Cyclophosphamide Treatment Group Research Articles

#1093 Remission rates and long-term outcomes of relapsed idiopathic nephrotic syndrome children treated with cyclophosphamide vs. cyclosporin A

Abstract Background and Aims Approximately seventy percent of nephrotic syndrome (NS) children experience relapse episodes which are classified as frequently-relapsing nephrotic syndrome (FRNS), steroid-dependent nephrotic syndrome (SDNS), or steroid-resistant nephrotic syndrome (SRNS). In such cases, immunosuppressive drugs are combined to reduce the steroid side effects and prolong the remission period. However, the benefit of immunosuppressants and their side effects should be balanced. Objectives This study aimed to determine the remission rates and long-term outcomes of FRNS, SDNS, and SRNS children treated with cyclophosphamide vs. cyclosporin A (Cy A). Methods A retrospective review of medical records of children (aged < 15 years) with relapsed idiopathic nephrotic syndrome at Prince of Songkla University Hospital, southern Thailand during 2010-2021 was conducted. Demographic data, treatment responses, and adverse events were recorded. The remission rates, incidences of infection and acute kidney injury (AKI) in FRNS/SDNS and SRNS were compared between oral cyclophosphamide and Cy A treatments. Results There were 148 relapsed NS children, 102 (68.9%) boys, with a median age of 4.6 (IQR 2.5-8.4) years. FRNS, SDNS, and SRNS accounted for 37 (25.0%), 50 (33.8%), and 61 (41.2%) children, respectively. The cyclophosphamide treatment group (N = 135) had significantly higher remission rates in FRNS/SDNS than SRNS (63/85 (74.1%) vs. 11/50 (22.0%), P < 0.001), while the difference in remission rates in the Cy A treatment group (N = 53) was not statistically significant between FRNS/SDNS and SRNS (14/20 (70.0%) vs. 18/33 (54.5%), P = 0.265). Patients who had the Cy A treatment had significantly higher proportions of infections and AKI than children in the cyclophosphamide treatment group (20/53 (37.7%) vs 10/95 (10.5%), P < 0.001 and 21/53 (39.6%) vs 9/95 (9.5%), P < 0.001, respectively). Of the 148 children, at a median follow-up time of 8.7 (IQR 5.2–12.2) years, 21 (14.2%) and 9 (6.1%) children had developed chronic kidney disease (CKD) stage III or end-stage kidney disease (ESKD), respectively. The mean duration from CKD stage III to ESKD was 5.0+5.5 months. Conclusions Seventy percent of FRNS/SDNS children achieved remission with either Cy A or cyclophosphamide, but the SRNS children achieved remission proportionately better with Cy A than cyclophosphamide. However, the Cy A-treated children had higher proportions of infections and AKI than the cyclophosphamide treatment group. Overall, one-fifth of the relapsed childhood NS children developed CKD.

Siklofosfamidin Neden Olduğu Deneysel Sıçan Testis Hasarında Resveratrolün Etkilerinin Çinko ile Karşılaştırmalı Olarak Değerlendirilmesi

Cyclophosphamide is a well-known alkylating cytotoxic chemotherapeutic agent. 
 Aim: To investigate protective effects of Resveratrol in combination or comparison with Zinc in experimental testicular injury induced by Cyclophosphamide is studied for the first time in literature.
 Materials and Methods: Rats (n=63) were randomly divided into 9 groups. After 21 days of drug administration biochemical and histological analysis were performed. Daily water consumption, body weights and weight of testes were measured. Johnsen’s testicular scoring and sperm morphology were evaluated. Hematoxylin&Eosin, Periodic acid-Schiff and Masson's trichrome stainings and iNOS, eNOS and CD34 antibodies were applied histologically. To determine oxidative stress, MDA and CAT values were determined. Statistically, one-way ANOVA with post Hoc Tukey HSD test for multiple comparisons was performed via IBM SPSS Version 25.0.
 Results: Cyclophosphamide caused an increase in testicular MDA levels due to elevated oxidant stress. Testicular MDA levels significantly decreased in Zinc and Resveratrol groups which revealed protective effects related to Cyclophosphamide treatment, while no significant improvement was observed for control and saline groups. However, the most significant decrease was observed in MDA for Cyclophosphamide+Zn+Resveratrol group in comparison to Cyclophosphamide. Telocytes, which are lately defined novel cells, were detected in the interstitium encircling seminiferous tubules as a sheath immunohistochemically.
 Conclusion: Not only Resveratrol and Zinc, but also their optimum administration separately protects testes in Cyclophosphamide treatment groups. Clinical adaptations of this in vivo model may lead to novel futuristic ideas in preventing infertility due to cancer chemotherapy.

Protective Activity of a Polyherbal Formulation in Cyclophosphamide-Induced Immunosuppression

A previous study reported on the immunostimulatory activity of a polyherbal formulation (PHF). However, its potential in immunosuppression is unknown. This murine study evaluates the protective activity of aqueous extract of the PHF in cyclophosphamide (CP)-induced immunosuppression. The PHF consists of Acacia polyacantha, Acacia senegal, Adansonia digitata, Allium sativum and Bauhinia rufescens. The study was conducted on 20 rats in four groups: normal saline group, negative control, treatment control group, and experiment group. Delayed type hypersensitivity (DTH) response, keyhole limpet haemocyanin (KLH)-IgG, serum IFN-γ, and IL-4 were measured using digital Vernier calliper and sandwich ELISA, respectively. Histology of liver, thymus, and bone marrow was examined. No significant difference was observed between treatment control and experimental groups in DTH response (p > 0.05). No significant difference prevailed in the mean concentration of KLH-IgG from PHF treatment group to CP treatment group in the experiment (p = 0.48). Also, the serum IFN-γ level in the PHF-treatment group was not statistically different from the CP-treatment group (p = 0.293). The serum level of IL-4 in the PHF-treatment group was also not significantly different from that of the CP-treatment group (p = 0.139). The histology of PHF treated group showed similar features to that of normal and treatment controls. The formulation has demonstrated good protective ability in cyclophosphamide-induced immunosuppressed rats.

PB2078: A RETROSPECTIVE ANALYSIS OF THE EFFICACY OF LOW-DOSE METRONOMIC CYCLOPHOSPHAMIDE FOR TREATMENT IN PATIENTS WITH LOW GRADE NON-HODGKIN LYMPHOMA

Background: Low-dose metronomic cyclophosphamide chemotherapy is an emerging strategy offering a potentially less toxic yet effective treatment modality. Aims: We evaluated the efficacy and safety of low-dose metronomic cyclophosphamide in patients with low grade non-Hodgkin lymphoma (NHL) by retrospectively reviewing the data. Methods: The patients received oral cyclophosphamide (50 mg per day) and/or oral methotrexate (2.5 mg twice weekly) until disease progression or unacceptable toxicity was noted. Results: Of the 36 patients, 17 (47.2%) were male, median age was 66.4 years (range, 37-91 years), and subtypes of NHL were mucosa associated lymphoid tissue lymphoma (55.6%), small lymphocytic lymphoma (13.9%), follicular lymphoma (11.1%), mantle cell lymphoma (8.3%), nodal marginal zone lymphoma (4.5%), splenic marginal zone lymphoma (2.8%), and lymphoplasmacytic lymphoma (2.8%). The stage I, II, III, IV were 38.9%, 13.9%, 11.1%, 36.1%, respectively and 55.6% of patients received this regimen as the first-line treatment, mainly due to frailty, refusal to standard chemotherapy. The overall best response rate (ORR) was 73.5% (12 complete responses, CRs and 13 partial responses, PRs), with 29.1 months of the median duration of response and the disease control rate was 88.2%. The median treatment duration was 8.8 months (range, 0.1-38.4 months); the median progression-free survival (PFS) was 43.5 months, and the median overall survival (OS) was not yet reached. Especially, the ORR in patients who were treated with metronomic cyclophosphamide as the first line treatment and as more than the second line treatment were 78.9% (10 CRs, 5 PRs) and 66.6% (2 CRs, 9 PRs), respectively. The median PFS were not reached in the first line cyclophosphamide treatment group and 26.5 months (range, 5.7-47.2 months) in the other group (p=0.110), and similarly, the median OS were not reached and 64.4 months (0-135.7 months) (p=0.058), respectively. The regimen was generally well tolerated, with small numbers of grade 3-4 toxicities; neutropenia (2%), anemia (3%), thrombocytopenia (3%), fatigue (4%), and anorexia (1%). Summary/Conclusion: We concluded that low-dose metronomic cyclophosphamide represents efficacious and well-tolerated treatment for low-grade NHL patients.

Immunoenhancement Effects of the Herbal Formula Hemomine on Cyclophosphamide-Induced Immunosuppression in Mice

Hemomine is an herbal blend comprising Angelicae Gigantis Radix and other herbs known to have immunomodulatory effects. We examined the immunopotentiating effect of this herbal blend on cyclophosphamide (CPA)-induced immunosuppression. Male mice were assigned to one of six groups: the intact control and five CPA treatment groups (one control, one reference (β-glucan), and three with the application of hemomine at different concentrations; 4, 2, or 1 mL/kg; n = 10 per group). Mice were injected with CPA to induce myelosuppression and immunosuppression, after which they received one of the experimental treatments. In immunosuppressed mice, hemomine treatment alleviated the noticeable reductions in body, spleen, and submandibular lymph node weights caused by CPA; caused changes in hematological markers; induced the reduced levels of serum IFN-γ and spleen TNF-α, IL-1β, and IL-10 by CPA; improved natural killer cell activities in the spleen and peritoneal cavity; and also improved lymphoid organ atrophy in a dose-dependent manner. We demonstrate that hemomine, a mixture of six immunomodulatory herbs, is an effective immunomodulatory agent, with the potential to enhance immunity.

Intravoxel Incoherent Motion Diffusion-Weighted MR Imaging for Monitoring the Immune Response of Immunogenic Chemotherapy.

ObjectiveTo evaluate the predictive value of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in the quantitative assessment of conventional chemotherapy-activated immune responses in mouse tumor models and clinics.MethodsA total of 19 subcutaneous tumor-bearing mice were randomly divided into treated and control groups. Both groups had orderly IVIM DWI examinations before and on days 6 and 12 after the administration of cyclophosphamide (CPA) or saline. Pathologic examinations were performed, including HE staining and immunohistochemistry (IHC). The expressions of immune-related genes in the tumor were measured by qPCR. In addition, six patients with breast cancer requiring neoadjuvant chemotherapy (NACT) also underwent functional MRI examinations and IHC to determine potential antitumor immune response.ResultsAt the end of the study, the CPA treatment group showed the lowest tumor volume compared to the control group. For pathological examinations, the CPA treatment group showed a lower percentage of CD31 staining (P < 0.01) and Ki-67 staining (P<0.01), and a higher percentage of TUNEL staining (P < 0.01). The tumoral pseudodiffusion coefficient (D*) value showed a positive correlation with the CD31-positive staining rate (r = 0.729, P < 0.0001). The diffusion related parameters (D) value was positively correlated with TUNEL (r = 0.858, P < 0.0001) and negatively correlated with Ki-67 (r = -0.904, P < 0.0001). Moreover, a strong induction of the expression of the immune responses in the CPA treatment group was observed on day 12. D values showed a positive correlation with the Ifnb1-, CD8a-, Mx1-, Cxcl10- (r = 0.868, 0.864, 0.874, and 0.885, respectively, P < 0.0001 for all). Additionally, the functional MRI parameters and IHC results in patients with breast cancer after NACT also showed a close correlation between D value and CD8a (r = 0.631, P = 0.028).ConclusionsThe treatment response induced by immunogenic chemotherapy could be effectively evaluated using IVIM-DWI. The D values could be potential, sensitive imaging marker for identifying the antitumor immune response initiated by immunogenic chemotherapy.

Evolution of Systemic Sclerosis-Associated Interstitial Lung Disease One Year After Hematopoietic Stem Cell Transplantation or Cyclophosphamide.

ObjectiveHematopoietic stem cell transplantation (HSCT) and cyclophosphamide (CYC) are treatment options for progressive systemic sclerosis associated with interstitial lung disease (SSc‐ILD). The aims of our retrospective observational study were to evaluate: 1) the evolution of SSc‐ILD in SSc patients treated with HSCT (assessed by high‐resolution computed tomography [HRCT]; a group of patients treated with CYC was included as frame of reference); 2) how results of pulmonary function tests (PFTs) are associated with HRCT findings; and 3) which factors predict ILD reduction.MethodsWe semiquantitatively scored total ILD extent, reticulations, and ground‐glass opacities (GGO) scores at baseline and at the 1‐year HRCTs of SSc patients treated with HSCT or CYC. Linear association between changes in HRCT scores and PFT results and predictors of ILD improvement were studied.ResultsWe included 51 patients (those treated with HSCT [n = 20] and those treated with CYC [n = 31]). The mean change in total ILD score was –5.1% (95% confidence interval [95% CI] –10.2, 0.0) in the HSCT treatment group (P = 0.050), and –1.0% (95% CI –4.3, 2.3) in the CYC treatment group (P = 0.535). For all patients, the evolution of HRCT scores was weakly associated with relative changes in PFT results. In univariate logistic regression, higher ground‐glass opacities, higher total ILD, and lower single‐breath diffusing capacity for carbon monoxide scores at baseline predicted improvement of ILD extent after treatment, but a multivariable model could not be built to assess independency of predictors.ConclusionOne year after treatment with HSCT, a nonsignificant but clear reduction of SSc‐ILD extent was observed. Changes in PFT results were associated with changes in HRCT scores but the correlation was weak and cannot be considered conclusive.

A Retrospective Analysis of the Efficacy of Low-Dose Metronomic Cyclophosphamide for Treatment in Patients with Low Grade Non-Hodgkin Lymphoma

BackgroundLow-dose metronomic cyclophosphamide chemotherapy is an emerging strategy offering a potentially less toxic yet effective treatment modality. We evaluated the efficacy and safety of low-dose metronomic cyclophosphamide in patients with low grade non-Hodgkin lymphoma (NHL) by retrospectively reviewing the data.MethodThe patients received oral cyclophosphamide (50 mg per day) and/or oral methotrexate (2.5 mg twice weekly) until disease progression or unacceptable toxicity was noted.ResultsOf the 36 patients, 17 (47.2%) were male, median age was 66.4 years (range, 37-91 years), and subtypes of NHL were mucosa associated lymphoid tissue lymphoma (55.6%), small lymphocytic lymphoma (13.9%), follicular lymphoma (11.1%), mantle cell lymphoma (8.3%), nodal marginal zone lymphoma (4.5%), splenic marginal zone lymphoma (2.8%), and lymphoplasmacytic lymphoma (2.8%). The stage I, II, III, IV were 38.9%, 13.9%, 11.1%, 36.1%, respectively and 55.6% of patients received this regimen as the first-line treatment, mainly due to frailty, refusal to standard chemotherapy.The overall best response rate (ORR) was 73.5% (12 complete responses, CRs and 13 partial responses, PRs), with 29.1 months of the median duration of response and the disease control rate was 88.2%. The median treatment duration was 8.8 months (range, 0.1-38.4 months); the median progression-free survival (PFS) was 43.5 months, and the median overall survival (OS) was not yet reached. Especially, the ORR in patients who were treated with metronomic cyclophosphamide as the first line treatment and as more than the second line treatment were 78.9% (10 CRs, 5 PRs) and 66.6% (2 CRs, 9 PRs), respectively. The median PFS were not reached in the first line cyclophosphamide treatment group and 26.5 months (range, 5.7-47.2 months) in the other group (p=0.110), and similarly, the median OS were not reached and 64.4 months (0-135.7 months) (p=0.058), respectively.The regimen was generally well tolerated, with small numbers of grade 3-4 toxicities; neutropenia (2%), anemia (3%), thrombocytopenia (3%), fatigue (4%), and anorexia (1%).ConclusionWe concluded that low-dose metronomic cyclophosphamide represents efficacious and well-tolerated treatment for low-grade NHL patients. DisclosuresNo relevant conflicts of interest to declare.

Outcome of Canine Multicentric Lymphoma after Single or Divided Treatment with Cyclophosphamide in Multidrug Chemotherapy

Cyclophosphamide is commonly used in combination chemotherapy to treat dogs with lymphoma. The metabolite of cyclophosphamide, acrolein, can irritate urinary bladder and cause sterile hemorrhagic cystitis. Dividing the administration of cyclophosphamide across multiple days may reduce the concentration of this metabolite in urinary bladder and reduce the possibility of cystitis. However, the impact of the therapeutic effect of this modification is not evaluated and compared to traditional single maximum-tolerated dose regimen. Seventy-two dogs with multicentric lymphoma received either bolus doses or divided doses of cyclophosphamide were included in this study. The incidence of hemorrhagic cystitis between 2 cyclophosphamide treatment groups was not significantly different (P = .357). There was no statistical difference in progression-free survival and survival time between 2 groups (P = .267 and P = .346). This modification of cyclophosphamide administration did not reduce the side effect of cystitis or affect remission and survival times in lymphoma dogs.

Cyclophosphamide for connective tissue disease-associated interstitial lung disease.

Cyclophosphamide for connective tissue disease-associated interstitial lung disease.

Immuno-enhancement effect of polysaccharide extracted from Stichopus japonicus on cyclophosphamide-induced immunosuppression mice.

Polysaccharide (SJP) was extracted from Sea cucumber, Stichopus japonicas, and its immune-enhancing activities were evaluated in vivo immune-suppressed mice systems. Cyclophosphamide(CY)-treated mice were orally administrated with SJP according to different concentrations. The results showed that administration of SJP significantly increased spleen index without variation of the body weight, compared to only CY treatment group. The proliferation of splenic lymphocyte and NK activity was also stimulated by SJP. In addition, the oral administration of SJP up-regulated COX-2 and TLR-4 as well as cytokines such as IL-1β, IL-4, IL-6, IL-10, TNF-α and IFN-γ, which are secreted from splenic lymphocytes in cyclophosphamide-treated mice. Moreover, our results showed that SJP stimulated macrophages via NF-κB and MAPK signaling pathways. These findings provided the potential use of SJP as an alternative means under immune-suppressed conditions, and furthermore can be utilized as a functional material for food and pharmaceutical industries.

Effects of Cyclophosphamide and/or Doxorubicin in a Murine Model of Postchemotherapy Cognitive Impairment.

Postchemotherapy cognitive impairment, or PCCI, is a common complaint, particularly among breast cancer patients. However, the exact nature of PCCI appears complex. To model the human condition, ovariectomized C57BL/6J mice were treated intravenous weekly for 4 weeks with saline, 2 mg/kg doxorubicin (DOX), 50 mg/kg cyclophosphamide (CYP), or DOX + CYP. For the subsequent 10 weeks, mice were assessed on several behavioral tests, including those measuring spatial learning and memory. After sacrifice, hippocampal spine density and morphology in the dentate gyrus, CA1, and CA3 regions were measured. Additionally, hippocampal levels of total glutathione, glutathione disulfide, MnSOD, CuZnSOD, and cytokines were measured. Body weight decreased in all groups during treatment, but recovered post-treatment. Most behaviors were unaffected by drug treatment: Open field activity, motor coordination, grip strength, water maze and Barnes maze performance, buried food test performance, and novel object and object location recognition tests. There were some significant effects of CYP and DOX + CYP treatment during the initial test of home cage behavior, but these did not persist into the second and third test times. Density of stubby spines, but not mushroom or thin spines, in the dentate gyrus was significantly decreased in the DOX, CYP, and DOX + CYP treatment groups. There were no significant effects in the CA1 or CA3 regions. CuZnSOD levels were significantly increased in DOX + CYP-treated mice; other hippocampal antioxidant levels were unaffected. Most cytokines showed no treatment-related effects, but IL-1β, IL-6, and IL-12 were slightly reduced in mice treated with DOX + CYP. Although the animal model, route of exposure, and DOX and CYP doses used here were reflective of human exposure, there were only sporadic effects due to chemotherapeutic treatment.

Anti-tumour effects of polysaccharide extracted from Acanthopanax senticosus and cell-mediated immunity.

Acanthopanax senticosus, also known as Siberian ginseng, is widely distributed throughout northern Asia and used in traditional Chinese medicine; it has been reported to prevent a number of diseases. However, the association between the antitumour and immunostimulatory activities of polysaccharide extracted from A. senticosus (ASPS) remains to be elucidated. The aim of the present study was to investigate the anti-tumour and immunomodulatory effects of polysaccharide extracted from ASPS on Crocker sarcoma S180, hepatic carcinoma H22 and uterine cervical carcinoma U14 tumour cell lines implanted in mice. High performance liquid chromatography, gas chromatography and infrared spectroscopy were used to analyse the monosaccharide composition of ASPS. The monosaccharide composition of ASPS (Arabic candy: Xylose: Glucose: Mannose) was 7.1:22.3:7.6:1.0. On day 0, female Kunming mice, were injected subcutaneously with 1×108 tumour cells in 0.2 ml. The inoculated mice were subsequently divided into five groups (10 mice/group) as follows: Model group, treated with normal saline; positive control group, treated with 30 mg/kg cyclophosphamide (CTX); and three treatment groups, treated with 200, 100 or 50 mg/kg ASPS. Non-inoculated mice were divided into the normal group, which was treated with normal saline, and the negative control group, which was treated with 200 mg/kg ASPS (n=10/group). CTX and ASPS were administered intragastrically once daily for 10 days. All mice were sacrificed on day 11. ASPS was observed to have an inhibitory effect on the growth of S180, H22 and U14 cells in solid and ascites tumour-bearing mice. Serum interleukin (IL)-2 and IL-12 levels were significantly increased in S180 solid tumour-bearing mice treated with 200 or 100 mg/kg ASPS compared with mice in the normal, control and model groups (P<0.05), whereas serum IL-2 and IL-12 levels were significantly decreased in the cyclophosphamide treatment group compared with the normal, control and model groups (P<0.05). No significant difference in serum levels of tumour necrosis factor-α level was observed between any groups. In S180 and U14 solid tumour-bearing mice, no significant differences in serum levels of interferon (INF)-γ level in were observed between groups; however, in H22 solid tumour-bearing mice, treatment with ASPS significantly increased serum INF-γ compared with the positive control group (P<0.05). The results may provide a basis for the potential application of ASPS in clinical treatment for cancer.

Cyclophosphamide promotes the proliferation inhibition of mouse ovarian granulosa cells and premature ovarian failure by activating the lncRNA-Meg3-p53-p66Shc pathway

The dysfunction of ovarian granulosa cells (OGCs) directly affects the premature ovarian failure (POF). In vivo experiments showed that cyclophosphamide significantly induced mouse ovarian atrophy and proliferation inhibition of OGCs. The expressions of p53, p66Shc and p16 were significantly higher in OGCs of the cyclophosphamide treatment group. MTT assay showed that cyclophosphamide effectively inhibited the proliferation of OGCs in vitro. SA-β-Gal staining showed that the OGCs in the cyclophosphamide treatment group had many senescent cells. And, the expression of p53, p66Shc, p16 and cleaved caspase-3 in the OGCs of the cyclophosphamide treatment group significant increases. The Northern blot showed that the intensity of the lncRNA-Meg3 hybridization signal of the OGCs in the cyclophosphamide treatment group was significantly higher than that in the control group. ChIP results confirmed the significant increase in the obtained p66Shc promoter DNA fragment, which was enriched on p53 protein, in the OGCs treated with cyclophosphamide. When cyclophosphamide treatment was conducted after siRNA-Meg3 was used, the expression of endogenous lncRNA-Meg3, p53, p66Shc, p16 and cleaved caspase-3 was significantly lower than that in the siRNA-Mock control group. In summary, cyclophosphamide promotes the proliferation inhibition of mouse OGCs and premature ovarian failure by activating the lncRNA-Meg3-p53-p66Shc pathway.

Effect of lactoferrin on some selective immunological parameters in rats immunosuppressed by cyclophosphamide

Eighty male albino rats (350±10 g) 10 to 12 weeks old were conducted in our study. Rats were randomly divided into four, equal groups. The groups treated as following: 1st control group (Gp. A) was given intraperitoneal normal saline (1 mL). 2nd group (Gp. B) was given a single intraperitoneal dose (250 mg/kg body weight) of Cyclophosphamide (CP) on the first day of the experimental period. 3rd group (Gp. C) CP and lactoferrin (LF) treated group. 4th group (Gp. D) administrated LF only (0.5%) in drinking water. Two separate blood samples were collected from heart puncture at end of 1st and 3rd week post treatment for hematological, biochemical and immunological studies. The leukogram of CP treatment group showed severe leucopenia (lymphopenia, neutropenia as well as eozinopenia) as well as decrease total protein and albumin blood level. Immunosuppressive effect of CP is documented in our work by decrease gamma globulin and elevation tumor necrosis factor Alfa (TNF ά). This study revealed that oral treatment with LF can partially

Treatment of Scleroderma-Interstitial Lung Disease With Cyclophosphamide Is Associated With Less Progressive Fibrosis on Serial Thoracic High-Resolution CT Scan Than Placebo: Findings From the Scleroderma Lung Study

The Scleroderma Lung Study (SLS) demonstrated significant treatment-associated improvements in pulmonary function and symptoms when patients with scleroderma-related interstitial lung disease (SSc-ILD) were treated with a 1-year course of cyclophosphamide (CYC) in a randomized, double-blinded, placebo-controlled clinical trial. This study examined thoracic high-resolution CT (HRCT) scans obtained during the SLS for treatment-associated changes over time. Ninety-eight of the 158 subjects (CYC group, 49 subjects; placebo group, 49 subjects) participating in the SLS underwent thoracic HRCT scans both at baseline and after 12 months of treatment, which were available for analysis. Two independent radiologists visually scored the baseline HRCT scans for the presence of ground-glass opacities (GGOs), fibrosis (FIB), and honeycomb cysts (HCs) on a scale of 0 to 4. The treatment effect at 12 months was assessed by a blinded comparison of baseline and follow-up scans for evidence of stability and improvement (not worse) or deterioration (worse). At the end of treatment, FIB was significantly worse in the placebo treatment group than in the CYC treatment group (p = 0.014). Furthermore, differences in the 12-month change in FIB between the CYC and placebo groups correlated significantly with other outcome measures, including the 12-month changes in FVC (p < 0.05), total lung capacity (p < 0.05), and dyspnea (p < 0.001) scores. However, no differences were noted between the two groups with respect to changes in either GGOs or HCs. A 1-year course of treatment of SSc-ILD with CYC was associated with treatment-related changes in FIB scores on HRCT scans, which correlated with other measures of treatment response. ClinicalTrials.gov Identifier: NCT00004563.

Reversibility of the effects of chronic paternal exposure to cyclophosphamide on pregnancy outcome in rats

Low-dose chronic treatment of the male rat with the antitumor drug cyclophosphamide causes a time-and dose-dependent increase in pre- and post-implantation loss in the untreated females to which he is mated. The objective of the present was to determine whether such effects are reversed, and if so at what time after cessation of drug treatment. Adult male Sprague-Dawley rats were gavage fed daily, 6 time per week for 9 weeks, with saline (control) or with 1 of 3 doses of cyclophosphamide, 1.4, 3.4 or 5.1 mg/kg/day. After the 9 weeks of treatment and at 2-week intervals thereafter, each male was mated with 2 females in proestrus. The female were caesarian sectioned 20 days later and pregnancy outcome assessed. After 9 weeks of drug treatment, pre-implantation loss increased more than 3-fold from 6% in the control group to 21% in the 5.1 mg/kg/day cyclophosphamide treatment group. Post-implantation loss increased in a dose dependent fashion from 5% in the control group to 74% in the 5.1 mg/kg/day cyclophosphamide treatment group. Pre-implantation loss rapidly decreased ceasstion of treatment with cyclophosphamide: within 2 weeks it had returned to within the control range. Within just 2 weeks after termination of drug treatment in the 5.1 mg/kg/day cyclophosphamide treatment group, post-implantation loss decreased by half to 44%; it had decreased to 11% by 4 weeks and then was maintained at 4–6% thereafter. In the 3.4 mg/kg/day cyclophosphamide treatment group, post-implantation loss returned to the control range by 4 weeks. Thus, the effects of paternally administered cyclophosphamide on progency outcome are reversible. The timing of reversal suggests that the effects on pre-implantation loss are due to a drug effect on spermatozoa either in the epididymis or near the time of spermiation while these on post-implantation loss are due to an additional effect on spermatids in the seminiferous tubules.

Occurrence of epidermal growth factor receptors in human adnexal tumors and their prognostic value in advanced ovarian carcinomas

Ninety-eight different malignant adnexal tumors were analyzed for the presence of epidermal growth factor (EGF)-specific binding sites and binding parameters were calculated by Scatchard plot analysis [G. Scatchard, Ann. N.Y. Acad. Sci. 51, 660–672 (1949)]. Thirty-four biopsies were EGF receptor (EGF-R) positive with dissociation constants ( K D ) of 0.5–12 × 10 −9 M and binding capacities ( B max) of 2–250 fmol/mg. One tumor had a K D of 60 × 10 −9 M and a B max of 1660 fmol/mg. The correlation of EGF-R status with clinical parameters showed no significant differences in primary, metastatic, or recurrent tumors, histological subtype, tumor differentiation, and tumor residual after primary surgery. As an inverse correlation, EGF-R-positive tumors are 39% and EGF-R-negative tumors 60% progesterone receptor positive. A response to chemotherapy was noticed in 50% of EGF-R-positive ovarian carcinomas with a mean survival time of patients of 28 months. The response rate of EGF-R negative ovarian carcinomas was 12% with a mean survival time of 16 months. Regarding the treatment schedule the major differences were noticed in the cis-platinum plus cyclophosphamide treatment group. These results suggest that the biology of ovarian carcinomas is influenced by growth factors and their receptors, which can be used as prognostic factors.

Effects of cyclophosphamide alone and scheduled methotrexate-5-fluorouracil combination chemotherapy on transplantable R-3327 prostatic adenocarcinoma in F 1 hybrid male rat

Male F 1 hybrid rats bearing the R-3327 transplantable adenocarcinoma demonstrating similar growth patterns within the original sample of animals were carefully separated into control and treatment groups for each growth pattern. This assured treatment of tumors with similar cell kinetics within each group. In one group, cyclophosphamide (100 mg/kg) was injected intraperitoneally once every four weeks for eight weeks (total of two doses). In the second group, methotrexate (7.5 mg/kg) followed in ninety minutes by 5 fluorouracil (50 mg/kg) were injected intraperitoneally once each week for eight weeks (total of eight doses). These drug dosages did not depress the white cell count of the animals, and they tolerated the medicines well. Excellent suppression of tumor growth was obtained in each group with the cyclophosphamide treatment group being significant at the 0.01 level and the methotrexate-5 fluorouracil treatment group being significant at the 0.05 level.