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Cureus Jan 2024Clozapine-induced agranulocytosis is documented in multiple studies, but there is limited literature on treatment-resistant agranulocytosis, the synergistic effect of...
Severe Clozapine-Induced Agranulocytosis, Pharmacodynamic Synergism, and Lithium Promyelocytic Effects in Granulocyte Colony-Stimulating Factor (G-CSF) Resistance or Delayed Response: A Case Report.
Clozapine-induced agranulocytosis is documented in multiple studies, but there is limited literature on treatment-resistant agranulocytosis, the synergistic effect of multiple agranulocytosis-inducing drugs, and lithium's promyelocytic effects. This case highlights these gaps by discussing a patient with an absolute neutrophil count of zero while being treated with Depakote, Haldol, and clozapine. This case proposes more research on lithium's promyelocytic effects, especially in patients who are unresponsive or have a delayed response to discontinuing offending agents and granulocyte colony-stimulating factor (G-CSF).
PubMed: 38344504
DOI: 10.7759/cureus.52092 -
Mucormycosis in children with cancer and hematopoietic cell transplant-A single center cohort study.PloS One 2024Although mucormycosis is an important cause of morbidity and mortality in children with cancer, our understanding of the typical characteristics of these infections is... (Review)
Review
Although mucormycosis is an important cause of morbidity and mortality in children with cancer, our understanding of the typical characteristics of these infections is incomplete. We reviewed all cases of mucormycosis diagnosed at a single pediatric cancer center over 5 decades to identify the clinical features of mucormycosis in pediatric oncology patients and to identify risk factors for mortality. There were 44 cases of mucormycosis diagnosed between 1970-2019. Most patients (89%) had hematological malignancies and a history of prolonged and severe neutropenia (91%). In this series, hyperglycemia and exposure to corticosteroids were common. Pulmonary (36%) and disseminated infections (32%) were most common; rhino-orbital-cerebral infections were relatively infrequent (11%). Rhizopus spp. was the most common etiological agent (40%) followed by Mucor spp. (31%), and Cunninghamella spp. (19%). Overall mortality was 44% and 51% and attributable mortality was 39% and 41% at the end of antifungal therapy and end of follow up, respectively. Attributable mortality fell to 18% in 2010-2019, from 58-60% in previous decades; adjunctive surgery was associated with decreased mortality. Mortality remains unacceptably high despite aggressive antifungal therapy and adjunctive surgery, suggesting novel therapeutic strategies are needed.
Topics: Humans; Child; Mucormycosis; Antifungal Agents; Hematopoietic Stem Cell Transplantation; Cohort Studies; Hematologic Neoplasms; Neutropenia
PubMed: 38335202
DOI: 10.1371/journal.pone.0297590 -
Cell Reports. Medicine Feb 2024ADG106, a ligand-blocking agonistic antibody targeting CD137 (4-1BB), exhibits promising results in preclinical studies, demonstrating tumor suppression in various...
ADG106, a ligand-blocking agonistic antibody targeting CD137 (4-1BB), exhibits promising results in preclinical studies, demonstrating tumor suppression in various animal models and showing a balanced profile between safety and efficacy. This phase 1 study enrolls 62 patients with advanced malignancies, revealing favorable tolerability up to the 5.0 mg/kg dose level. Dose-limiting toxicity occurs in only one patient (6.3%) at 10.0 mg/kg, resulting in grade 4 neutropenia. The most frequent treatment-related adverse events include leukopenia (22.6%), neutropenia (22.6%), elevated alanine aminotransferase (22.6%), rash (21.0%), itching (17.7%), and elevated aspartate aminotransferase (17.7%). The overall disease control rates are 47.1% for advanced solid tumors and 54.5% for non-Hodgkin's lymphoma. Circulating biomarkers suggest target engagement by ADG106 and immune modulation of circulating T, B, and natural killer cells and cytokines interferon γ and interleukin-6, which may affect the probability of clinical efficacy. ADG106 has a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers (this study was registered at ClinicalTrials.gov: NCT03802955).
Topics: Humans; Lymphoma, Non-Hodgkin; Neoplasms; Antibodies, Monoclonal; Treatment Outcome; Neutropenia
PubMed: 38330942
DOI: 10.1016/j.xcrm.2024.101414 -
BMC Infectious Diseases Feb 2024This meta-analysis focused on systematically assessing the clinical value of mNGS for infection in hematology patients. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
This meta-analysis focused on systematically assessing the clinical value of mNGS for infection in hematology patients.
METHODS
We searched for studies that assessed the clinical value of mNGS for infection in hematology patients published in Embase, PubMed, Cochrane Library, Web of Science, and CNKI from inception to August 30, 2023. We compared the detection positive rate of pathogen for mNGS and conventional microbiological tests (CMTs). The diagnostic metrics, antibiotic adjustment rate and treatment effective rate were combined.
RESULTS
Twenty-two studies with 2325 patients were included. The positive rate of mNGS was higher than that of CMT (blood: 71.64% vs. 24.82%, P < 0.001; BALF: 89.86% vs. 20.78%, P < 0.001; mixed specimens: 82.02% vs. 28.12%, P < 0.001). The pooled sensitivity and specificity were 87% (95%CI: 81-91%) and 59% (95%CI: 43-72%), respectively. The reference standard/neutropenia and research type/reference standard may be sources of heterogeneity in sensitivity and specificity, respectively. The pooled antibiotic adjustment rate according to mNGS was 49.6% (95% CI: 41.8-57.4%), and the pooled effective rate was 80.9% (95% CI: 62.4-99.3%).
CONCLUSION
mNGS has high positive detection rates in hematology patients. mNGS can guide clinical antibiotic adjustments and improve prognosis, especially in China.
Topics: Humans; High-Throughput Nucleotide Sequencing; Neutropenia; Anti-Bacterial Agents; China; Hematology; Sensitivity and Specificity; Retrospective Studies
PubMed: 38326763
DOI: 10.1186/s12879-024-09073-x -
Scientific Reports Feb 2024Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall... (Meta-Analysis)
Meta-Analysis
Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall survival (OS). A robust comparative evaluation of OS, safety, and tolerability of the three drugs is warranted. A systematic literature search identified phase 3 randomized clinical trials reporting OS of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy in ER-positive/HER2-negative advanced breast cancer. Trial-level data on OS and common and serious adverse events (AE) were extracted for each drug. In the absence of direct comparisons, a network meta-analysis was performed to evaluate pairwise comparative efficacy, safety, and tolerability of each of the CDK4/6i. Seven studies comprising of 4415 patients met the inclusion criteria. Median follow-up was 73.3 months (range: 48.7-97.2 months). There were no statistically significant differences in OS between any of the CDK4/6i. Compared to palbociclib, ribociclib and abemaciclib both showed significantly higher GI toxicity (grade 1-2 vomiting OR 1.87 [95% CI 1.37-2.56] and OR 2.27 [95% CI 1.59-3.23] respectively). Compared to palbociclib, abemaciclib was associated with more grade 3-4 diarrhea OR 118.06 [95% CI 7.28-1915.32]. In contrast, palbociclib was associated with significantly more neutropenia than ribociclib and abemaciclib but significantly lower risk of grade 3-4 infections. Abemaciclib had significantly less grade 3-4 transaminitis and grade 3-4 neutropenia than ribociclib. Treatment discontinuation and death due to AE were significantly higher with abemaciclib than palbociclib and ribociclib. There is no statistically significant difference in OS between CDK4/6i despite differing statistical significance levels of individual trials. Real-world data analyses may help to identify if there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes.
Topics: Female; Humans; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor Proteins; Neutropenia; Purines; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 38326452
DOI: 10.1038/s41598-024-53151-8 -
Current Problems in Diagnostic Radiology 2024Computed tomography (CT) imaging has become a first line investigation for most cases of febrile neutropenia (FN) which can be the only sign of infection in oncology... (Observational Study)
Observational Study
BACKGROUND
Computed tomography (CT) imaging has become a first line investigation for most cases of febrile neutropenia (FN) which can be the only sign of infection in oncology patients undergoing active chemotherapy and bone marrow transplants. The utility of routine non-targeted imaging remains unclear.
OBJECTIVE
To assess and compare the diagnostic rate between targeted, non-targeted and pan-scan CT in identifying an acute source of infection in adult oncology patients with FN.
MATERIALS AND METHODS
A retrospective observational study was conducted between February 2019 and March 2023 on 417 consecutive CT examinations for the clinical indication of source identification in FN. Scans were noted for the anatomical regions that were imaged and reports were classified as positive, negative or equivocal for infection. Pre-existing pathology was also noted. Results were tabulated and statistical analyses for comparison between groups of scans was performed using chi-square test.
RESULTS
All targeted regional scans had statistically significant difference in positive rate compared to non-targeted scans of the respective region; chest (Χ²(1)=18.11, P<.001); sinus (Χ²(1)=15.36, P<.001); abdomen and pelvis (Χ²(1)=5.95, P=.01). Pneumonia (41.3 %) was much more likely to be the diagnosis compared to sinusitis (16.2 %) in concomitant CT chest to sinus examinations (Χ²(1)=45.3, P<.001). Pan-scans had a higher incidence of positive diagnosis compared to all-targeted scans (Χ²(1)=4.91, P=.03) but when compared to higher yield targeted scans (abdomen and chest), there was no statistical difference (Χ²(1)=2.43, P=.12). 20/54 patients had pan-scans despite having localising symptoms.
CONCLUSION
Imaging guided by presenting signs and symptoms can help to reduce unnecessary imaging and promote more judicious use of non-targeted and pan-scan CT in current practices.
Topics: Adult; Humans; Neoplasms; Tomography, X-Ray Computed; Sinusitis; Medical Oncology; Retrospective Studies; Febrile Neutropenia
PubMed: 38309990
DOI: 10.1067/j.cpradiol.2024.01.003 -
JCO Global Oncology Feb 2024Febrile neutropenia (FN) is a serious complication in hematologic malignancies, and lung infiltrates (LIs) remain a significant concern. An accurate microbiological... (Observational Study)
Observational Study
PURPOSE
Febrile neutropenia (FN) is a serious complication in hematologic malignancies, and lung infiltrates (LIs) remain a significant concern. An accurate microbiological diagnosis is crucial but difficult to establish. To address this, we analyzed the utility of a standardized method for performing bronchoalveolar lavage (BAL) along with a two-step strategy for the analysis of BAL fluid.
PATIENTS AND METHODS
This prospective observational study was conducted at a tertiary cancer center from November 2018 to June 2020. Patients age 15 years and older with confirmed leukemia or lymphomas undergoing chemotherapy, with presence of FN, and LIs observed on imaging were enrolled.
RESULTS
Among the 122 enrolled patients, successful BAL was performed in 83.6% of cases. The study used a two-step analysis of BAL fluid, resulting in a diagnostic yield of 74.5%. Furthermore, antimicrobial therapy was modified in 63.9% of patients on the basis of BAL reports, and this population demonstrated a higher response rate (63% 45%; = .063).
CONCLUSION
Our study demonstrates that a two-step BAL fluid analysis is safe and clinically beneficial to establish an accurate microbiological diagnosis. Given the crucial impact of diagnostic delays on mortality in hematologic malignancy patients with FN, early BAL studies should be performed to enable prompt and specific diagnosis, allowing for appropriate treatment modifications.
Topics: Adolescent; Humans; Bronchoalveolar Lavage Fluid; Febrile Neutropenia; Hematologic Neoplasms; Leukemia; Lung; Lymphoma; Prospective Studies
PubMed: 38301183
DOI: 10.1200/GO.23.00292 -
JCO Global Oncology Feb 2024This study aimed to identify the patient characteristics of children with febrile neutropenia, the associated bacterial organisms, and their sensitivity patterns.
PURPOSE
This study aimed to identify the patient characteristics of children with febrile neutropenia, the associated bacterial organisms, and their sensitivity patterns.
MATERIALS AND METHODS
A descriptive cross-sectional study was conducted at the Moi Teaching and Referral Hospital (MTRH) pediatric oncology ward, from June 2021 to April 2022. A total of 110 children who developed fever and neutropenia during chemotherapy were enrolled. Blood samples for culture were collected aseptically. Patient characteristics were presented in frequency tables. Antimicrobial sensitivity patterns were plotted in tables against the bacterial isolates cultured. Chi-square/Fisher's exact test was used to determine any association between patient characteristics, bacterial growth, and antimicrobial sensitivity.
RESULTS
The majority (n = 66; 60%) were males. The median age was 6.3 years (standard deviation, 3.7). The majority of patients 71 (64.5%) had hematologic malignancies, the most common being AML. There was a significant association between severity of neutropenia and hematologic malignancies ( = .028). In total, 31/110 (28.2%) blood cultures were positive for bacterial growth. Gram-positive bacteria were more frequent (n = 20; 58.1%). The most common organism was (n = 6; 18.2%), followed by (n = 5; 15.2%). All the isolates were sensitive to linezolid and vancomycin and also showed good sensitivity toward meropenem (n = 10/11; 90.9%). High resistance to cephalosporins was noted with ceftriaxone (n = 5/6; 83.3%), cefepime (n = 4/7; 57.1%), and ceftazidime (n = 3/4; 75%).
CONCLUSION
The most common malignancy associated with febrile neutropenia was AML. Gram-positive bacteria were the most common isolates. There was high resistance to cephalosporins.
Topics: Male; Child; Humans; Female; Anti-Bacterial Agents; Tertiary Care Centers; Cross-Sectional Studies; Kenya; Bacteremia; Cephalosporins; Hematologic Neoplasms; Febrile Neutropenia; Leukemia, Myeloid, Acute
PubMed: 38301180
DOI: 10.1200/GO.23.00313 -
Investigational New Drugs Feb 2024Part E of the KEYNOTE-011 (NCT01840579) study assessed the safety and antitumor activity of pembrolizumab plus platinum-etoposide chemotherapy in Japanese patients with...
BACKGROUND
Part E of the KEYNOTE-011 (NCT01840579) study assessed the safety and antitumor activity of pembrolizumab plus platinum-etoposide chemotherapy in Japanese patients with previously untreated extensive-stage small-cell lung cancer (ES-SCLC).
METHODS
Patients received 4 cycles of pembrolizumab (200 mg) every 3 weeks in combination with cisplatin (75 mg/m) and etoposide (100 mg/m; days 1, 2, 3) in cohort 1; with carboplatin (AUC 5 mg/mL/min) and etoposide (100 mg/m; days 1, 2, 3) in cohort 2; or with cisplatin/etoposide and pegfilgrastim (3.6 mg; cycle 1, day 4) in cohort 3. Combination therapy was followed by pembrolizumab monotherapy (31 cycles). The primary endpoint was safety and tolerability (including dose-limiting toxicities; DLTs).
RESULTS
Fifteen patients were included in the study (cohort 1, n = 6; cohort 2, n = 6; cohort 3, n = 3). Median time from treatment allocation to data cutoff was 22.1 months (range, 4.1‒32.4 months). DLTs occurred in 3 patients in cohort 1 (one patient with grade 4 laryngeal stenosis and grade 3 febrile neutropenia; two patients with grade 3 febrile neutropenia); no patients in cohorts 2 or 3 experienced DLTs. Grade ≥ 3 treatment-related adverse events included leukopenia (67%) and neutropenia (87%). Among all patients, ORR was 67% (95% CI, 38%‒88%) and median DOR was 4.5 months (range, 2.8‒28.8 months). Median PFS was 4.2 months (95% CI, 3.0‒7.8 months) and median OS was 22.1 months (95% CI, 7.4‒25.9 months).
CONCLUSION
Pembrolizumab in combination with platinum-etoposide therapy had manageable toxicity with no new safety signals and was associated with antitumor activity in Japanese patients with ES-SCLC.
TRIAL REGISTRATION
ClinicalTrials.gov , NCT01840579.
Topics: Humans; Lung Neoplasms; Cisplatin; Etoposide; Platinum; Japan; Small Cell Lung Carcinoma; Antineoplastic Combined Chemotherapy Protocols; Febrile Neutropenia; Antibodies, Monoclonal, Humanized
PubMed: 38300341
DOI: 10.1007/s10637-023-01411-1 -
Clinical Case Reports Feb 2024Most drugs that cause adverse events are difficult to identify in critically ill patients undergoing polypharmacy. We share our experience in identifying the causative...
KEY CLINICAL MESSAGE
Most drugs that cause adverse events are difficult to identify in critically ill patients undergoing polypharmacy. We share our experience in identifying the causative drug among four suspect drugs administered during emergency treatment.
ABSTRACT
We present the case of a 93-year-old man who was admitted for the treatment of cerebrovascular events. The patient was initially prescribed dual antiplatelet therapy with aspirin and clopidogrel along with lansoprazole, Hange-koboku-toh, and elobixibat. On day 36 after admission, the patient was found to have developed agranulocytosis. To improve his cerebrovascular prognosis, we first discontinued medications other than the anticoagulant medicines and initiated filgrastim. We discontinued clopidogrel 9 days after the discontinuation of the other medicines considering his low white blood cell count. One day after the discontinuation of clopidogrel, the agranulocytosis was alleviated. Considering the time course, clopidogrel, lansoprazole, Hange-koboku-toh, and elobixibat were suspected as the culprit medicines. This case highlights the considerable challenges encountered in clinical practice when attempting to identify the drugs responsible for agranulocytosis, particularly in patients on intensive medication therapy.
PubMed: 38292220
DOI: 10.1002/ccr3.8311