointestinal toxicity. Older adults had higher overall and gastrointestinal toxicities but lower neutropenia than younger adults. The study underscores the need for close monitoring and management of chemotoxicity in CRC patients. Community contributions have been instrumental in raising awareness about these issues, advocating for patient support, and future research to improve treatment toxicities in CRC. Background: Colorectal cancer (CRC) patients experience multiple types of chemotoxicity affecting treatment compliance, survival, and quality of life (QOL). Prior research shows clinician-reported chemotoxicity (i.e., grading scales or diagnostic codes) predicts rehospitalization and cancer survival. However, a comprehensive synthesis of clinician-reported chemotoxicity is still lacking. Objectives: We conducted a systematic review and meta-analysis to determine chemotoxicity's prevalence and risk factors in CRC. Methods: A systematic search from 2009 to 2024 yielded 30 studies for review, with 25 included in the meta-analysis. Results: Pooled prevalences of overall, non-hematological, and hematological moderate-to-severe toxicities were 45.7%, 39.2%, and 25.3%, respectively. The most common clinician-reported chemotoxicities were gastrointestinal (GI) toxicity (22.9%) and neuropathy or neutropenia (17.9%). Significant risk factors at baseline were malnutritional status, frailty, impaired immune or hepato-renal functions, short telomere lengths, low gut lactobacillus levels, age, female sex, aggressive chemotherapy, and low QOL. Age was associated with neutropenia (β: −1.44) and GI toxicity (β:1.85) (p-values < 0.01). Older adults (>65 y.o.) had higher prevalences of overall (OR: 1.14) and GI (OR: 1.65) toxicities, but a lower prevalence of neutropenia (OR: 0.65) than younger adults (p-values < 0.05). Conclusions. Our findings highlight the importance of closely monitoring and managing chemotoxicity in CRC patients receiving chemotherapy. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy. Methods: In this prospective, single-center, single-arm study, we enrolled patients (18–70 years) with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1r-IVA and IVB (distant metastasis only with inguinal lymph node metastasis) cervical cancer. Eligible patients should have normal function of the bone marrow (absolute neutrophil count (ANC) ≥ 2.0 × 109/L) and adequate hepatic and renal functions. Key exclusion criteria included: previous chemotherapy and/or radiotherapy; a history of bone marrow dysplasia or other hematopoietic abnormalities. All patients underwent radical radiotherapy (pelvic radiotherapy or extended-field irradiation) plus brachytherapy. The chemotherapy regimen included four cycles of 3-weekly paclitaxel and cisplatin. PEG-rhG-CSF was administered 48–72 h after each treatment cycle. Salvage granulocyte colony-stimulating factor (G-CSF) was only permitted in certain circumstances. The primary endpoint was the incidence of grade 3–4 neutropenia. The secondary endpoints included frequency of febrile neutropenia (FN), chemotherapy completion rate in cycles 2–4, time to complete radiotherapy, and safety. Results: Overall, 52 patients were enrolled in this study from July 2019 to October 2020. The incidence of grade 3–4 neutropenia was 28.8%, with an average duration of grade 3–4 neutropenia persistence of 3.85 days (1–7 days). The incidence rate of FN was 3.8%. The chemotherapy completion rate was 94.2%, 82.7%, and 75.0% for cycles 2–4, respectively. The incidences of grade 3–4 neutropenia for cycles 1–4 were 9.6% (5/52), 8.2% (4/49), 14.0% (6/43), and 2.6% (1/39), respectively. All patients completed radiotherapy within 8 weeks (median, 48 days; range: 41–56 days), except one patient who withdrew consent and did not receive radiotherapy. Severe non-hematologic toxicity was not observed in any patient. Conclusion: PEG-rhG-CSF is an effective and safe prophylactic treatment for neutropenia in patients with cervical cancer undergoing concurrent chemoradiotherapy. Trial registration: Chinese Clinical Trial Registry, ChiCTR1900024494. Date of Registration:13/July/2019. [ABSTRACT FROM AUTHOR]

PSTPIP1‐associated myeloid‐related proteinemia inflammatory (PAMI) syndrome is a rare autoinflammatory disorder often arising in pediatric patients. We present a case of an 18‐year‐old female with a past medical history of growth failure, immunoglobulin A nephropathy, and inflammatory arthritis who presented to a pediatric dermatology clinic with findings of acne, psoriasiform dermatitis, and hidradenitis suppurativa, whose clinical, genetic, and laboratory findings were most consistent with PAMI syndrome. We conducted a literature review to better characterize this rare condition in the context of dermatologic findings. Recognition of the distinctive skin findings seen in PAMI syndrome can help distinguish it from other inflammatory disorders, enabling expedited diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background Study Design/Methods Results Discussion Granulocyte transfusions for patients with prolonged neutropenia and severe infections has been a controversial practice. Previous studies suggest a benefit of high‐dose granulocyte transfusions (≥0.6 × 109/kg), although, until recently, the consistent production of high‐dose units has been challenging. Here, we present our experience and results utilizing high‐dose granulocyte transfusions at a large, tertiary academic medical center for the treatment of infections in adult, neutropenic patients.A retrospective chart review (2018–2021) was conducted for all patients who received high‐dose granulocyte transfusions from donors stimulated with granulocyte colony‐stimulating factor (G‐CSF) and dexamethasone. Gathered parameters included patient demographics, clinical history, infection status, dose, clinical outcomes, pre‐ and post‐absolute neutrophil count (ANC), and transfusion times including time between granulocyte collection, administration, and posttransfusion ANC count. Gathered parameters were summarized using descriptive statistics, outcomes were assessed utilizing Kaplan–Meier curves/log‐rank/regression testing.Totally 28 adult, neutropenic patients refractory to antimicrobial agents and/or G‐CSF received a total of 173 granulocyte concentrates. Median ANC increased from 0.7 × 109/L pre‐transfusion to 1.6 × 109/L posttransfusion. The mean granulocyte yield was 77.4 × 109 resulting in an average dose per kilogram of 0.90 × 109 ± 0.30 × 109 granulocytes. Composite day 42 survival and microbial response was 42.9% (n = 12/28) without significant adverse reactions.Here, we demonstrate the successful and safe implementation of high‐dose granulocyte transfusions for neutropenic patients. Given the rapid and consistent production, distribution, and improved granulocyte quality, further investigations to determine the clinical efficacy of G‐CSF primed granulocyte transfusions is now possible. [ABSTRACT FROM AUTHOR]

Background Methicillin-resistant Staphylococcus aureus (MRSA) nares screening has been shown to be a powerful antibiotic stewardship tool for MRSA infections within 7 days of screening across a variety of anatomical locations given the high negative predictive value (NPV). However, the utility outside of 7 days and among transplant recipients and patients with neutropenia is less clear. Methods This was a retrospective cohort study across Veterans Affairs medical centers in the United States from 1 January 2007 to 1 January 2023 of patients tested for MRSA colonization and who had a subsequent positive bacterial culture within 28 days of MRSA sc---reening. Sensitivity, specificity, positive predictive value, and NPV were calculated across different time points and anatomical culture locations. Results The cohort consisted of 686 174 patients, 6 277 437 MRSA nares tests, and 2 446 766 positive bacterial cultures within 28 days of MRSA testing. The NPV of MRSA nares screening for ruling out a MRSA infection within 28 days was 95.8% across all anatomical culture sites. The NPV was 97.9% among patients with neutropenia and 97.5% in solid organ and hemopoietic stem cell transplant recipients. Conclusions MRSA nares screening can reliably be used for de-escalation of anti-MRSA therapy within 28 days of bacterial culture for all patients, including solid organ and hematopoietic transplant recipients and patients with neutropenia. [ABSTRACT FROM AUTHOR]

Summary: Combination checkpoint inhibitor (CPI) and chemotherapy is an effective and safe treatment strategy for patients with untreated classic Hodgkin lymphoma. Recent studies of programmed cell death protein 1 inhibitors combined with doxorubicin, vinblastine and dacarbazine have demonstrated high overall and complete response rates. This combination has a unique toxicity profile that should be managed appropriately so as not to compromise treatment efficacy. Common toxicities include rash, hepatoxicity, neutropenia and thyroid dysfunction. Here, we present four cases and the management strategies around such toxicities. In addition, we highlight key clinical decision‐making around the administration of subsequent doses of CPI and chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Clozapine is known to cause agranulocytosis. Mandatory monitoring schemes are aimed at reducing the risk of agranulocytosis and of the consequences of agranulocytosis. All cases of agranulocytosis occurring in people prescribed clozapine are assumed to be caused by clozapine. Methods: In a previous study, we examined a cohort of patients listed on our hospital database as having had clozapine-induced agranulocytosis and applied specific criteria to identify those with confirmed clozapine-related, life-threatening agranulocytosis. In this study, we examine the cases not meeting these specific criteria. Results: In the original study, 9 of 23 cases met the criteria for clozapine-induced, life-threatening agranulocytosis. Of the 13 remaining cases for whom data were available, 5 were probably caused by clozapine but were not life-threatening. Three cases were the result of concomitant cancer chemotherapy. Three were anomalous results probably related to measurement error. For the remaining two cases, the cause was not identified. Conclusion: Not all cases of agranulocytosis occurring in people taking clozapine are caused by clozapine. The widely used threshold criterion-based diagnosis overestimates the risk of agranulocytosis. True clozapine-related agranulocytosis is best identified by pattern-based criteria: rapid fall in neutrophil counts over around 2 weeks to below 0.5 × 109/L for two consecutive days (unless clozapine is stopped very early or granulocyte colony stimulating factor is given) where other possible causes (benign ethnic neutropenia, cancer chemotherapy) can be ruled out. [ABSTRACT FROM AUTHOR]

Background: Few studies have evaluated the post-endoscopic adverse events in patients with neutropenia and thrombocytopenia. Current guidelines do not provide clear direction on this topic. Aim: We explore the pooled rates of safety and adverse effects of endoscopic interventions in thrombocytopenia and neutropenia patients via a systematic review & meta-analysis. Methods: Databases, including Medline, Scopus, and Embase, were searched (in May 2023) using specific terms for studies evaluating the clinical outcomes of endoscopy in patients with thrombocytopenia and neutropenia. Standard meta-analysis methods were employed using the random-effects model. I2% heterogeneity was used to assess the heterogeneity. Results: Six studies and four studies evaluated endoscopic outcomes in patients with thrombocytopenia and neutropenia respectively with mean age was 56 years. The pooled rate of total post-biopsy bleeding and total post-polypectomy bleeding among patients with thrombocytopenia was 4% (95% CI 1–11), I2 = 84%, and 12% (95% CI 3–36) I2 = 43%. The total rate of post procedure-related bleeding in thrombocytopenia was 5% (95% CI 1–14) I2 = 95%. The pooled rate of post-endoscopic infection (fever from any cause, bacteremia) in neutropenia was 10% (95% CI 3–28%) I2 = 96%. On sub analysis, the pooled rate of bacteremia and 30 days all-cause mortality in neutropenia was 4% (95% CI 3–5%) I2 = 0% and 13% (95% CI 4–34%) I2 = 95% respectively. Conclusion: Our data supports the notion that endoscopic procedures are safe for neutropenic, thrombocytopenic patients with suitable indications and reasonable functional status and have an acceptable risk/benefit ratio. [ABSTRACT FROM AUTHOR]

Simple Summary: Ribosomes are essential for the life of all cells. A reduction in the production of ribosomes always leads to a delay in cell cycle progression and to impaired growth, at least at the cellular level. We define ribosomopathies as a number of inherited monogenic diseases characterized by the partial loss of ribosomal factors. Not surprisingly, ribosomopathies show multi-organ signs and reduced cellular fitness. Strikingly, cancer is also a common comorbidity of ribosomopathies. The reconciliation of reduced growth with increased cancer risk poses an interpretative challenge. However, if we consider cancer as a systemic disease in which tumor cells thrive in a favorable microenvironment, we may find the right answers. Ribosomopathies are defined as inherited diseases in which ribosomal factors are mutated. In general, they present multiorgan symptoms. In spite of the fact that in cellular models, ribosomal insufficiency leads to a reduced rate of oncogenic transformation, patients affected by ribosomopathies present a paradoxical increase in cancer incidence. Several hypotheses that explain this paradox have been formulated, mostly on the assumption that altered ribosomes in a stem cell induce compensatory changes that lead to a cancer cell. For instance, the lack of a specific ribosomal protein can lead to the generation of an abnormal ribosome, an oncoribosome, that itself leads to altered translation and increased tumorigenesis. Alternatively, the presence of ribosomal stress may induce compensatory proliferation that in turns selects the loss of tumor suppressors such as p53. However, modern views on cancer have shifted the focus from the cancer cell to the tumor microenvironment. In particular, it is evident that human lymphocytes are able to eliminate mutant cells and contribute to the maintenance of cancer-free tissues. Indeed, many tumors develop in conditions of reduced immune surveillance. In this review, we summarize the current evidence and attempt to explain cancer and ribosomopathies from the perspective of the microenvironment. [ABSTRACT FROM AUTHOR]

Background: Tunnelled catheters improve venous access in haematological diseases and malignancies, but are associated with complications. We prospectively analysed the episodes of CABSI and its associated risk factors. Aims: To study the incidence and risk factors for CABSI in children with tunnelled central venous catheters (both Hickmans and Chemoports). Materials and Methods: This is a prospective observational study done at our institute. Children under the age of 18 who underwent insertion of a Hickman or Chemoport from March 2018 to Dec 2022 were enrolled. Episodes of CABSI were noted and its risk factors were analysed. Results: In total, 258 catheters were inserted in 250 children. Age ranged from 1 month to 18 years (median 67 months) with 60% being boys. A total of 152 Hickmans, 106 chemoports were inserted. Indications for insertions were for requirement of BMT and chemotherapy in majority of cases. CABSI were seen in 28.6% of catheters. Younger children (< 4years), Neutropenia (counts < 1000) and use of TPN were significantly associated with CABSI(p value<0.05).Infection was more with externalized catheters (Hickman) than implantable ports (Chemoports) but was not statistical significant(p value>0.05). Almost 30% of catheters with CABSI required removal because of florid sepsis. Others could be salvaged with aggressive antibiotics. Conclusions: CABSI is a serious complications related to tunnelled catheter. Smaller children (<4 years), neutropenia and usage of TPN is a risk factor for development of CABSI. It can be treated with appropriate antibiotics and required removal in almost a third of all the cases. [ABSTRACT FROM AUTHOR]

Granulocyte transfusions are indicated for patients with severe neutropenia and evidence of bacterial or fungal infection who are unresponsive to standard antimicrobial therapy. With a limited expiration time of 24 hours after collection, granulocytes are often transfused before results of infectious-disease screening tests are available, and before a transfusion service can perform a risk assessment if postdonation information is provided after the collection. The case we describe herein demonstrates a clinical scenario meeting indications for granulocyte transfusion, coupled with the clinical management undertaken after the granulocyte donor disclosed a positive result for a COVID-19 self-test taken 1 day after donation. In this case, the patient did not develop new COVID-19 symptoms and tested negative for COVID-19 after transfusion of the implicated unit. These findings add to the body of evidence in the literature that COVID-19 is not transmitted via blood transfusion. [ABSTRACT FROM AUTHOR]

A previously healthy woman, 5 weeks pregnant, was admitted to the intensive care unit in critical condition for septic shock and acute respiratory distress syndrome due to methicillin‐resistant Staphylococcus aureus (MRSA) after being infected with Influenza for 3 days. The patient in this case suffered from severe sequelae due to necrotizing pneumonia and later died on the 20th day after admission. We would like to remind clinicians to be aware of this rare but serious diagnosis. The key is to begin appropriate treatment immediately because MRSA necrotizing pneumonia is mediated by toxins and once the toxins are released they cannot be limited by antibiotic treatments. Necrotizing pneumonia related to MRSA should be considered in young patients with pneumonia, sepsis, and neutropenia following seasonal influenza infection with rapidly progressive symptoms. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) demonstrate unique advantages in the treatment of lung cancer and are widely used in the era of immunotherapy. However, ICIs can cause adverse reactions. Hematological toxicities induced by immunotherapy are relatively rare. Agranulocytosis, a rare hematologic adverse event associated with immune checkpoint inhibitors, has received limited attention in terms of treatment and patient demographics. Herein, we report the case of a 68-year-old male with non-small cell lung cancer(NSCLC) who received two cycles of programmed cell death-1 (PD-1) antibody sintilimab immunotherapy combined with albumin-bound paclitaxel and carboplatin chemotherapy and one cycle of sintilimab monotherapy. He was diagnosed with grade 4 neutropenia and sepsis (with symptoms of fever and chills) after the first two cycles of treatment. Teicoplanin was promptly initiated as antimicrobial therapy. The patient presented with sudden high fever and developed agranulocytosis on the day of the third cycle of treatment initiation, characterized by an absolute neutrophil count of 0.0×109/L. The patient was treated with granulocyte colony-stimulating factor but did not show improvement. He was then treated with corticosteroids, and absolute neutrophil counts gradually returned to normal levels. To the best of our knowledge, this is the first reported case of sintilimab-induced agranulocytosis in a patient with NSCLC. Sintilimab-induced severe neutropenia or agranulocytosis is a rare side effect that should be distinguished from chemotherapy-induced neutropenia and treated promptly with appropriate therapies; otherwise, the condition may worsen. [ABSTRACT FROM AUTHOR]

A 3-year-old male pit bull terrier was presented for a 4-day history of progressive tetraparesis and cervical pain. Magnetic resonance imaging confirmed an extradural mass within the left lateral vertebral canal extending from caudal C5 to mid-T2. Lumbar cerebrospinal fluid (CSF) demonstrated marked (90%) eosinophilic inflammation. A C6-7 dorsal laminectomy and C7-T2 left hemilaminectomy were done, with gross disease remaining. Histopathology revealed a large T cell lymphoma with marked eosinophilic infiltration. The dog underwent CHOP-based chemotherapy with resolution of clinical signs, with a similar course of therapy performed at recurrence 37 months after initial presentation. The dog was euthanized 39 months after presentation for multiorgan failure secondary to neutropenic sepsis and aspiration pneumonia. This represents a positive long-term response to multimodal treatment of extradural T-cell lymphoma within the vertebral canal associated with a marked CSF eosinophilia.

Abstract Background The management of febrile neutropenia (FN) in pediatric cancer patients has traditionally been conducted in a hospital setting. However, recent evidence has indicated that outpatient management of FN can be equally effective compared to inpatient care. Based on this evidence, we conducted a cost-minimization analysis (CMA) specifically focused on pediatric cancer patients in Mexico. Methods A piggy-back study was conducted during the execution of a non-inferiority clinical trial that compared outpatient treatment to inpatient treatment for FN in children with cancer. A CMA was performed from a societal perspective using patient-level data. In the previous study, we observed that step-down oral outpatient management of low-risk FN was as safe and effective as inpatient intravenous management. Direct and indirect costs were collected prospectively. The costs were adjusted for inflation and converted to US dollars, with values standardized to July 2022 costs. Statistical analysis using bootstrap methods was employed to obtain robust estimations for decision-making within the Mexican public health care system. Results A total of 117 FN episodes were analyzed, with 60 in the outpatient group and 57 in the inpatient group; however, complete cost data were available for only 115 FN episodes. The analysis revealed an average savings of $1,087 per FN episode managed on an outpatient basis, representing a significant 92% reduction in total cost per FN episode compared to inpatient treatment. Length of hospital stay and inpatient consultations emerged as the primary cost drivers within the inpatient care group. Conclusion This CMA demonstrates that the step-down outpatient management approach is cost-saving when compared to inpatient management of FN in pediatric cancer patients. The mean difference observed between the treatment groups provides support for decision-making within the public health care system, as outpatient management of FN allows for substantial cost savings without compromising patient health.

Aim. To evaluate the effectiveness and safety of Extimia® (empegfilgrastim, JSC "BIOCAD") in reducing the frequency, duration of neutropenia, the incidence of febrile neutropenia (FN) and infections caused by FN in patients with solid tumors receiving myelosuppressive therapy. Materials and methods. The paper presents the final results of a multicenter prospective observational post-marketing study of the safety and effectiveness of Extimia® (empegfilgrastim) in patients with solid tumors receiving cytotoxic therapy. For the primary prevention of FN, all patients received empegfilgrastim at 7.5 mg subcutaneously once per course of chemotherapy (CT) 24 hours after the end of CT administration. The primary endpoint included an assessment of the relative dose-intensity (RDI) of the CT courses administered. The endpoints of interest included the assessment of the RDI of CT courses by nosology and CT regimen, the frequency of dose-limiting neutropenia, and the incidence of all adverse events (AEs) in patients who received at least one dose of the study medication, including serious AEs. Results. From February 2021 to December 2022, 3218 patients with various malignancies were included in 41 study centers of the Russian Fede- ration. Of these, 3217 (99.97%) patients received at least one dose of the study drug, and 2663 (82.8%) patients were included in the RDI evaluation population according to the study protocol. The mean age in this group was 56.9 (18–84) years. RDI ≥85% was achieved in 2,415 (90.7%) patients. The mean RDI was 96.2%, with a median of 100%. FN risk factors were present in 1216 (45.7%) patients, with age ≥65 years being the most common risk factor at 761/2663 (28.6%). It should be noted that in patients younger than 65 years, the RDI was 91.5%, and in elderly patients (≥65 years) 88.7%. Dose-limiting neutropenia was reported in 19 (0.7%) patients. There were 74 cases of grade 3–4 AEs (according to CTCAE v.5) in 59 (1.8%) patients. The most common were neutropenia, anemia, and diarrhea in 19 (0.7%), 7 (0.2%), and 6 (0.2%) patients, respectively. Serious AEs were reported in 17 patients (0.5%). Conclusion. Primary prophylaxis of FN with long-acting granulocyte colony-stimulating factor empegfilgrastim effectively maintains RDI in various nosological and therapeutic groups of patients with different CT regimens in real-world clinical practice.

Abstract Background This study aimed to investigate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy. Methods In this prospective, single-center, single-arm study, we enrolled patients (18–70 years) with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1r-IVA and IVB (distant metastasis only with inguinal lymph node metastasis) cervical cancer. Eligible patients should have normal function of the bone marrow (absolute neutrophil count (ANC) ≥ 2.0 × 109/L) and adequate hepatic and renal functions. Key exclusion criteria included: previous chemotherapy and/or radiotherapy; a history of bone marrow dysplasia or other hematopoietic abnormalities. All patients underwent radical radiotherapy (pelvic radiotherapy or extended-field irradiation) plus brachytherapy. The chemotherapy regimen included four cycles of 3-weekly paclitaxel and cisplatin. PEG-rhG-CSF was administered 48–72 h after each treatment cycle. Salvage granulocyte colony-stimulating factor (G-CSF) was only permitted in certain circumstances. The primary endpoint was the incidence of grade 3–4 neutropenia. The secondary endpoints included frequency of febrile neutropenia (FN), chemotherapy completion rate in cycles 2–4, time to complete radiotherapy, and safety. Results Overall, 52 patients were enrolled in this study from July 2019 to October 2020. The incidence of grade 3–4 neutropenia was 28.8%, with an average duration of grade 3–4 neutropenia persistence of 3.85 days (1–7 days). The incidence rate of FN was 3.8%. The chemotherapy completion rate was 94.2%, 82.7%, and 75.0% for cycles 2–4, respectively. The incidences of grade 3–4 neutropenia for cycles 1–4 were 9.6% (5/52), 8.2% (4/49), 14.0% (6/43), and 2.6% (1/39), respectively. All patients completed radiotherapy within 8 weeks (median, 48 days; range: 41–56 days), except one patient who withdrew consent and did not receive radiotherapy. Severe non-hematologic toxicity was not observed in any patient. Conclusion PEG-rhG-CSF is an effective and safe prophylactic treatment for neutropenia in patients with cervical cancer undergoing concurrent chemoradiotherapy. Trial registration Chinese Clinical Trial Registry, ChiCTR1900024494. Date of Registration:13/July/2019.

Neutropenia and elevated concentrations of hepatic transaminases often lead to referrals from emergency or outpatient departments to relevant specialists to diagnose underlying inborn errors of metabolism. Glycogen storage disease type (GSD) Ib, a rare congenital disorder of glucose metabolism caused by the SLC37A4 gene mutations, shows various manifestations, including persistent neutropenia and elevated hepatic transaminases. Empagliflozin has demonstrated its efficacy in treating GSD Ib-associated neutropenia by reducing the entry of 1,5-anhydroglucitol-6-phosphate into the neutrophils. This article reports successful empagliflozin therapy for GSD Ib-related neutropenia in 2 Korean adolescents. Diagnosing GSD Ib is complex and usually initiated by a referral from emergency or outpatient departments when there is a high index of suspicion. Once diagnosed, empagliflozin shows promising outcomes in restoring counts and function of the neutrophils without severe adverse effects in children with GSD Ib, supporting it as a safe and effective therapeutic option for GSD Ib-associated neutropenia.