Suppression of basal plasma cortisol and adrenal androgen concentrations, but not of ACTH and cortisol responses to hCRH by low-dose dexamethasone in rhesus monkeys

Glucocorticoid treatment at replacement doses does not result in a suppression of ACTH and cortisol responses to corticotropin-releasing hormone (CRH), while basal plasma concentrations of cortisol and adrenal androgens are efficiently suppressed 34 h after starting treatment. This finding could be demonstrated in rhesus monkeys receiving a continuous infusion of dexamethasone (1 microgram/kg per h) for 48 h and confirms our observations in patients on alternate-day prednisone therapy and in patients with congenital adrenal hyperplasia on glucocorticoid replacement therapy. We conclude that the decrease of basal adrenal steroid secretion resulting from glucocorticoid replacement therapy represents an effect on hypothalamic rather than on pituitary function.     

Cyclophosphamide Therapy in the Nephrotic Syndrome in Childhood

Forty-six children with the nephrotic syndrome whose renal biopsy specimens showed minimal changes and whose response to corticosteroid therapy was unsatisfactory were treated with cyclophosphamide. Three patients were completely steroid-resistant from the outset and the remainder were steroid-dependent. In several patients steroids controlled the condition less effectively with time. Most patients showed signs of steroid toxicity, and growth retardation was striking.A moderate leucopenia was induced with cyclophosphamide, and treatment was maintained for three to four months in the majority of cases. Thirty-eight children (83%) have remained in complete remission off all treatment for periods of 3 to 23 months, 33 after one course of cyclophosphamide and five after a second course. Two other patients who remitted but relapsed later are still on treatment. In only six patients was full remission not obtained, and three of these were steroid-resistant from the start. Two died from pneumonia and adrenal failure and four continued to have proteinuria, though in one an impressive reduction occurred.The results indicate that cyclophosphamide therapy is an effective alternative for nephrotic children with normal glomeruli on light microscopy who develop steroid dependence or resistance, and who exhibit toxic effects of steroid therapy.     

High-dose combination alkylating agents with autologous bone-marrow support in patients with breast cancer: preliminary assessment of DNA damage in individual peripheral blood lymphocytes using the single cell gel electrophoresis assay

The single cell gel (SCG) assay is a sensitive electrophoretic technique for detecting the presence of DNA single strand breaks and alkali-labile damage in individual cells. This technique was used to evaluate the levels of DNA damage in cryopreserved peripheral blood lymphocytes (PBLs) from 11 breast cancer patients treated with high doses of cyclophosphamide and cisplatin and provided autologous bone marrow transplantation after treatment. PBL specimens for the SCG study were obtained just prior to treatment, following the administration of cyclophosphamide and cisplatin for 2 days, and upon lymphocytic recovery. Based on a concurrent analysis of DNA damage in cryopreserved and noncryopreserved PBL samples from three patients, the mean level of DNA migration or the dispersion of damage among cells was not affected by the process of cryopreservation. The pre-treatment samples of several patients contained PBL with increased levels of DNA damage, presumably reflecting persistent DNA damage induced by previous treatment regimens. Chemotherapy resulted in a significant but variable increase in DNA damage in PBL samples from all patients. In this limited study, the level of damage did not correlate with serum levels of cyclophosphamide or with lymphocyte toxicity. Among the post-treatment samples, increased levels of DNA damage were absent in most but not all patients. The presence of damaged cells in the post-treatment samples may be indicative of an inadequate therapy regimen or of DNA damage resulting from non-therapy related processes. Because of its simplicity and short processing time, the SCG assay can be used to evaluate levels of DNA damage during the course of therapy, allowing the dose schedule to be altered to achieve a desired effect level.     

Effects of acute and chronic cyclophosphamide treatment on meiotic progression and the induction of DNA double-strand breaks in rat spermatocytes

Male rats treated with cyclophosphamide, an alkylating agent commonly used clinically in both acute and chronic regimens, present with damaged male germ cells and abnormal progeny outcome. The extent and type of damage induced by cyclophosphamide largely depend on the germ cell type exposed to the drug and its ability to respond to insult. In the present study, the response of pachytene spermatocytes to damage was evaluated by assessing their ability to undergo meiotic G2/MI transition following exposure to acute or chronic cyclophosphamide. Male rats were given an acute high dose (70 mg/kg, once) or chronic low doses (6 mg/kg, daily for 5-6 wk) of cyclophosphamide. Pachytene spermatocytes were isolated, cultured, and induced to undergo G2/MI transition with okadaic acid. To determine the effect of DNA damage on meiotic progression, induction of DNA double-strand breaks was detected after each treatment regimen by the formation of foci of phosphorylated histone H2AX. The transition from G2 to MI was impaired after acute cyclophosphamide treatment; this impairment in the progression of pachytene spermatocytes was correlated with extensive DNA double-strand breaks. In contrast, despite the presence of significant levels of DNA damage, meiotic progression was not impaired in spermatocytes after chronic cyclophosphamide exposure. We suggest that the cell cycle impairment induced after acute cyclophosphamide treatment could be mediated by a G2/M checkpoint activated in response to DNA damage. The absence of impairment after chronic treatment raises concern about the functionality of defense mechanisms in male germ cells after repeated exposure to low doses of genotoxic agents.     

Sister chromatid exchange studies for monitoring DNA damage and repair capacity after cytostatics in vitro and in lymphocytes of leukaemic patients under cytostatic therapy.

The effect of various cytostatic drugs was studied on the frequency of sister chromatid exchanges (SCEs) in vitro and in PHA-stimulated lymphocytes of leukaemic patients under cytostatic therapy. The lymphocyte system is a sensitive one for the detection of DNA damage after administration of cytostatic drugs in vitro. Mitomycin C, busulphan, vincristine, chlorambucil, cytosine arabinoside, cyclophosphamide and lycurim were tested. All except cyclophosphamide induced high frequencies of SCEs in the first mitosis after their administration. The experiments with PHA-stimulated lymphocytes in vivo from patients treated with cytostatics showed that cytosine arabinoside, in combination with thioguanine, did not induce higher frequencies of SCEs, whereas in patients who were treated with cyclophosphamide alone or in combination with other cytostatic drugs, there was a higher incidence of SCEs during treatment. About 10 days after the termination of the treatment the elevated freuqencies of SCEs returned to the initial level. After administration of some mutagens, especially alkylating agents in vivo, the lymphocyte system can be used to assess induced DNA repair by continuously monitoring for SCEs.     

Obituaries

The outcome in 110 patients first treated with radioiodine (mean dose 6.56 mCi) for hyperthyroid Graves'' disease in 1980 was reviewed. In 23% of the patients the disease had not been controlled by the initial dose after 3 months, and 17% were given one or two more doses. Within 2 years 65% of the patients required replacement thyroxine therapy. Although about half of the patients were biochemically hypothyroid 3 months after the last dose of iodine 131, this condition was transient in a third of them; five of these patients even became hyperthyroid again. Patients with transient, as opposed to permanent, hypothyroidism at 3 months tended to be clinically euthyroid but to have residual palpable thyroid tissue and only a modest reduction in the serum thyroxine level. It is therefore recommended that patients not overtly hypothyroid 3 months after treatment with 131I be observed still longer before thyroxine replacement therapy is instituted.     

High-dose combination alkylating agents with autologous bone-marrow support in patients with breast cancer: preliminary assessment of DNA damage in individual peripheral blood lymphocytes using the single cell gel electrophoresis assay.

The single cell gel (SCG) assay is a sensitive electrophoretic technique for detecting the presence of DNA single strand breaks and alkali-labile damage in individual cells. This technique was used to evaluate the levels of DNA damage in cryopreserved peripheral blood lymphocytes (PBLs) from 11 breast cancer patients treated with high doses of cyclophosphamide and cisplatin and provided autologous bone marrow transplantation after treatment. PBL specimens for the SCG study were obtained just prior to treatment, following the administration of cyclophosphamide and cisplatin for 2 days, and upon lymphocytic recovery. Based on a concurrent analysis of DNA damage in cryopreserved and non-cryopreserved PBL samples from three patients, the mean level of DNA migration or the dispersion of damage among cells was not affected by the process of cryopreservation. The pre-treatment samples of several patients contained PBL with increased levels of DNA damage, presumably reflecting persistent DNA damage induced by previous treatment regimens. Chemotherapy resulted in a significant but variable increase in DNA damage in PBL samples from all patients. In this limited study, the level of damage did not correlate with serum levels of cyclophosphamide or with lymphocyte toxicity. Among the post-treatment samples, increased levels of DNA damage were absent in most but not all patients. The presence of damaged cells in the post-treatment samples may be indicative of an inadequate therapy regimen or of DNA damage resulting from non-therapy related processes. Because of its simplicity and short processing time, the SCG assay can be used to evaluate levels of DNA damage during the course of therapy, allowing the dose schedule to be altered to achieve a desired effect level.     

Investigations into sister chromatid exchange in patients under cytostatic therapy

Summary In vivo sister chromatid exchange (SCE) determinations were carried out in patients with Psoriasis vulgaris under methotrexate therapy and patients with histologically verified bronchial carcinoma under cyclophosphamide, methotrexate or a combined chemotherapy. A pronounced increase in SCE rate was only found after cyclophosphamide treatment.Abbreviation Cyclo cyclophosphamide - MTX methotrexate - FU fluorouracil - Pred prednisolone - VB vinblastine - VC vincristine - BM bleomycin     

MACOP-B chemotherapy for the treatment of high grade and intermediate grade non Hodgkin's lymphoma.

Between Nov. 1985 and Nov. 1988, sixty-three patients with high grade malignant (hg) and intermediate grade malignant (img) Non Hodgkin's Lymphoma (NHL) were treated with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin). Thirty-seven patients received MACOP-B as an upfront treatment modality, whereas twenty-six patients had relapsed disease and received MACOP-B as a salvage protocol. Four weeks after termination of therapy, 75% of patients with de novo NHL and 72% of the patients with relapsed NHL were in complete remission (CR). In the group of newly diagnosed NHL, 22% achieved partial remission (PR) and 3% no change (NC), whereas in the group with relapsed disease 14% had PR and 14% had progressive disease (PD). At a medium follow-up of 12 months (range 1 month to 33 months), 74% of patients with de novo NHL continued to be in CR whereas the continuous CR rate in patients with relapsed disease was 35%. Overall survival after 30 months of observation for the patient group with de novo NHL was 75% and 40% for patients with relapsed NHL. The mean duration for completion of the projected 12 chemotherapy cycles, given in weekly intervals, was 12.9 and 13.5 weeks in upfront or salvage therapy, respectively. With low incidence of major toxicities, application of drugs on an outpatient basis, and high efficacy, MACOP-B shows substantial advantages for therapy of de novo and relapsed NHL.     

Raised plasma glutathione S-transferase values in hyperthyroidism and in hypothyroid patients receiving thyroxine replacement: evidence for hepatic damage.

Using plasma glutathione S-transferase measurements hepatocellular integrity was assessed in groups of hyperthyroid and hypothyroid patients before and after treatment. Ten of 14 hyperthyroid patients had clearly raised plasma glutathione S-transferase values at presentation and in each patient treatment with either iodine-131 or carbimazole resulted in a significant fall in glutathione S-transferase. The eight hypothyroid patients had normal glutathione S-transferase values at presentation and all showed a significant increase in these after thyroxine replacement therapy. In three of these patients in whom standard doses of replacement therapy were associated with a raised free thyroxine (T4) concentration but normal total and free triiodothyronine (T3) values glutathione S-transferase was increased. Similar though less consistent changes were seen in the results of standard chemical tests of liver function. It is concluded that hyperthyroidism may produce subclinical liver damage in a high proportion of patients and that this resolves with effective treatment. More important, the data suggest that hypothyroid patients receiving thyroxine replacement therapy may have similar subclinical liver damage. Patients receiving thyroxine should be monitored by the measurement of free, not total hormone concentrations, and in those in whom free T4 is raised the dose of thyroxine should be reduced. It would also be expedient to include periodic biochemical assessment of liver function in patients receiving thyroxine.     

Acute lymphoblastic leukemia: a comprehensive review and 2017 update

Remission rates remain low among adult patients with relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph⁻ ALL). The standard 4-week reduction chemotherapy regimen cannot be administered due to serious hematopoietic toxicity and infection during induction therapy, which can decrease the elimination of blast cells. In this study, a modified shortened P-CIOD chemotherapy protocol (comprising pegaspargase, cyclophosphamide, idarubicin, vindesine, and dexamethasone) was used as a reinduction therapy for relapsed Ph⁻ ALL. Remarkably, 80% (4 out of 5) of the patients achieved complete remission (CR) with minimal residual disease (MRD) negativity and without treatment-related mortality. Two patients were lost to follow-up after consolidation treatment, while the remaining three patients survived. The longest disease-free survival (DFS) recorded was 27 months. The results suggest that the novel protocol shows a favorable second complete remission (CR2) with low toxicity for adult patients with relapsed Ph⁻ ALL.     

Prevention of chemotherapy-induced alopecia in rodent models

Alopecia (hair loss) is experienced by thousands of cancer patients every year. Substantial-to-severe alopecia is induced by anthracyclines (e.g., adriamycin), taxanes (e.g., taxol), alkylating compounds (e.g., cyclophosphamide), and the topisomerase inhibitor etoposide, agents that are widely used in the treatment of leukemias and breast, lung, ovarian, and bladder cancers. Currently, no treatment appears to be generally effective in reliably preventing this secondary effect of chemotherapy. We observed in experiments using different rodent models that localized administration of heat or subcutaneous/intradermal injection of geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin induced a stress protein response in hair follicles and effectively prevented alopecia from adriamycin, cyclophosphamide, taxol, and etoposide. Model tumor therapy experiments support the presumption that such localized hair-saving treatment does not negatively affect chemotherapy efficacy.     

Clinical trial with long-term therapy of generalized plasmacytoma]

The authors report on findings in long-term therapy made by means of a combination of cyclophosphamide as attack dosis (partially also with polychemotherapy--COP, COPP-scheme) and double plasmapheresis. Since 1967 33 patients have been treated in this way. A group (6 patients) only received cyclophosphamide in a attack therapy of 15...25 mg/5g per body weight; a second group of 14 patients received the same dosis in combination with a double plasmapheresis. The third group of 13 patients in an advanced stage of the illness was treated polychemotherapeutically according to various schemes (COP-cyclophosphamide, vincristine, prednisone; COPP with Natulan) likewise in combination with double plasmapheresis. The observations made for 4 years in the two groups first mentioned showed favourable results in the second group with an average survival time of 35 months. In the third group only experiences of two years can be reported and thus a final answer cannot be given. However, it can already be stated that a clinical success requires the cytostatic therapy to be continued for a long time in combination with plasmapheresis.     

Combined radiation and chemotherapy in posttransplant lymphoproliferative disorder

The optimal treatment for posttransplant lymphoproliferative disorder which has progressed despite a reduction in immunosuppression has not been defined. We report on two patients with stage I posttransplant lymphoproliferative disorder who developed progressive disease despite a reduction in the level of immunosuppression. Both patients were treated with combined short course CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed by involved-field radiation therapy. In both patients, a rapid response was obtained followed by complete remission. Combined modality therapy can be utilized successfully in progressive limited stage posttransplant lymphoproliferative disorder.     

Extensive intraglomerular fibrin deposition after renal transplantation: recovery without anticoagulation.

Acute renal failure developed in a 55-year-old man 6 days after he had received a cadaver renal allograft. This was associated with thrombocytopenia. Extensive intraglomerular fibrin deposition was seen in a renal biopsy specimen. He was treated with corticosteroids, azathioprine, cyclophosphamide and hemodialysis with regional heparinization but not with systemic anticoagulation. This was followed by complete recovery of both renal function and histologic damage despite the fact that he did not receive anticoagulant therapy. This suggests that treatment with anticoagulants may not be necessary for all patients with intraglomerular deposits of fibrin.     

Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies

Introduction

The purpose of the present study was to systematically review the effect of cyclophosphamide treatment on pulmonary function in patients with systemic sclerosis and interstitial lung disease.

Methods

The primary outcomes were the mean change in forced vital capacity and in diffusing capacity for carbon monoxide after 12 months of therapy in patients treated with cyclophosphamide.

Results

Three randomized clinical trials and six prospective observational studies were included for analysis. In the pooled analysis, the forced vital capacity and the diffusing capacity for carbon monoxide predicted values after 12 months of therapy were essentially unchanged, with mean changes of 2.83% (95% confidence interval = 0.35 to 5.31) and 4.56% (95% confidence interval = -0.21 to 9.33), respectively.

Conclusions

Cyclophosphamide treatment in patients with systemic sclerosis-related interstitial lung disease does not result in clinically significant improvement of pulmonary function.     

Selective restoration of immunosuppressive effect of cytotoxic agents by thymopoietin fragments

Summary Swiss male mice were immunosuppressed by cyclophosphamide, cisplatinum, vincristine and methotrexate. The ability of the thymopoietin (TP) fragments TP-3, TP-4 and TP-5 to restore antibody production and phagocytosis was studied. Impaired antibody production after vincristine treatment was partially or totally restored by TP-3, TP-4 or TP-5. Only TP-3 or TP-5 interfered with the antibody-production-damaging effect of cisplatinum. The same effect of methotrexate could not be influenced by any of the TP fragments. The phagocytic capacity of peritoneal macrophages was reduced by vincristine, methotrexate and cyclophosphamide treatment. In this respect, TP-3 protected the function of macrophages against vincristine and cyclophosphamide treatment. TP-4 was active in the case of damage caused by vincristine and methotrexate, and TP-5 interfered with the phagocytosis-inhibiting effect of methotrexate. Each TP fragment seems to have a specific target orientation within the immune system. This also means that the proper TP fragment should always be chosen for combination therapy with various types of cytotoxic drugs.     

An inhibitor in the Willebrand-Jürgens syndrome and its effect on the factor VIII molecule properties]

In a patient with a clinically serious Willebrand-Jürgen's syndrome an inhibitor appeared at the age of 1 1/2 years, which, contrary to inhibitors in haemophilia A, was directed against all properties of factor VIII molecule. In a quantitative test the height of the inhibitor level to factor VIIIag was determined. Administrations of plasma concentrate resulted in a titre increase which could not be suppressed even by an immunosuppressive therapy with cyclophosphamide. After a long break in the substitution a severe bleeding could be successfully treated and the substitution effect for factor VIIIc, factor VIIIag and Ristocetin co-factor could be identified for several days.     

Intradermal administration of lipopolysaccharide in treatment of human cancer

 Lipopolysaccharide (LPS) has been recognized as a potent antitumor agent in animal tumor models; however, its use in human cancer therapy has been limited to only one trial, in which LPS from Salmonella was given intravenously. It was not very successful because of poor tumor response and was also toxic. We originally developed LPS prepared from Pantoea agglomerans (LPSp), and this was a well-purified, small-molecular-mass (5 kDa) agent. We chose intradermal rather than intravenous administration in the hope that the former would release LPS slowly into the bloodstream, and thus be less toxic while preserving antitumor activity. In our animal tumor models, intradermal administration was indeed less toxic and more beneficial for tumor regression than intravenous administration. We made a pilot study with intradermal administration of LPSp on the treatment of ten advanced cancer patients. Five of them had evaluable tumor, which had failed earlier to respond to conventional chemotherapy. Cyclophosphamide was also administered in this trial, in anticipation of its synergistic effect with LPSp. In this study LPSp was injected intradermally into each patient twice a week, starting with an initial dose of 0.4 ng/kg, and raising it to 600 or 1800 ng/kg. A 400-mg/m² dose of cyclophosphamide was given intravenously every 2 weeks. After completion of the dose escalation, the treatment was continued for at least 4 months, and it was found that 1800 ng/kg LPSp was well tolerated. A significant level of cytokines was observed in the sera for at least 8 h. These results indicate higher tolerable doses and remarkably more continuous induction of the cytokines than were reported in a previous study by others using intravenous administration. Three of the five evaluable tumors showed a significant response to our combined therapy. Intradermally administered, LPS was less toxic and elicited a tumor response in combination with cyclophosphamide; it can thus can be applied to cancer treatment even in humans. Received: 3 August 1995 / Accepted: 2 April 1996     

Metronomic cyclophosphamide regimen selectively depletes CD4<Superscript>+</Superscript>CD25<Superscript>+</Superscript> regulatory T cells and restores T and NK effector functions in end stage cancer patients

CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.