Real-life clinical benefit of oral metronomic cyclophosphamide administration in elderly and heavily pretreated epithelial ovarian cancer patients.

PURPOSE: Oral metronomic cyclophosphamide (OMC) implicates the daily administration of low doses of chemotherapy. Its antitumor activity combined with an oral administration route and a good toxicity profile makes OMC an attractive option for heavily pretreated patients. We retrospectively evaluated OMC's clinical benefit and objective response in recurrent ovarian cancer patients. METHODS: This is a retrospective observational study involving patients treated with OMC (50 mg daily) from 2017 to 2022 at the Academic Division Gynaecology, Mauriziano Hospital, Torino, Italy. Clinical benefit assessment included CA125 response, radiological response, and reported symptomatic improvement. Toxicities were reported using Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Thirty-eight patients (average age 72, range 49-88) were included. 90% had FIGO stage III/IV at diagnosis and 64% underwent ≥ 3 previous lines of chemotherapy. Before OMC, 79% had ECOG 1 or 2. 8.6% of patients had a partial response (PR), and 40% a stable disease (SD). Median duration of response was 7.4 months. After 3 months on OMC, 51% experienced symptom improvement, and 53.3% experienced Ca125 reduction or stabilization. 66.7% of patients older than 75 responded to treatment; in 40% of cases, responses lasted ≥ 6 months (p = 0.08). No G3-4 hematological toxicities occurred. Nausea and fatigue G1-G2 were reported in 5 (13%) and 13 (34%) cases, respectively. CONCLUSION: OMC is a feasible therapeutic option for recurrent ovarian cancer, providing satisfying clinical responses with a good toxicity profile, even in elderly and heavily pretreated patients with a suboptimal performance status.

Azilsartan as a preventive agent against cyclophosphamide-induced testicular injury in male rats.

Cyclophosphamide (CP) is a popular cancer treatment; however, despite its efficacy, it is known to cause harm to the testicles. To mitigate the reproductive damage caused by CP in male rats, we examined the protective effect of azilsartan (AZ) on CP-induced testicular damage. Thirty Sprague-Dawley male rats were equally divided into three groups: normal control group: received 0.5% CMC suspension for 13 days; induction group: received a single dose of 200 mg/kg of CP on day 6 by intraperitoneal (IP) injection, azilsartan group: received azilsartan (4 mg/kg) orally for 5 days followed by a single dose of 200 mg/kg of (CP) on day 6 by IP injection, then azilsartan administered again for 7 days. Animals were sacrificed on day 14, and sperm characteristics, testosterone levels, and testicular histopathology were evaluated. Induction with CP caused a significant reduction in median value compared to normal control in sperm count (12.0 vs. 22.0 × 106/mm3), sperm motility (30 vs. 90%), abnormal sperm (30.32 vs. 14.43%), dead sperm count (32.43 vs. 10.49 × 106/mm3), DNA fragmentation (21.57 vs. 5.49%); meanwhile, azilsartan prevent these effects on median sperm count (17.0 × 106/mm3), sperm motility (70.0%), abnormal sperm (23.19%), dead sperm count (26.17 × 106/mm3), DNA fragmentation (13.81%), and improved plasmatic testosterone levels compared to the CP group and prevented histopathological alterations of the testes. Azilsartan's mitigation of CP's effects suggests it can prevent male rats' reproductive damage caused by CP. One possible explanation for AZ's protective effects is that it inhibits lipid peroxidation and has antioxidant properties.

Allogeneic blood or marrow transplantation using haploidentical grandchildren donors and post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis.

BACKGROUND: High-dose post-transplant cyclophosphamide allows safe and effective use of allografts from haploidentical relatives (siblings, parents and children) in patients undergoing allogeneic blood or marrow transplant (alloBMT). More recently, second- and third-degree relatives have also been shown to be safe allograft donors. An increasing number of older patients undergoing alloBMT have been receiving allografts from haploidentical donors. However, older patients are more likely to have older siblings and children, and older donor age is associated with worse outcomes. OBJECTIVE: In the current study, we report the safety and utility of grandchildren as haploidentical donors and compared with children as donors in patients undergoing alloBMT. METHODS: We compared characteristics and outcomes of alloBMT patients aged 55 years and older with children older than 30 years as donors (C group; n = 276) and those with grandchildren as donors (GC group; n = 40). Because many important baseline characteristics predict outcomes after alloBMT, we performed propensity score matched analysis based on recipient age, alloBMT year, disease, graft source and haematopoietic cell transplantation comorbidity index (HCT-CI). RESULTS: The median age of recipients was 67 years (range 55-79) in the C group and 73 years (range 57-78) in the GC group. More than 70% of recipients in the GC group were older than 70 years, compared with 27% in the C group. The median donor age was 37 years (range 31-52) in the C group and 20 years (range 14-34) in the GC group. More patients in the GC group had HCT-CI scores ≥3 than in the C group (32.5% vs. 23%, p = 0.27). Two-year overall survival did not differ between the two groups (GC 62% vs. C 60%, hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.53-1.75, p = 0.90) despite recipients of allografts from grandchildren being older. The 2-year RFS was 55% in the C group compared with 50% in the GC group (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Non-relapse mortality subdistribution [SD] (SDHR 1.36, 95% 0.70-2.63, p = 0.36), relapse (SDHR 0.72, 95% CI 0.33-1.58, p = 0.42) or relapse-free survival (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Propensity score matching analysis showed no significant differences in 2-year overall survival (GC 64% vs. C 53%; HR 0.77, 95% CI 0.42-1.42, p = 0.40), non-relapse mortality (SDHR 1.26, 95% 0.66-2.41, p = 0.48), relapse (SDHR 0.57, 95% CI 0.21-1.52, p = 0.26) or relapse-free survival (HR 0.94, 95% CI 0.57-1.54, p = 0.81). CONCLUSION: Our results indicate that outcomes of alloBMT patients with grandchild donors are similar to those with child donors, despite recipients' older age and higher comorbidities in the GC group. Grandchildren should be considered when selecting a donor for older alloBMT recipients.

Magnolin alleviates cyclophosphamide-induced oxidative stress, inflammation, and apoptosis via Nrf2/HO-1 signaling pathway.

In the present study, we investigated the protective effect of magnolin (MAG) against oxidative stress induced by cyclophosphamide (CP) and its role in the Nrf2/HO-1 signaling pathway. Rats were administered MAG (1 mg/kg, i.p.) for 14 days and CP (75 mg/kg, i.p.) on the 14th day. CP administration increased tissue damage, as evidenced by elevated levels of transaminases (aspartate and alanine), alkaline phosphatase, and renal parameters (blood urea nitrogen and creatinine). Additionally, 8-hydroxy-2'-deoxyguanosine and malondialdehyde levels were increased, whereas glutathione levels, along with catalase and superoxide dismutase activities, decreased in CP-treated rats. CP also down-regulated the expression of Bcl-2, HO-1, Nrf2, and NQO-1, while up-regulating Bax, Cas-3, TNF-α, Cox-2, iNOS, IL-6, IL-1ß, and NFκB in liver and kidney tissues. In addition, CP treatment caused histopathological changes in heart, lung, liver, kidney, brain, and testis tissues. Treatment with MAG improved biochemical and oxidative stress parameters and prevented histopathological changes in CP-treated rats. Moreover, MAG suppressed the expression of inflammatory cytokines and apoptosis markers. In conclusion, MAG effectively prevented CP-induced toxicity by reducing oxidative stress, inflammation, and apoptosis, with its protective efficacy associated with the up-regulation of Nrf2/HO-1 signaling.

Outcomes of older adults undergoing allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide based prophylaxis.

This study evaluates the feasibility of using post-transplant cyclophosphamide (PTCY) prophylaxis in allo-hematopoietic cell transplantation (HCT) for adults aged 65 and older. PTCY is increasingly used to prevent graft-versus-host disease (GVHD) across all donor types, but concerns remain about potential risks, especially in older patients. Fifty-seven adults aged 65 or older with hematological malignancies, undergoing their first allo-HCT with PTCY prophylaxis between January 2011 and January 2023 were included. Overall, 94.8% of patients achieved primary engraftment. The median durations for neutrophil and platelet engraftments were 19 and 21 days. The day +30 cumulative incidence of bacterial bloodstream infection was 43.9%. No CMV reactivations occurred within the first 100 days after letermovir implementation. The day +180 cumulative incidences of grade II-IV and III-IV acute GVHD, and the 2-year cumulative incidence of moderate/severe chronic GVHD were 26.3%, 10.5%, and 4.8%. Eighteen patients (31.6%) relapsed, and 30 (52.6%) died, with relapse (16.4%) and infection (11.5%) being the main causes of death. The estimated 2-year overall survival, non-relapse mortality, cumulative incidence of relapse, and GVHD-free relapse-free survival rates were 45.5%, 27.1%, 33.9%, and 37.0%. Adults aged 70 or older had similar outcomes to those aged 65-69. This study confirms the safety and feasibility of PTCY-based allo-HCT in older adults.

Interventional Effect of Donkey Bone Collagen Peptide Iron Chelate on Cyclophosphamide Induced Immunosuppressive Mice.

Immunodeficiency can disrupt normal physiological activity and function. In this study, donkey bone collagen peptide (DP) and its iron chelate (DPI) were evaluated their potential as immunomodulators in cyclophosphamide (Cytoxan®, CTX)-induced Balb/c mice. The femoral tissue, lymphocytes, and serum from groups of mice were subjected to hematoxylin and eosin (H&E) staining, methylthiazolyldiphenyl-tetrazolium bromide (MTT) cell proliferation assays, and enzyme-linked immunosorbent assay (ELISA), respectively. Furthermore, a non-targeted metabolomics analysis based on UPLC-MS/MS and a reverse transcription polymerase chain reaction (RT-qPCR) technology were used to explore the specific metabolic pathways of DPI regulating immunocompromise. The results showed that CTX was able to significantly reduce the proliferative activity of mouse splenic lymphocytes and led to abnormal cytokine expression. After DP and DPI interventions, bone marrow tissue damage was significantly improved. In particular, DPI showed the ability to regulate the levels of immune factors more effectively than Fe2+ and DP. Furthermore, metabolomic analysis in both positive and negative ion modes showed that DPI and DP jointly regulated the levels of 20 plasma differential metabolites, while DPI and Fe2+ jointly regulated 14, and all 3 jointly regulated 10. Fe2+ and DP regulated energy metabolism and pyrimidine metabolism pathways, respectively. In contrast, DPI mainly modulated the purine salvage pathway and the JAK/STAT signaling pathway, which are the key to immune function. Therefore, DPI shows more effective immune regulation than Fe2+ and DP alone, and has good application potential in improving immunosuppression.

The protection afforded by kefir against cyclophosphamide induced testicular toxicity in rats by oxidant antioxidant and histopathological evaluations.

Cyclophosphamide (CTX) is the most commonly used effective alkylating drug in cancer treatment, but its use is restricted because its toxic side effect causes testicular toxicity. CTX disrupts the tissue redox and antioxidant balance and the resulting tissue damage causes oxidative stress. In our study based on this problem, kefir against CTX-induced oxidative stress and testicular toxicity were investigated. Rats were divided into 6 groups: control, 150 mg/kg CTX, 5 and 10 mg/kg kefir, 5 and 10 mg/kg kefir + 150 CTX. While the fermented kefirs were mixed and given to the rats for 12 days, CTX was given as a single dose on the 12th day of the experiment. Testis was scored according to spermatid density, giant cell formation, cells shed into tubules, maturation disorder, and atrophy. According to our biochemical findings, the high levels of total oxidant status (TOS), and the low levels of total antioxidant status (TAS) in the CTX group, which are oxidative stress markers, indicate the toxic effect of CTX, while the decrease in TOS levels and the increase in TAS levels in the kefir groups indicate the protective effect of kefir. In the CTX-administered group, tubules with impaired maturation and no spermatids were observed in the transverse section of the testicle, while in the kefir groups, the presence of near-normal tubule structures and tubule lumens despite CTX showed the protective effect of kefir. In our study, it was observed that kefir had a protective and curative effect on CTX-induced toxicity and oxidative stress and could be a strong protector.

Shilajit mitigates chemotherapeutic drug-induced testicular toxicity: Study on testicular germ cell dynamics, steroidogenesis modulation, and Nrf-2/Keap-1 signaling.

BACKGROUND: Medications, including chemotherapeutic drugs, contribute to male infertility as external factors by inducing oxidative stress in testicular cells. Shilajit is a naturally occurring bioactive antioxidant used in Ayurvedic medicine to treat a variety of ailments. OBJECTIVE: This study examines the potential of Shilajit to counteract the negative effects of the chemotherapeutic drug cyclophosphamide (CPA) on testicular germ cell dynamics. MATERIAL AND METHODS: Male Parkes mice received single intraperitoneal CPA injection (200 mg/kg BW) on day one, followed by daily supplementation of Shilajit (100 and 200 mg/kg BW) for one spermatogenic cycle. RESULTS: CPA adversely affected testicular germ cell dynamics by inhibiting the conversion of spermatogonia-to-spermatids, altering testicular histoarchitecture, impairing Sertoli cell function and testicular steroidogenesis, and disturbing the testicular oxido-apoptotic balance. Shilajit supplementation restores testicular germ cell dynamics in CPA-exposed mice, as evidenced by improved histoarchitecture of the testis. Shilajit improves testicular daily production and sperm quality by promoting the conversion of spermatogonia (2C) into spermatids (1C), stimulating germ cell proliferation (PCNA), improving Sertoli cell function (N-Cadherin and ß-Catenin), and maintaining the Bax/Bcl2 ratio. Additionally, Shilajit enhances testosterone biosynthesis by activating enzymes like 3ß-HSD, and 17ß-HSD. Shilajit also reduces testicular oxidative stress by increasing antioxidant enzyme activity (SOD) and decreasing lipid peroxidation (LPO). These effects are mediated by upregulation of the antioxidant protein Nrf-2 and downregulation of Keap-1. CONCLUSION: The findings underscore the potent androgenic and antioxidant characteristics of Shilajit, as well as its ability to enhance fertility in cases of testicular damage caused by chemotherapeutic drugs.

Total Body Irradiation and Fludarabine with Post-Transplant Cyclophosphamide for Mismatched Related or Unrelated Donor HCT.

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment for most patients with hematological malignancies. A well-matched donor (related or unrelated) remains as the preferred donor for patients undergoing allogeneic HCT; however, a large number of patients rely on alternative donor choices of mismatched related (haploidentical) or unrelated donors to access HCT. In this retrospective study, we described outcomes of patients who underwent mismatched donor (related or unrelated) HCT with radiation-based MAC regimen in combination with FLU, and PTCy as higher intensity GVHD prophylaxis. We analyzed outcomes based on donor type. METHODS: We retrospectively assessed HCT outcomes in 155 patients who underwent mismatched donor HCT [related/haploidentical vs unrelated (MMUD)] with fractionated-total body irradiation (FTBI) plus fludarabine and post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis at City of Hope from 2015 to 2021. Diagnoses included ALL (46.5%), AML (36.1%) and MDS (6.5%). The median age at HCT was 38 years and 126 (81.3%) patients were from ethnic minorities. HCT-CI was ≥3 in 36.1% and 29% had a disease-risk-index (DRI) of high/very high. Donor type was haplo (67.1%) or MMUD (32.9%). RESULTS: At 2-years post-HCT, disease-free survival (DFS) and overall survival (OS) for all subjects were 75.4% and 80.6%, respectively. Donor type did not impact OS [HR=0.72, (95% CI: 0.35,1.49), p=0.37] and DFS [HR=0.78, (95% CI: 0.41,1.48), p=0.44] but younger donors resulted in less grade III-IV acute GVHD (aGVHD, [HR=6.60, (95% CI: 1.80,24.19), p=0.004] and less moderate or severe chronic GVHD [HR=3.53, (95% CI: 1.70,7.34), p<0.001] with a trend toward better survival (p=0.099). MMUD led to significantly faster neutrophil (median 15 vs 16 days, p=0.014) and platelet recovery (median 18 vs 24 days, p=0.029); however, there was no difference in GVHD outcomes between these groups. Non-relapse mortality [HR=0.86, (95% CI: 0.34,2.20), p=0.76] and relapse risk [HR=0.78, 95%CI: (0.33,1.85), p=0.57] were comparable between the two groups. Patient age <40-years and low-intermediate DRI showed a DFS benefit (p=0.004 and 0.029, respectively). High or very High DRI was the only predictor of increased relapse [HR=2.89, 95%CI: (1.32, 6.34), p=0.008]. CONCLUSION: In conclusion, FLU/FTBI with PTCy was well-tolerated in mismatched donor HCT, regardless of relationship with patient, provided promising results, and improved access to HCT for patients without a matched donor especially patients from ethnic minorities and mixed race.

Cedrol in ginger (Zingiber officinale) as a promising hair growth drug: The effects of oral and external administration on hair regeneration and its mechanism.

Ginger is an important cooking spice and herb worldwide, and scientific research has gradually confirmed the effect of ginger on preventing hair loss. Cedrol (CE) is a small sesquiterpene molecule in ginger and its external administration (EA) has shown hope in promoting hair growth, and alternative administration mode has become a potential treatment scheme to improve the efficacy of CE. The purpose of this study is to evaluate the effects of oral administration (OA) and EA of CE on hair regeneration of C57BL/6 alopecia areata (AA) mice induced by cyclophosphamide (CP) and to clarify the potential hair growth mechanism of CE in AA model in vitro and in vivo. The results showed that CE-OA has a shorter hair-turning black time and faster hair growth rate, and can lessen hair follicle damage induced by CP and promote hair follicle cell proliferation. Its effect is superior to CE-EA. At the same time, CE can increase the cytokines IFN-γ, IL-2, and IL-7 in the serum of mice, and decrease the expression of adhesion factors ICAM-1 and ELAM-1, thus alleviating the immunosuppression induced by CP. Mechanism research shows that CE regulates the JAK3/STAT3 signaling pathway, activates the Wnt3α/ß-catenin germinal center, and ameliorates oxidative stress induced by CP, thus promoting the proliferation of hair follicle cells and reversing AA. These results provide a theoretical basis for understanding the anti-AA mechanism of CE-OA, indicating that CE can be used as raw material for developing oral hair growth drugs.

Lower Weight-Based Mycophenolate Mofetil Dosing is Associated with Superior Outcomes after Haploidentical Hematopoietic Cell Transplant with Post-transplant Cyclophosphamide.

BACKGROUND: Mycophenolate mofetil (MMF) is commonly included in post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GVHD) prophylaxis after haploidentical (haplo) hematopoietic cell transplant (HCT). In the non-PTCy setting, higher MMF dose/kg has been shown to reduce rates of acute graft-versus-host disease (GVHD). When used in conjunction with PTCy, MMF is dosed at 15 mg/kg three times daily up to a maximum dose of 3 g/day. Thus, patients who weigh ≥67 kg receive 3 g/day and a variable dose/kg of MMF. OBJECTIVE: We investigated the impact of MMF dose/kg on clinical outcomes following haploidentical PBSCT with PTCy-based GVHD prophylaxis. STUDY DESIGN: All consecutive adult patients with hematologic malignancies receiving haploidentical T cell replete peripheral blood stem cell transplant (PBSCT) with PTCy/MMF and either tacrolimus or sirolimus at the Moffitt Cancer Center or City of Hope between April 2014-August 2020 were included. For analyses, MMF dose relative to patient actual body weight (mg/kg/day), was stratified into categories of low (<29 mg/kg/day), low intermediate (29-34 mg/kg/day), high intermediate (35-41 mg/kg/day), and high (>41 mg/kg/day). RESULTS: Three hundred eighty-six patients were included. Of these, 54 patients received low dose, 73 low intermediate, 137 high intermediate and 122 high dose MMF by relative weight exposure. In multivariate analysis, low MMF dose exposure was associated with reduced rates of relapse in comparison to the high dose group (HR=0.45, 95% CI: 0.21 to 0.94, p=0.03). This led to superior PFS among patients with low compared to high MMF dose exposure (HR=0.58, 95% CI: 0.34 to 0.99, p=0.045). MMF relative dose exposure was not associated with engraftment, GVHD, non-relapse mortality, or OS. CONCLUSION: In this study of patients receiving haploidentical PBSCT with PTCy based GVHD prophylaxis, low MMF dose/kg was associated with improved rates of relapse and PFS. Future prospective studies should investigate optimal dosing strategies of MMF when given with the PTCy regimen.

Association between global longitudinal strain and occurrence of cardiovascular events among pediatric patients following high-dose cyclophosphamide chemotherapy: a prospective cohort study.

Background: The fatal cyclophosphamide cardiotoxicity is associated with high mortality in the adult population, and the study of its effects on children represents a gap in the field. This study aimed to evaluate the potential of global longitudinal strain (GLS) as a predictor of cardiovascular events among children with high-dose cyclophosphamide chemotherapy. Methods: This was a prospective cohort study of patients aged 14 years or younger who received high-dose (>120 mg/kg) cyclophosphamide chemotherapy recruited consecutively. Blood collection and echocardiography were performed 1 day before and after cyclophosphamide chemotherapy, and patients were followed up for 30 days with echocardiography. GLS and other echocardiography indicators were calculated accordingly. The primary outcome was the occurrence of cardiovascular events within 30 days after cyclophosphamide chemotherapy. The association between GLS and outcome was analyzed by using univariate and multivariable-adjusted Poisson regression. Results: A total of 29 subjects were included. Among them, 10 patients (34.48%) developed cardiovascular events during a median follow-up of 10 (interquartile range, 5-13) days. Although similar before cyclophosphamide chemotherapy, GLS 1 day after cyclophosphamide chemotherapy was significantly lower in the cardiac injury group than in the noncardiac injury group (-18.33%±1.81% vs. -20.03%±1.49%, P=0.01). In the multivariable analysis adjusted for total cyclophosphamide dose (160 vs. 120-159 mg/kg) and global circumferential strain, GLS remained an independent predictor for cardiovascular events [incidence rate ratio: 1.46, 95% confidence interval: 1.02-2.09, P=0.04]. Conclusions: GLS after cyclophosphamide chemotherapy may be a reliable indicator to predict cardiovascular events in patients receiving cyclophosphamide chemotherapy, which might be essential in optimizing treatment strategies for this high-risk patient group.

Anti-melanoma Differentiation-Associated Gene 5 (Anti-MDA5) Dermatomyositis-Associated Interstitial Lung Disease Complicated by Pneumomediastinum: A Case Report and Literature Review.

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) dermatomyositis (DM) is a subset of amyopathic myositis and is associated with unique cutaneous manifestations and rapidly progressive interstitial lung disease (RP-ILD). A rare complication associated with high mortality is the occurrence of pneumomediastinum. We present a case of a 58-year-old female with anti-MDA5 DM-associated interstitial lung disease (ILD) complicated by pneumomediastinum. Treatment with pulse dose steroids and intravenous cyclophosphamide led to clinical improvement and resolution of the pneumomediastinum. Our case emphasizes the recognition of ILD-associated pneumomediastinum in patients with anti-MDA5 DM. Swift diagnosis and aggressive treatment are crucial due to the associated high mortality.

Glucocorticoid Minimization in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: An International Survey of Clinicians.

Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV. Study Design: International, online survey. Setting & Participants: Clinicians in various countries with experience in managing vasculitis. Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction. Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial. Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to-high for usefulness to demonstrate safety and efficacy (scores 6-7/10), and moderate (scores 5-6/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients. Limitations: Representativeness of survey sample and generalizability of findings. Conclusions: Combination cyclophosphamide-rituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important.

Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on using less glucocorticoids to limit side effects. New drugs that drastically limit glucocorticoid use are not available in many countries. Studies are needed to find other ways of reducing glucocorticoid exposure to treat AAV, but it is unclear how best to achieve this. We administered a survey to doctors with experience in treating AAV and had them grade different combinations of widely available treatments with 2 or 4 weeks of glucocorticoids. We found that a combination of 2 doses cyclophosphamide with 2 doses rituximab and 4 weeks of glucocorticoids was the preferred treatment. The results will guide the development of a trial studying minimal use of glucocorticoids for the treatment of AAV.

Dexamethasone-sparing strategies in anthracycline and cyclophosphamide-based chemotherapy with a focus on 5-HT3 receptor antagonists: a network meta-analysis.

Background: The effectiveness of a dexamethasone-sparing strategy in the treatment of breast cancer with anthracycline-cyclophosphamide therapy when combined with first-generation 5-HT3 receptor antagonists (RAs) and neurokinin-1 RAs is unclear. This is attributable to a lack of evidence from direct comparison of multiple doses of DEX to a single dose of DEX in combination with first-generation 5-HT3 RAs in anthracycline-cyclophosphamide therapy. Our goal was to clarify the impact of dexamethasone-sparing strategies that involve both first-generation 5-HT3 RAs and palonosetron when combined with neurokinin-1 RAs, using a network meta-analysis. Materials and methods: A literature search was conducted on PubMed/Medline for articles published up to July 4, 2023. We included randomized controlled trials which assessed the efficacy of antiemetic regimens which combined 5-HT3 RAs and dexamethasone, with or without neurokinin-1 RAs, for the initial dose in anthracycline-cyclophosphamide therapy for patients with breast cancer. The primary outcome was the proportion of patients achieving a complete response during the delayed phase (CR-DP). Results: The difference in the proportion of patients achieving CR-DP between multiple and single doses of dexamethasone was 0.1% (95%CI: -12.4 to 12.5) with palonosetron and neurokinin-1 RAs, compared to 5.3% (95%CI: -13.4 to 23.0) with a single dose of a first-generation 5-HT3 receptor antagonist. Additionally, the difference was 12.7% (95% CI: -2.8 to 28.2) when comparing palonosetron against first-generation 5-HT3 RAs in combination with a single dose of dexamethasone and neurokinin-1 RAs. Conclusion: Palonosetron is recommended rather than a single dose of first-generation 5-HT3 RAs in dexamethasone-sparing strategies for anthracycline-cyclophosphamide therapy.

DHA-enriched phosphatidylserine ameliorates cyclophosphamide-induced liver injury via regulating the gut-liver axis.

OBJECTIVE: This study explores the therapeutic effects and mechanisms of DHA-enriched phosphatidylserine (DHA-PS) on liver injury induced by cyclophosphamide (CTX) in mice, focusing on the gut-liver axis. METHODS: A mouse model was established by administering CTX (80 mg/kg) intraperitoneally for 5 days. DHA-PS (50 or 100 mg/kg) was administered for the next 7 days to assess its reparative impact on liver damage. RESULTS: The findings revealed significant improvements in liver biochemical indices, inflammatory markers, and oxidative stress levels in the mice treated with DHA-PS. Through non-targeted metabolomics analysis, DHA-PS mitigated CTX-induced metabolic disruptions by modulating lipid, amino acid, and pyrimidine metabolism. Immunofluorescence analysis further confirmed that DHA-PS reduced the expression of liver-associated inflammatory proteins by inhibiting the TLR4/NF-κB pathway. Additionally, DHA-PS restored the intestinal barrier, evidenced by adjustments in the levels of intestinal lipopolysaccharide (LPS), secretory immunoglobulin A (sIgA), and tight junction proteins (Claudin-1, Occludin, and ZO-1). It also improved gut microbiota balance by enhancing microbial diversity, increasing beneficial bacteria, and altering community structures. CONCLUSION: These results suggest that DHA-PS could be a potential therapeutic agent or functional food for CTX-induced liver injury through its regulation of the gut-liver axis.

Assessing the impact of aprepitant on response to dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP).

BACKGROUND: Despite evidence demonstrating the effectiveness of aprepitant for chemotherapy-induced nausea and vomiting (CINV), its use in stem cell transplant settings across Canada is not standard. While pharmacokinetic data exists, the clinical significance of cytochrome P450 3A4 (CYP 3A4) inhibition of cyclophosphamide by aprepitant is unclear. Reduced activation of cyclophosphamide may reduce the effectiveness of dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP). OBJECTIVES: To compare response rates to DICEP in patients with Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) in the presence and absence of aprepitant. METHODS: A retrospective review of patients who received full-dose DICEP for relapsed/refractory HL or DLBCL between June 1995 and September 2018 at the Foothills Medical Centre (FMC) in Calgary, Alberta, Canada was conducted. Descriptive statistics were used to assess response rate, as defined by the 2007 International Working Group response criteria. RESULTS: Of the 218 patients included in this study, 87.6% of patients in the control group and 88.5% of patients in the aprepitant group responded to DICEP (difference 0.025 [95% CI, -0.066 to 0.114], p = 0.827). Univariate analyses for age, sex, type of cancer, stage of cancer, number of prior relapses, and relapse status were not significant. No significant differences were observed for secondary outcomes. CONCLUSION: Response rates to DICEP in relapsed/refractory HL and DLBCL patients were similar regardless of aprepitant use. Considering these results and the effectiveness of aprepitant in CINV, its addition to standard antiemetic therapy in patients receiving DICEP should be given strong consideration in the transplant setting.

Correlation of Genetic Polymorphism of CYP3A5 to Cyclophosphamide Efficacy and Toxicity in Rhabdomyosarcoma Pediatric Egyptian Cancer Patients.

OBJECTIVES: Rhabdomyosarcoma (RMS) accounts for 50% of soft tissue sarcomas and 7% of pediatric malignancies. Cyclophosphamide (CPA) is the cornerstone of therapy and is a prodrug that is activated by the highly polymorphic drug-metabolizing enzyme CYP3A5. We aim to examine the possible CYP3A5 polymorphism association with CPA efficacy, survival outcomes, and toxicity in Egyptian pediatric RMS patients. METHODS: The three non-functional SNPs, CYP3A5*3 rs776746 (C_26201809_30), CYP3A5*6 rs10264272 (C_30203950_10), and CYP3A5*7 rs41303343 (C_32287188_10) were genotyped by real-time PCR. We conducted a cohort retrospective study of 150 pediatric RMS patients treated with CPA-based first-line treatment to analyze the association between these genotypes and CPA efficacy/toxicities in RMS patients. KEY FINDINGS: The frequency of having normal, intermediate, and poor metabolizers was 4.7%, 34%, and 61.3%, respectively. There was an association between these different phenotypes, genotypes, and CPA efficacy/toxicity. Hemorrhagic cystitis and pancytopenia were present in all patients, while nephrotoxicity incidence was 87.3%. There was a notable difference in the occurrence of hemorrhagic cystitis among CYP3A5 intermediate metabolizers *1/*3, *1/*6, and poor metabolizers *3/*3, *3/*6 with a significance level of p<0.05. Neither CYP3A5*7 polymorphism nor *6/*6 genotype was identified in our study. CONCLUSION: Our results demonstrate that CYP3A5*3 (rs776746) and CYP3A5*6 (rs10264272) have a great association with CPA efficacy and toxicity in RMS patients.

Anti-neutrophil Cytoplasmic Antibody-Negative Rapid Progressive Glomerulonephritis With Mild Pathological Presentation in an Older Patient: A Case Report.

This case report discusses the management of anti-neutrophil cytoplasmic antibodies (ANCA)-negative rapid progressive glomerulonephritis (RPGN) in a 68-year-old man with a complex medical history, presenting with fatigue, edema, and acute renal failure. Despite the absence of positive biomarkers for specific RPGN types, the clinical progression suggested microscopic polyangiitis, leading to intensive immunosuppressive therapy with cyclophosphamide and rituximab. The patient's condition was further complicated by the coexistence of nephritic and nephrotic syndromes, requiring nuanced management strategies, including prolonged hemodialysis. After initial treatment failure, remission was eventually achieved, allowing cessation of dialysis and significant recovery of renal function. This case highlights the challenges of diagnosing and managing ANCA-negative RPGN, particularly the importance of a tailored, dynamic approach to treatment in resource-limited settings. The recovery observed underscores the potential for renal function improvement even after prolonged periods of intensive therapy, reinforcing the need for persistence and adaptability in managing complex RPGN cases.

Therapeutic effects of Medicago sativa against cyclophosphamide-induced toxicity in rats.

Objective: Medicago sativa (M. sativa) has been traditionally used for treating anemia; therefore, M. sativa hydro-ethanolic extract therapeutic effects against cyclophosphamide (CP) -induced hematologic and liver toxicity were examined. Materials and Methods: Thirty male Wistar rats were randomly divided to control (saline); CP (100 mg/kg, day 1-3, subcutaneously); CP+ M. sativa 200 mg/kg (MS 200); CP+ M. sativa 400 mg/kg (MS 400); CP+ dexamethasone (0.1 mg/kg), (all groups n=6). Treated animals received M. sativa or dexamethasone by gavage from days 7-14. On days 0, 7, and 14, hematologic parameters, and on the 14th day, serum and liver tissue oxidative stress markers including nitric oxide, malondialdehyde (MDA) and total thiol levels, superoxide dismutase (SOD) and catalase (CAT) activities, serum lipids, and liver enzymes were measured. Results: Animal weight, platelet, white blood cells, and red blood cells counts, hemoglobin and hematocrit as well as thiol, SOD, and CAT activities in serum and liver tissue were significantly reduced, but serum nitric oxide, MDA, total cholesterol, triglycerides, low-density lipoproteins levels, and liver enzymes were increased in the CP group compared to the control group (p<0.05 to p<0.001). Administering M. sativa extract (400 mg/kg) significantly enhanced platelet count, and SOD and CAT activities and inhibited all of the CP toxic effects, while dexamethasone improved platelet count and oxidative stress markers compared to the CP group (p<0.05 to p<0.001). Conclusion: The extract of M. sativa (400 mg/kg) showed therapeutic effects against the CP-induced myelosuppression and thrombocytopenia and improved oxidative stress markers which were comparable to the effect of dexamethasone.