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Kidney360 May 2024Cisplatin is an effective first line therapy for a variety of cancers. Cisplatin is highly emetogenic and resulting volume depletion can contribute to acute kidney...
BACKGROUND
Cisplatin is an effective first line therapy for a variety of cancers. Cisplatin is highly emetogenic and resulting volume depletion can contribute to acute kidney injury (AKI). Anti-emetic drugs such as 5-hydroxytryptamine type 3 receptor antagonists (5-HT3RAs) are commonly prescribed to prevent this complication. Preclinical studies suggest first generation 5-HT3RAs may alter the renal clearance and increase cisplatin toxicity. This retrospective study evaluated whether different 5-HT3RAs modify the risk of AKI in patients receiving cisplatin.
METHODS
Patients with cancer who received cisplatin between January 1, 2010 and December 31, 2016 were included. Patients over 18 years old with available data for baseline and post-treatment serum creatinine, cisplatin cumulative dose, and administration of 5-HT3RAs including first generation (ondansetron, granisetron, and ramosetron) and second generation (palonosetron) were analyzed. AKI defined as 1.5x increase in serum creatinine. Fisher's exact and Wilcoxon rank-sum tests were used to assess univariable associations between baseline covariates and AKI, and logistic regression for multivariable associations with AKI.
RESULTS
Of 8703 patients identified with cisplatin exposure, 6889 were included. A total of 3881 (56.3%) patients received at least one 5-HT3RA, including palonosetron (3750, 54.4%), ondansetron (1399, 20.3%) and granisetron (11, 0.2%). AKI developed in 1666 (24.2%) patients following cisplatin. Patients who received any 5-HT3RAs were less likely to experience AKI as compared to patients that did not (22.6% vs 26.2%, p=0.001). Older age, male gender, African ethnicity, and cumulative cisplatin dose were univariately associated with higher risk for AKI (P<0.001). After adjusting for these variables, use of any of these antiemetic drugs was protective for AKI (OR 0.84, 95% CI: 0.75, 0.94; P= 0.003) with no difference detected between type of 5-HT3RA.
CONCLUSION
Nephrotoxicity continues to be a concern following cisplatin therapy. Given its emetogenic nature, use of antiemetic drugs such as 5-HT3RAs can lessen emesis and lower risk of kidney injury. This retrospective analysis supports use of any 5-HT3RAs to lower risk of AKI.
PubMed: 38814726
DOI: 10.34067/KID.0000000000000464 -
Respiratory Research May 2024Steroid insensitivity in Chronic Obstructive Pulmonary Disease (COPD) presents a problem for controlling the chronic inflammation of the airways. The glucocorticoid...
BACKGROUND
Steroid insensitivity in Chronic Obstructive Pulmonary Disease (COPD) presents a problem for controlling the chronic inflammation of the airways. The glucocorticoid receptor (GR) mediates the intracellular signaling of inhaled corticosteroids (ICS) by interacting with transcription factors and histone deacetylases (HDACs). The aim of this study was to assess if COPD patients' response to ICS in vivo, may be associated with the expression of GR, the complex of GR with transcription factors, and the expression of various HDACs in vitro.
METHODS
Primary airway smooth muscle cells (ASMC) were established from endobronchial biopsies obtained from patients with asthma (n = 10), patients with COPD (n = 10) and subjects that underwent diagnostic bronchoscopy without pathological findings and served as controls (n = 6). ASMC were also established from 18 COPD patients, 10 responders and 8 non-responders to ICS, who participated in the HISTORIC study, an investigator-initiated and driven clinical trial that proved the hypothesis that COPD patients with high ASMC in their endobronchial biopsies respond better to ICS than patients with low ASMC. Expression of GR and its isoforms GRα and GRβ and HDACs was investigated in primary ASMC in the absence or in the presence of dexamethasone (10M) by western blotting. The complex formation of GR with transcription factors was assessed by co-immunoprecipitation.
RESULTS
Expression of GR and its isoform GRα but not GRβ was significantly reduced in ASMC from COPD patients as compared to controls. There were no significant differences in the expression of GR, GRα and GRβ between responders and non-responders to ICS. However, treatment with dexamethasone upregulated the expression of total GR (p = 0.004) and GRα (p = 0.005) after 30 min in responders but not in non-responders. Τhe formation of the complex GR-c-Jun was increased 60 min after treatment with dexamethasone only in responders who exhibited significantly lower expression of HDAC3 (p = 0.005) and HDAC5 (p < 0.0001) as compared to non-responders.
CONCLUSIONS
These data suggest that ASMC from COPD patients who do not respond to treatment with ICS, are characterized by reduced GR-c-Jun complex formation and increased expression of HDAC3 and HDAC5.
TRIAL REGISTRATION
ISRCTN11017699 (Registration date: 15/11/2016).
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid; Histone Deacetylases; Myocytes, Smooth Muscle; Male; Middle Aged; Female; Aged; Cells, Cultured; Adrenal Cortex Hormones; Glucocorticoids; Dexamethasone; Treatment Outcome; Administration, Inhalation; Bronchi
PubMed: 38812021
DOI: 10.1186/s12931-024-02769-3 -
BMC Anesthesiology May 2024This study evaluated the effectiveness, psychological effects, and sleep quality using intramuscular diazepam infusion compared with placebo in patients with herpes... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
This study evaluated the effectiveness, psychological effects, and sleep quality using intramuscular diazepam infusion compared with placebo in patients with herpes zoster (HZ)-related pain.
METHODS
The patients were randomized to either the diazepam or control group. The diazepam group received an intramuscular injection of diazepam for 3 consecutive days, while the control group received an intramuscular injection of 0.9% normal saline. The primary outcome was pain relief on posttreatment day 4, as measured using the Visual Analog Scale (VAS). Moreover, anxiety and depression were evaluated using the Generalized Anxiety Disorder-7 (GAD7) and Patient Health Questionnaire-9 (PHQ9), respectively. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI).
RESULTS
In total, 78 patients were enrolled in the trial. The mean differences in VAS scores between the two groups were 0.62 (P = 0.049) on posttreatment day 3 and 0.66 (P = 0.037) on posttreatment day 4. The effective rates of pain management in the diazepam group ranged from 10.26 to 66.67%, which were higher than those in the control group on posttreatment days 3 and 4 (P < 0.05). The mean difference in PSQI scores between the diazepam and control groups was 1.36 (P = 0.034) on posttreatment day 7. No differences were found in the incidence of analgesia-adverse 1reactions between the diazepam and placebo groups.
CONCLUSIONS
The intramuscular injection of diazepam for 3 consecutive days provides effective pain management and improves the quality of life. Our study suggests that diazepam is more effective than the placebo in patients with HZ-related pain.
TRIAL REGISTRATION
The study was prospectively registered at https://www.isrctn.com/trialist(Registration date: 24/01/2018; Trial ID: ISRCTN12682696).
Topics: Humans; Male; Female; Double-Blind Method; Injections, Intramuscular; Aged; Herpes Zoster; Diazepam; Pain Measurement; Middle Aged; Sleep Quality; Anxiety; Pain
PubMed: 38811866
DOI: 10.1186/s12871-024-02576-9 -
Blood Cancer Journal May 2024We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) without autologous stem cell...
We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) without autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM) irrespective of ASCT eligibility in a single-arm, phase II study. The primary endpoint was the rate of stringent complete response (sCR) and/or measurable residual disease (MRD) < 10 by next-generation sequencing (NGS) at the end of cycle 8 (C8). MRD was also assessed on peripheral blood samples using both the EXENT system and liquid chromatography-mass spectrometry (LC-MS). Forty-two patients entered the treatment phase; forty were evaluable for the primary endpoint. The rate of sCR and/or MRD < 10 following C8 was 30/40 (75%), meeting the statistical threshold for efficacy. The 10 MRD negative rate improved with treatment beyond C8. Agreement between EXENT and NGS was high and increased over time; agreement between LC-MS and NGS was lower. The estimated 3-year progression-free survival progression-free survival was 85%, and 3-year overall survival was 95%. Upper respiratory infections occurred in 67% (7% grade 3-4). There were no treatment-related deaths. Extended frontline Dara-KRd induced a high rate of sCR and/or MRD negativity; the rate and depth of MRD negativity improved beyond C8.
Topics: Humans; Multiple Myeloma; Dexamethasone; Lenalidomide; Female; Male; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Oligopeptides; Antibodies, Monoclonal; Adult; Neoplasm, Residual; Treatment Outcome
PubMed: 38811560
DOI: 10.1038/s41408-024-01045-3 -
Nature Communications May 2024Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the...
Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.
Topics: Receptors, CXCR4; Humans; Animals; Signal Transduction; Drug Resistance, Neoplasm; Dexamethasone; Type C Phospholipases; Cell Line, Tumor; Glucocorticoids; Mice; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Mice, Inbred NOD; Cell Survival
PubMed: 38811530
DOI: 10.1038/s41467-024-48818-9 -
Critical Care (London, England) May 2024Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have...
BACKGROUND
Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, COVID-19, and ARDS, but the mechanisms of this benefit remain unclear. The primary objective of this study was to investigate the effects of corticosteroids on the pulmonary biology of pneumococcal pneumonia in a mouse model. A secondary objective was to identify shared transcriptomic features of pneumococcal pneumonia and steroid treatment in the mouse model and clinical samples.
METHODS
We carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify the mechanisms of lung injury in Streptococcus pneumoniae with and without adjunctive steroid therapy. We also studied lower respiratory tract gene expression from a cohort of 15 mechanically ventilated patients (10 with Streptococcus pneumoniae and 5 controls) to compare with the transcriptional studies in the mice.
RESULTS
In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathologic lung injury score, and (5) hypoxemia but did not increase bacterial burden. Transcriptomic analyses identified effects of steroid therapy in mice that were also observed in the clinical samples.
CONCLUSIONS
In combination with appropriate antibiotic therapy in mice, treatment of pneumococcal pneumonia with steroid therapy reduced hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The transcriptional studies in patients suggest that the mouse model replicates some of the features of pneumonia in patients with Streptococcus pneumoniae and steroid treatment. Overall, these studies provide evidence for the mechanisms that may explain the beneficial effects of glucocorticoid therapy in patients with community acquired pneumonia from Streptococcus Pneumoniae.
Topics: Animals; Pneumonia, Pneumococcal; Mice; Disease Models, Animal; Adrenal Cortex Hormones; Humans; Dexamethasone; Female; Male; Streptococcus pneumoniae
PubMed: 38807178
DOI: 10.1186/s13054-024-04956-6 -
Journal of Cancer Research and Clinical... May 2024The aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with... (Randomized Controlled Trial)
Randomized Controlled Trial
A prospective randomized controlled clinical trial investigating the efficacy of low-dose olanzapine in preventing nausea and vomiting associated with oxaliplatin-based and irinotecan-based chemotherapy.
OBJECTIVE
The aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) among female patients diagnosed with gastrointestinal tract tumors.
METHODS
Patients undergoing the oxaliplatin/irinotecan chemotherapy regimen were enrolled in this prospective controlled study. The olanzapine group received a 5 mg dosage of olanzapine along with palonosetron and dexamethasone, while the control group received a standard two-combination regimen consisting of dexamethasone and palonosetron. The primary endpoints included the total protection (TP) rates for the entire age group and the subgroup aged 60 years and above. Secondary endpoints encompassed the total protection rates during the acute and delayed phases within the two age brackets, as well as the total control (TC) rates and complete remission (CR) rates across all three phases (total, acute, and delayed). Additionally, the study involved the assessment of quality of life and the collection of adverse events associated with the interventions.
RESULTS
1) Regarding the primary endpoint, the total phase TP rates within both the entire age group and the age group exceeding 60 years demonstrated superiority in the olanzapine group when compared to the control group (66.7% vs 37.25%, P = 0.003; 68.8% vs 44.4%, P = 0.044). 2) In terms of secondary endpoints, the olanzapine group exhibited superior acute phase TP rates in both age brackets when compared to the control group (P < 0.05). The olanzapine group also demonstrated higher delayed-phase TP rates, TC rates across all three phases, and CR rates within the two age brackets, although the differences were not statistically significant (P > 0.05). Furthermore, the quality of life in the olanzapine group surpassed that of the control group for both age brackets (P < 0.05), characterized by enhanced appetite and a higher incidence of drowsiness in the patients treated with olanzapine when compared to those in the control group (P < 0.05).
CONCLUSION
Olanzapine can enhance CINV induced by MEC regimen in female patients across all age groups, including the elderly, and therefore improve the quality of life for these patients.
CLINICAL TRIAL REGISTRATION
https://www.chictr.org.cn/index.html , identifier: ChiCTR20000368269, 25/08/2020.
Topics: Humans; Olanzapine; Female; Middle Aged; Nausea; Vomiting; Antineoplastic Combined Chemotherapy Protocols; Prospective Studies; Oxaliplatin; Irinotecan; Aged; Adult; Antiemetics; Gastrointestinal Neoplasms; Palonosetron; Quality of Life; Dexamethasone
PubMed: 38806870
DOI: 10.1007/s00432-024-05712-7 -
Renal Failure Dec 2024Acute kidney injury (AKI) is one of the most common and severe clinical syndromes of diffuse proliferative lupus nephritis (DPLN), of which poor prognosis is indicated...
BACKGROUND AND OBJECTIVES
Acute kidney injury (AKI) is one of the most common and severe clinical syndromes of diffuse proliferative lupus nephritis (DPLN), of which poor prognosis is indicated by aggravated renal function deterioration. However, the specific therapy and mechanisms of AKI in DPLN remain to be explored.
METHODS
The correlation between AKI and clinical pathological changes in DPLN patients was analyzed. Expression of STAT3 signaling was detected in MRL/lpr mice with DPLN using immunohistochemical staining and immunoblotting. Inhibition of STAT3 activation by combination therapy was assessed in MRL/lpr mice.
RESULTS
Correlation analysis revealed only the interstitial leukocytes were significantly related to AKI in endocapillary DPLN patients. MRL/lpr mice treated with vehicle, which can recapitulate renal damages of DPLN patients, showed upregulation of STAT3, pSTAT3 and caspase-1 in renal cortex. FLLL32 combined with methylprednisolone therapy significantly inhibited the STAT3 activation, improved acute kidney damage, reduced the interstitial infiltration of inflammatory cells and decreased the AKI incidence in MRL/lpr mice.
CONCLUSION
STAT3 activation may play an important role in the pathogenesis of DPLN and the development of AKI. Hence, STAT3 inhibition based on the combination of FLLL32 with methylprednisolone may represent a new strategy for treatment of DPLN with AKI.
Topics: Animals; Lupus Nephritis; STAT3 Transcription Factor; Mice, Inbred MRL lpr; Mice; Female; Disease Models, Animal; Acute Kidney Injury; Humans; Methylprednisolone; Kidney; Signal Transduction; Adult; Male
PubMed: 38803234
DOI: 10.1080/0886022X.2024.2358187 -
Scientific Reports May 2024The COVID-19 pandemic has posed a major challenge to healthcare systems globally. Millions of people have been infected, and millions of deaths have been reported...
The COVID-19 pandemic has posed a major challenge to healthcare systems globally. Millions of people have been infected, and millions of deaths have been reported worldwide. Glucocorticoids have attracted worldwide attention for their potential efficacy in the treatment of COVID-19. Various glucocorticoids with different dosages and treatment durations have been studied in patients with different severities, with a suitable dosage and treatment duration not yet defined. This study aimed to investigate whether in-hospital survival differs between critically ill patients treated with low-dose glucocorticoids, high-dose glucocorticoids or no glucocorticoids. All critically ill patients admitted to the intensive care unit of the Charité Hospital-Universitätsmedizin Berlin between February 2020 and December 2021 with COVID-19 pneumonia receiving supplemental oxygen were eligible to participate in this multicenter real-world data study. Patients were retrospectively assigned to one of three groups: the high corticosteroid dose (HighC) group (receiving 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), the low corticosteroid dose (LowC) group (receiving less than 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), or the no corticosteroid (NoC) group. Overall survival and risk effects were compared among groups within the total observation period, as well as at 35 days after the onset of COVID-19 symptoms. Adjusted multivariable Cox proportional hazard regression analysis was performed to compare the risk of death between the treatment groups. Out of 1561 critically ill COVID-19 patients, 1014 were included in the baseline analysis. In the survival study, 1009 patients were assigned to the NoC (n = 346), HighC (n = 552), or LowC group (n = 111). The baseline characteristics were balanced between groups, except for age, BMI, APACHE II score, SOFA and SAPS II. While the 35-day survival did not show any differences, a landmark analysis of the patients surviving beyond 35 days revealed differences between groups. The restricted mean survival time was 112 days in the LowC group [95% CI: 97 - 128], 133 days in the HighC group [95% CI: 124 - 141] and 144 days in the NoC group [95% CI: 121 - 167]. The multivariable-adjusted Cox proportional hazard analysis indicated that, regardless of age, sex, health status or invasive oxygenation, a low-dose treatment increased the hazard of death of critically ill COVID-19 patients by a factor of 2.09 ([95% CI: 0.99, 4.4], p = 0.05) and a high-dose corticosteroid treatment increased the risk by a factor of 1.07 ([95% CI: 0.53, 2.15], p = 0.85) compared to no treatment with glucocorticoids. The analysis reveals that corticosteroid treatment does not influence the survival of critically ill COVID-19 patients in the intensive care unit within 35 days. Our evaluations further suggest that regardless of ventilation status, the decision-making process for administering corticosteroid therapy should account for the individual severity of the illness.
Topics: Humans; Critical Illness; Male; Female; Aged; Middle Aged; Glucocorticoids; COVID-19; Retrospective Studies; COVID-19 Drug Treatment; Hospital Mortality; Intensive Care Units; Dexamethasone; SARS-CoV-2; Aged, 80 and over
PubMed: 38802435
DOI: 10.1038/s41598-024-62302-w -
Cureus Apr 2024Introduction Erector spinae plane (ESP) block was first introduced for the management of thoracic pain but has become increasingly popular for the treatment of abdominal...
Introduction Erector spinae plane (ESP) block was first introduced for the management of thoracic pain but has become increasingly popular for the treatment of abdominal surgical pain. Previous studies have shown the ESP block can be easily adapted to abdominal procedures at the corresponding dermatome level and provide postoperative analgesia. Though the versatility, simplicity, and safety of the ESP block have been demonstrated, there is a gap in the literature regarding its comparison between thoracic and abdominal surgeries. This study aims to evaluate the efficacy of the ESP block in treating acute postoperative pain in patients undergoing thoracic and abdominal surgeries. Methods This retrospective study included 50 patients in the non-cardiac thoracic surgery group (bilateral breast mastectomy with reconstruction) and 50 patients in the abdominal surgery group (robotic or laparoscopic sleeve gastrectomy). Data was obtained via the acute pain service records at a tertiary care center from 2018 to 2022. All patients received bilateral ESP blocks, performed under ultrasound guidance. Various parameters were evaluated including oral morphine equivalents (OMEs) and visual analog scale (VAS) scores during post-anesthesia care unit (PACU), 6, 12, and 24 hours postop. The use of abortive antiemetic medications within 24 hours was also measured to evaluate the incidence of nausea and vomiting. The results were analyzed and compared. No control group is included, as all patients at our institution receive a peripheral nerve block as a part of the institution's enhanced recovery pathway (ERP). Results This retrospective study included 50 patients in the non-cardiac thoracic surgery group (bilateral breast mastectomy with reconstruction) and 50 patients in the abdominal surgery group (robotic or laparoscopic sleeve gastrectomy). Compared to the thoracic group, the abdominal group had a statistically higher VAS score in PACU with mean difference (MD) 1.3 VAS, 95% confidence interval (CI) 0.03-2.56, p-value 0.0443, statistically higher OME consumption in the PACU (difference 13.35 OME, 95% CI 4.97-21.73, p-value 0.0003), and required significantly more antiemetic pharmacotherapy (mean 1.4 antiemetics administered, 95% CI 0.84-2.04, p-value <0.0001). Despite the abdominal group having more OME utilization in the PACU, there was no difference in cumulative OME use in the first 24 hours (95% CI -9.745-24.10, p-value 0.4021). Conclusion In this study, we demonstrated that ESP blocks are an effective regional anesthesia technique to reduce postoperative pain and opioid consumption. The ESP block can serve as a useful and safe alternative to either thoracic epidural or paravertebral block techniques in thoracic and upper abdominal surgeries for perioperative pain management.
PubMed: 38800304
DOI: 10.7759/cureus.58926