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Critical Care Explorations Feb 2024Secondary hemophagocytic lymphohistiocytosis (sHLH) is a cytokine-driven inflammatory syndrome that is associated with substantial morbidity and mortality and frequently...
Ruxolitinib, IV Immunoglobulin, and High-Dose Glucocorticoids for Critically Ill Adults With Secondary Hemophagocytic Lymphohistiocytosis: A Single-Center Observational Pilot Study.
OBJECTIVES
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a cytokine-driven inflammatory syndrome that is associated with substantial morbidity and mortality and frequently leads to ICU admission. Overall survival in adults with sHLH remains poor, especially in those requiring intensive care. Classical chemotherapeutic treatment exhibits myelosuppression and toxicity. Recently, inhibition of Janus kinase signaling by ruxolitinib has shown efficacy in pediatric HLH. We therefore aimed to determine the activity and safety of a ruxolitinib-based regimen, in critically ill adults with sHLH.
DESIGN
Observational pilot study.
SETTING
Single-center tertiary academic ICU.
PATIENTS
Nine adults (≥ 18 yr) who fulfilled at least five of the eight HLH-2004 criteria.
INTERVENTION
Triplet regimen combining: 1) ruxolitinib, 2) polyvalent human IV immunoglobulins (IVIG) at a dose of 1 g/kg bodyweight for 5 days, and 3) high-dose corticosteroids (CSs, dexamethasone 10 mg/m² body surface area, or methylprednisolone equivalent) with subsequent tapering according to the HLH-2004 protocol.
MEASUREMENT AND MAIN RESULTS
Nine patients (median age: 42 yr [25th-75th percentile: 32-54]; male: = 6 males, median H-score: 299 [255-304]) were treated with the triplet regimen. The median Sequential Organ Failure Assessment score at HLH diagnosis was 9 (median; 25th-75th percentile: 7-12), indicating multiple-organ dysfunction in all patients. Within 10 days a significant decrease of the inflammatory parameters soluble interleukin-2 receptor and ferritin as well as a stabilization of the blood count could be shown. All patients were alive at ICU discharge (100% ICU survival), 1 patient died after ICU discharge because of traumatic intracerebral hemorrhage that might be related to HLH or treatment, corresponding to an overall survival of 86% in a 6 months follow-up period.
CONCLUSION
In this small case series, a triplet regimen of ruxolitinib in combination with IVIG and CS was highly effective and save for treating critically ill adults with sHLH.
PubMed: 38511127
DOI: 10.1097/CCE.0000000000001046 -
Neuro-oncology Practice Apr 2024Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are...
BACKGROUND
Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx).
METHODS
A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers.
RESULTS
A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease.
CONCLUSIONS
GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.
PubMed: 38496907
DOI: 10.1093/nop/npad067 -
Asia Pacific Journal of Clinical... Mar 2024To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patient.
METHODS AND STUDY DESIGN
40 women with early breast cancer were randomly assigned to the BF839 (n=20) or placebo (n=20) during the administration of adjuvant chemotherapy (4 cycles of epirubicin 100mg/m2 and cyclophosphamide 600mg/m2). Myelosuppression and gastrointestinal adverse effects were monitored in both groups.
RESULTS
Throughout the four treatment cycles, the percentage of patients experiencing myelosuppression was 42.5% in the BF839 group, significantly lower than the 66.3% observed in the control group (p=0.003). Two patients in the BF839 group and three patients in the placebo group received recombinant human granulocyte colony-stimulating factor (rhG-CSF) due to leuko-penia/neutropenia. When considering an ITT analysis, which included all patients regardless of rhG-CSF treatment, the BF839 group exhibited less reduction from baseline in white blood cells (-0.31±1.19 vs -1.15±0.77, p=0.012) and neutrophils (0.06±1.00 vs -0.84±0.85, p=0.004) compared to the placebo group. The difference became even more significant when excluding the patients who received rhG-CSF injections. Throughout the four treatment cycles, compared to the placebo group, the BF839 group had significantly lower rates of 3-4 grade nausea (35.0% vs 71.3%, p=0.001), vomiting (20.0% vs 45.0%, p=0.001), and diarrhea (15.0% vs 30.0%, p=0.023).
CONCLUSIONS
These findings suggest that BF839 has the potential to effectively mitigate myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patients.
Topics: Female; Humans; Antineoplastic Agents; Bacteroides fragilis; Breast Neoplasms; Cyclophosphamide; Epirubicin; Granulocyte Colony-Stimulating Factor; Recombinant Proteins
PubMed: 38494684
DOI: 10.6133/apjcn.202403_33(1).0003 -
Leukemia Jun 2024Thrombopoietin (Tpo), which binds to its specific receptor, the Mpl protein, is the major cytokine regulator of megakaryopoiesis and circulating platelet number. Tpo...
Thrombopoietin (Tpo), which binds to its specific receptor, the Mpl protein, is the major cytokine regulator of megakaryopoiesis and circulating platelet number. Tpo binding to Mpl triggers activation of Janus kinase 2 (Jak2) and phosphorylation of the receptor, as well as activation of several intracellular signalling cascades that mediate cellular responses. Three tyrosine (Y) residues in the C-terminal region of the Mpl intracellular domain have been implicated as sites of phosphorylation required for regulation of major Tpo-stimulated signalling pathways: Mpl-Y565, Mpl-Y599 and Mpl-Y604. Here, we have introduced mutations in the mouse germline and report a consistent physiological requirement for Mpl-Y599, mutation of which resulted in thrombocytopenia, deficient megakaryopoiesis, low hematopoietic stem cell (HSC) number and function, and attenuated responses to myelosuppression. We further show that in models of myeloproliferative neoplasms (MPN), where Mpl is required for pathogenesis, thrombocytosis was dependent on intact Mpl-Y599. In contrast, Mpl-Y565 was required for negative regulation of Tpo responses; mutation of this residue resulted in excess megakaryopoiesis at steady-state and in response to myelosuppression, and exacerbated thrombocytosis associated with MPN.
Topics: Animals; Receptors, Thrombopoietin; Myeloproliferative Disorders; Mice; Hematopoiesis; Thrombopoietin; Tyrosine; Phosphorylation; Mice, Inbred C57BL; Hematopoietic Stem Cells; Signal Transduction; Mutation; Janus Kinase 2; Thrombopoiesis
PubMed: 38491305
DOI: 10.1038/s41375-024-02219-5 -
Journal of Infection in Developing... Feb 2024Linezolid (LZD) plays an important role in the treatment of severe infections caused by Gram-positive bacteria. Thrombocytopenia is regarded as one of the most common...
INTRODUCTION
Linezolid (LZD) plays an important role in the treatment of severe infections caused by Gram-positive bacteria. Thrombocytopenia is regarded as one of the most common side effects of linezolid, which results from the destruction of platelets or myelosuppression. The study aimed to identify the risk factors associated with the development of thrombocytopenia in Vietnamese patients.
METHODOLOGY
This retrospective, descriptive cross-sectional study was performed on adult patients who received parenteral LZD therapy (1,200 mg/day) in at least 3 days between January 2020 and June 2021 at a tertiary referral hospital in Vietnam. Thrombocytopenia was defined as either a final platelet count of less than 100 G/L or a 25% decrease in platelet count from baseline. Multivariate logistic regression analysis was applied to predict risk factors associated with LZD-induced thrombocytopenia.
RESULTS
In the 208 patients included in the study, the average age was 69 and males accounted for 73.1%. LZD-induced thrombocytopenia occurred in 37% of patients. LZD-induced thrombocytopenia was significantly associated with shock (HR = 8.26, 95% CI 3.82 - 17.84, p < 0.001), baseline creatinine clearance (HR = 1.02, 95% CI [1.01 - 1.03], p = 0.002), and duration of LZD treatment of at least 14 days (HR = 4.45, 95% CI [1.83 - 11.05], p = 0.001).
CONCLUSIONS
The results showed that thrombocytopenia was fairly common in patients using linezolid. Shock, renal failure, and duration of linezolid therapy of at least 14 days were significant risk factors for the incidence of linezolid-induced thrombocytopenia.
Topics: Male; Adult; Humans; Aged; Linezolid; Retrospective Studies; Cross-Sectional Studies; Thrombocytopenia; Platelet Count; Anemia; Anti-Bacterial Agents
PubMed: 38484357
DOI: 10.3855/jidc.18488 -
Journal of Infection in Developing... Feb 2024Patients with severe neutropenia who develop septic shock (SS) have high mortality. This study aimed to evaluate the risk factors and mortality of SS in patients with HM...
INTRODUCTION
Patients with severe neutropenia who develop septic shock (SS) have high mortality. This study aimed to evaluate the risk factors and mortality of SS in patients with HM and febrile neutropenia.
METHODOLOGY
We included all patients with hematological malignancies (HM) who presented fever and severe neutropenia, admitted to an oncological tertiary care center in Mexico City for one year.
RESULTS
Two hundred ninety-two episodes of fever and severe neutropenia were documented; 68 patients (23.2%) developed SS. Documented clinical infection was different between SS and non-SS patients (94.1% vs. 63.4%, p < 0.001); pneumonia was the most frequent infection (36.8% vs. 23.2%, p = 0.02). Also, in SS vs. non-SS, there were more positive cultures (69.1% vs. 38.4%, p < 0.001), higher frequency of Gram-negative bacteria (89.3% vs. 63.9%, p < 0.001), particularly Escherichia coli (68% vs. 44.2%) and Klebsiella spp. (23.4% vs. 15.1%). There were no differences when multidrug-resistant (MDR) microorganisms were compared. In the multivariate analysis, associated risk factors for SS were: prolonged neutropenia, a documented site of infection, and having received highly myelosuppressive chemotherapy. Risk factors for mortality at 30 days were: older patients, prolonged neutropenia, and SS.
CONCLUSIONS
Severe and prolonged neutropenia was associated with SS development and mortality at 30 days. ICU management should be offered to all critically ill patients with HM if long-term survival of the underlying malignancy is expected.
Topics: Humans; Shock, Septic; Hematologic Neoplasms; Neoplasms; Risk Factors; Escherichia coli; Febrile Neutropenia; Retrospective Studies
PubMed: 38484344
DOI: 10.3855/jidc.17451 -
Advanced Science (Weinheim,... Jun 2024Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints and bone destruction. Because of systemic administration... (Review)
Review
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints and bone destruction. Because of systemic administration and poor targeting, traditional anti-rheumatic drugs have unsatisfactory treatment efficacy and strong side effects, including myelosuppression, liver or kidney function damage, and malignant tumors. Consequently, mesenchymal stem cells (MSCs)-involved therapy is proposed for RA therapy as a benefit of their immunosuppressive and tissue-repairing effects. This review summarizes the progress of MSCs-involved RA therapy through suppressing inflammation and promoting tissue regeneration and predicts their potential clinical application.
Topics: Arthritis, Rheumatoid; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Animals
PubMed: 38477559
DOI: 10.1002/advs.202305116 -
Integrative Cancer Therapies 2024Jixueteng, the vine of the bush Dunn., is widely used to treat irregular menstruation and arthralgia. Yinyanghuo, the aboveground part of the plant Maxim., has the...
Jixueteng, the vine of the bush Dunn., is widely used to treat irregular menstruation and arthralgia. Yinyanghuo, the aboveground part of the plant Maxim., has the function of warming the kidney to invigorate yang. This research aimed to investigate the effects and mechanisms of the Jixueteng and Yinyanghuo herbal pair (JYHP) on cisplatin-induced myelosuppression in a mice model. Firstly, ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) screened 15 effective compounds of JYHP decoction. Network pharmacology enriched 10 genes which may play a role by inhibiting the apoptosis of bone marrow (BM) cells. Then, a myelosuppression C57BL/6 mice model was induced by intraperitoneal (i.p.) injection of cis-Diaminodichloroplatinum (cisplatin, CDDP) and followed by the intragastric (i.g.) administration of JYHP decoction. The efficacy was evaluated by blood cell count, reticulocyte count, and histopathological analysis of bone marrow and spleen. Through the experiments, we found the timing of JYHP administration affected the effect of drug administration, JYHP had a better therapeutical effect rather than a preventive effect. JYHP obviously recovered the hematopoietic function of bone marrow from the peripheral blood cell test and pathological staining. Flow cytometry data showed JYHP decreased the apoptosis rate of BM cells and the western blotting showed JYHP downregulated the cleaved Caspase-3/Caspase-3 ratios through RAS/MEK/ERK pathway. In conclusion, JYHP alleviated CDDP-induced myelosuppression by inhibiting the apoptosis of BM cells through RAS/MEK/ERK pathway and the optimal timing of JYHP administration was after CDDP administration.
Topics: Mice; Animals; Female; Cisplatin; Caspase 3; Network Pharmacology; Mice, Inbred C57BL; Drugs, Chinese Herbal; Mitogen-Activated Protein Kinase Kinases
PubMed: 38462913
DOI: 10.1177/15347354241237969 -
International Journal of Infectious... May 2024A patient with disseminated nocardiosis developed pancytopenia after treatment with recombinant interferon-gamma (IFN-γ). While no previous clinical reports link...
A patient with disseminated nocardiosis developed pancytopenia after treatment with recombinant interferon-gamma (IFN-γ). While no previous clinical reports link pancytopenia to IFN-γ, our observations align with basic research on myelosuppressive effects of IFN-γ. Adjunctive IFN-γ may improve standard nocardiosis therapy, but vigilant monitoring of its hematologic effects is necessary.
Topics: Humans; Interferon-gamma; Pancytopenia; Nocardia Infections; Recombinant Proteins
PubMed: 38458424
DOI: 10.1016/j.ijid.2024.106997 -
Scientific Reports Mar 2024Sofosbuvir is one of the crucial drugs used in the treatment of chronic hepatitis C virus (HCV) in adults and children with compensated liver disease, including...
The deleterious effects of sofosbuvir and ribavirin (antiviral drugs against hepatitis C virus) on different body systems in male albino rats regarding reproductive, hematological, biochemical, hepatic, and renal profiles and histopathological changes.
Sofosbuvir is one of the crucial drugs used in the treatment of chronic hepatitis C virus (HCV) in adults and children with compensated liver disease, including cirrhosis. It may be used alone or with other drugs. Ribavirin is an antiviral medication used to treat HCV infection. It is not effective when used alone and must be used in combination with other medications, such as sofosbuvir. This study pertains to a comprehensive assessment of the deleterious effects of sofosbuvir (an antiviral drug against chronic HCV) or sofosbuvir combined with ribavirin (an antiviral drug against RNA and DNA viruses) on several biological activities of the body, including hematological, hormonal, biochemical, histological, and immunohistochemical examinations during a long-standing period on male healthy rats. In addition, fertility assessments were performed, including sperm collections and semen parameter investigations. This study was conducted on 21 male rats divided into three equal groups. Group I (control group) received distilled water; group II (sofosbuvir group) received sofosbuvir (4 mg/kg); and group III (sofosbuvir + ribavirin) received sofosbuvir (4 mg/kg) plus ribavirin (30 ml/kg). All groups received the specific drug for six months. Blood and tissue samples were collected for hematological, hormonal, biochemical, histological, and immunohistochemical examinations. In addition, sperm collection and assessments of semen parameters were performed. Results revealed that sofosbuvir causes a highly significant decrease in the mean of most hematological, immunological, hormonal, and biochemical parameters, except for a few numbers of parameters such as neutrophils, monocytes, basophils, cortisol, GOT, and lipase, which exhibit a significant increase. The same occurred in the sofosbuvir + ribavirin group, but at much higher levels, as most hematological, immunological, hormonal, and biochemical parameters exhibit a highly significant decrease except for monocytes, triglyceride, and lipase, which exhibit a significant increase. When compared to the sofosbuvir group alone, the sofosbuvir + ribavirin group demonstrated a highly significant decline in the mean of most hematological, immunological, hormonal, and biochemical parameters except lymphocytes and triglycerides, which exhibit a substantial increase. For the reproductive parameters, both groups exhibit a significant decrease in the total sperm motility percentage. Finally, it can be concluded that sofosbuvir causes acute pancreatitis and combined immunodeficiency. Ribavirin is associated with hormonal deficiency, which indicates the occurrence of hypopituitarism. Moreover, sofosbuvir and ribavirin synergistically affect myelosuppression and cause iron-deficiency anemia. However, sofosbuvir, or its combination with ribavirin, is associated with a reduced risk of hepatocellular carcinoma. Besides, adding ribavirin to be combined with sofosbuvir improved the immunodeficiency caused by sofosbuvir; this confirms that using ribavirin with sofosbuvir reduces the side effects of both alone.
Topics: Humans; Adult; Child; Male; Animals; Rats; Antiviral Agents; Sofosbuvir; Ribavirin; Hepatitis C, Chronic; Hepacivirus; Acute Disease; Treatment Outcome; Drug Therapy, Combination; Pancreatitis; Semen; Sperm Motility; Liver Cirrhosis; Lipase; Genotype
PubMed: 38453980
DOI: 10.1038/s41598-024-55950-5