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PubMed1996

Treatment of children and adolescents with Hodgkin's disease: the experience of the German-Austrian Paediatric Study Group.

In treatment strategies adapted to the specific problems in children with Hodgkin's disease (HD) high priority has been given to the reduction of late effects caused by radio- and chemotherapy, without sacrificing high survival rates. Combined modality treatment, as a standard option, has enabled reduced doses and fields of radiotherapy and lower cumulative total doses of critical cytotoxic agents. In Germany and Austria 1242 children and adolescents with HD have been treated in five consecutive multicentre studies since 1978. The main general objectives were to determine the extent to which radio- and chemotherapy can be reduced within a combined modality treatment concept and to find an effective chemotherapy of low long-term toxicity. Mechlorethamine in MOPP was replaced by adriamycin (OPPA) in the first 2 cycles of CT and by cyclophosphamide (COPP) in the additional cycles. The total number of cycles was reduced for early and intermediate stages. From the second study (HD-82) onward, patients were allocated to three treatment groups (2, 4 or 6 cycles, respectively) according to disease stage, and involved-field instead of extended-field irradiation was given. With radiation doses of 35, 30 and 25 Gy, high rates for event-free survival (97, 92 and 85%, respectively) at 14 years were achieved, demonstrating that microfoci in adjacent fields are safely eradicated by the chemotherapy used. Late effects of OPPA and OPPA/COPP: the cumulative risk of secondary leukaemias in 686 patients after 15 years was 0.9% for all patients and 0.8% for those who remained in first remission. Cardiomyopathies have not been observed (cumulative total dose of adriamycin 160 mg/m2). Increased FSH-levels indicating impaired spermatogenesis were found in 40% of the male patients without relapse. The prevalence was related to the number of procarbazine containing cycles (29% after 2 cycles, 46% after 4, and 63% after 6). In study HD-90, procarbazine in OPPA was replaced by etoposide (OEPA) for the boys (cumulative dose 1000 mg/m2), whereas girls received OPPA again. In TGs 2 and 3, both boys and girls received an additional 2 or 4 COPP cycles. Standard doses of involved-field irradiation were reduced to 25, 25 and 20 Gy. The preliminary evaluation after nearly 5 years reveals that the reduction in radiation doses did not affect the results with OPPA and OPPA/COPP chemotherapy. In localized stages, 2 OEPA (boys) and 2 OPPA (girls) cycles produced identical results. An additional objective of the German-Austrian trials was to re-evaluate the relevance of exploratory laparotomy and splenectomy within a combined modality treatment concept for all patients. While all children were laparotomized and splenectomized in the first study, the frequency of splenectomy and laparotomy was reduced step by step on the basis of retrospective analyses of the study data regarding infra-diaphragmatic involvement. Splenectomy has been completely abandoned since 1990. In conclusion, the ratio of cure rates and late effects has been favourably balanced with OPPA and OPPA/COPP plus low-dose involved-field irradiation, especially in female patients. In boys, the risk of testicular dysfunction can be further reduced by substituting OEPA for OPPA. Age up to 18 years does not appear to bear any prognostic significance for the treatment results under the conditions of the therapy concept described.

Adolescent↗
PubMed1996

Risk of acute myelogenous leukaemia and myelodysplasia following cancer treatment.

Now that a substantial group of cancer patients has such a favourable prognosis, it has become increasingly important to evaluate the long-term complications of treatment. Of all late effects of treatment, secondary leukaemia is one of the most serious. Increased risk of AML has been observed both after RT and after CT; however, several types of CT have much stronger leukaemogenic properties than RT. Limited field radiation in the therapeutic dose range is associated with very little or no increased risk of leukaemia, which has been attributed to cell killing at the higher radiation doses. With respect to CT, two different syndromes of treatment-related AML have been recognized. Risk of alkylating agent-related AML is highest in the 5-10 year follow-up period and seems to decrease afterwards. This type of leukaemia is often preceded by MDS, and is characterized by deletions of chromosomes 5 and 7. Leukaemias related to treatment with the topoisomerase II inhibitors are characterized by a short induction period, presentation as myelomonocytic or monocytic leukaemia (rather than MDS) and balanced chromosomal translocations involving bands 11q23 and 21q22. This review addresses the risk of secondary AML and MDS following treatment of HD, NHL, testicular cancer, ovarian cancer, breast cancer and paediatric malignancies. In patients with HD, the risk of AML is higher with an increasing number of mechlorethamine-procarbazine-containing cycles, a greater number of CT episodes, and after splenectomy. The majority of data shows that RT does not add to the leukaemia risk from CT, but this issue is still surrounded by some controversy. ABV(D)-treated patients have a very low risk of AML. Generally, patients with NHL, testicular cancer and breast cancer experience much lower risk of AML than patients with HD. NHL and breast cancer treatment regimens with cumulative cyclophosphamide doses of 20 g or less do not confer an appreciable increase of AML. Recently, strongly increased AML risk has been observed following autologous bone marrow transplantation and other dose intensification strategies. Risk factors for this excess remain to be defined. PVB treatment for testicular cancer is not followed by increased leukaemia risk, but modern etoposide-containing regimens do confer excess risk, of which the magnitude at conventional drug doses is not yet well known. High risk of leukaemia has been reported in children treated with epipodophyllotoxins. The leukaemogenic hazards of cancer treatment should be weighed against their therapeutic benefits.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Diepoxybutane cross-links DNA at 5'-GNC sequences.

Epoxides are cancer-causing agents chemically analogous to the nitrogen mustards, a family of powerful antitumor drugs. We found that the DNA interstrand cross-linking sequence preference of diepoxybutane is the same as that of the mustard mechlorethamine: 5'-GNC. Therefore, the genomic site of cross-linking alone cannot explain why some interstrand cross-linkers act as antitumor agents whereas others are deadly toxins.

Base Sequence↗
PubMed2005

DNA damage by fasicularin.

Fasicularin is a structurally novel thiocyanate-containing alkaloid isolated from the ascidian Nephteis fasicularis. Early biological experiments suggested that this compound's cytotoxic properties may stem from its ability to damage cellular DNA. Sequence gel analysis reveals that treatment of a 5'-32P-labeled DNA duplex with fasicularin in pH 7.0 buffer causes strand cleavage selectively at guanine residues. Further experiments indicate that production of these base-labile lesions in DNA involves alkylation of guanine residues by a fasicularin-derived aziridinium ion. This work reveals fasicularin as the first natural product found to generate a DNA-alkylating aziridinium ion via a mechanism analogous to the clinically used anticancer drugs mechlorethamine, melphalan, and chlorambucil.

Base Sequence↗
PubMed1987

Linear free energy relationships and cytotoxicities of para-substituted 2-haloethyl aryl selenides and bis(2-chloroethyl) selenides.

Examples of a new class of alkylating agents, selenium mustards, were prepared for study of their chemical kinetic properties and cytotoxicities against human lymphoblastoid CCRF-CEM cells. In a series of para-substituted aryl 2-chloroethyl selenides, a linear free energy relationship between the first-order rate constant, k'nbp and sigma p gave a rho value of -1.3, indicating that formation of a cyclic ethylene selenonium ion is the rate-controlling step for alkylation of 4-(4-nitrobenzyl)pyridine (NBP). Consistent with the ethyleneselenonium ion pathway, rates of solvolyses were extremely sensitive to increasing water content, and a positive correlation was found between reactivity with NBP and nucleophilic selectivity (Swain-Scott s constant). The s constant, which predicts for variation in intracellular product spread, varied from 0.53 up to 0.95, equal to aliphatic nitrogen mustards. Alkylating activities based on extent of NBP alkylation, however, showed relatively low values, 8-23% of that of mechlorethamine, possibly due to hydrolysis occurring by a separate pathway from nucleophilic substitution. Reactivities and nucleophilic selectivities both showed positive correlations with cytotoxicities, suggesting that the rate and extent of alkylation of relatively strong nucleophilic centers mediate the biologic effects of these compounds. Two bifunctional selenium mustards were substantially more cytotoxic than monofunctional aromatic selenides. No additional cytotoxicity due to the selenium atom was observed, with the exception of diselenide (-SeSe-) compounds. Thus, selenium alkylating agents kinetically and biologically resemble classical, mustard-type alkylating agents.

Alkylating Agents↗
PubMed1991

Studies in phlebitis: detection and quantitation using a thermographic camera.

A new method for the detection of acute phlebitis in superficial veins is investigated. A thermographic camera is utilized for the quantitation of temperature changes in a rabbit ear model. A control group receiving no injection is compared against each of five treatment groups receiving these commercially available parenterals: amiodarone hydrochloride, phenytoin sodium, mechlorethamine hydrochloride, cephalothin sodium, and diazepam. The vehicles of the above-mentioned drugs as well as several commonly used organic cosolvents are also investigated. Local tissue responses to the parenteral challenges are measured and a good correlation between the visual and the thermographic data was seen.

Animals↗
PubMed2003

Early and intermediate stage Hodgkin's lymphoma--report from the Swedish National Care Programme.

In Sweden a National Care Programme provides treatment principles for Hodgkin's lymphoma (HL) since 1985, for early and intermediate stages often less extensive than international recommendations. The purpose is to evaluate long-term results of these principles. A total of 308 patients (167 men and 141 women), 17-59 yr old (median 31), diagnosed during 1985-92, pathological stage (PS) I-III1A and I-IIB and clinical stage (CS) I-IIA, mean follow-up 8.8 yr, were studied. Staging laparotomy was recommended in CS IIA. Recommended treatment was mantle or mini-mantle radiotherapy (RT) alone in CS IA, and PS I-IIA and subtotal nodal irradiation in PS III1A if the disease was not bulky. Patients in PS I-IIA and III1A with bulky disease, and PS I-IIB received one cycle of mechlorethamine, vincristine, prednisone, procarbazine/doxorubicin, bleomycin, vinblastine, lacarbazine (MOPP/ABVD) before irradiation. The remaining patients received three to four cycles of MOPP/ABVD with RT to bulky disease. Relapse-free (RFS), Hodgkin specific (HLS), and overall survival (OS) at 10 yr were 74%, 92% and 85%. In the individual stages, RFS ranged from 53% (PSIII1A) to 90% (PS IA). RFS (P = 0.006), HLS, and OS were significantly better in patients treated with chemotherapy compared with those treated with RT alone, especially in patients with bulky disease (P = 0.0005). The international prognostic score did not provide any prognostic information. The OS rates are in agreement with results from international centres during that time. The recommended treatment was sufficient to produce the desired results of <20-30% recurrences, except in PS III1A. Most relapses could be salvaged. Patients with risk factors treated with one MOPP/ABVD and RT had an excellent outcome, superior to those without risk factors treated with RT alone. These results favour the trend to treat early and intermediate stages with a short course of chemotherapy followed by limited RT.

Adolescent↗
PubMed1986

Pairing pentobarbital with one toxin causes it to attenuate taste aversions produced by a different toxin: implications for conditioned antisickness theory.

Normally, if pentobarbital and then a toxin are injected after a rat drinks saccharin solution, a taste aversion produced by the pentobarbital summates with that produced by the toxin. An opposite effect is obtained after a preconditioning series in which pentobarbital is injected prior to a toxic dose of lithium or amphetamine in the absence of saccharin drinking: The pentobarbital attenuates the saccharin aversion normally produced by the toxin. Lett (1983) theorized that a conditioned antisickness response (CAR) to pentobarbital is responsible for this conditioned attenuation of saccharin aversion. It is reported here that this attenuation of taste aversion occurs even if the toxin paired with pentobarbital is different from the toxin used during saccharin aversion conditioning. Preconditioning pentobarbital with a high dose of amphetamine allows it to attenuate saccharin aversions produced by lithium and by gamma radiation (as well as by amphetamine itself). Preconditioning pentobarbital with a high dose of lithium allows it to attenuate aversions produced by amphetamine, gamma radiation, cisplatin, mechlorethamine, dactinomycin, and doxorubicin (as well as by lithium itself). This means that the CAR cannot be due to conditioned amelioration of specific effects of specific toxins (which would not be effective if the toxin were changed) and suggests a central alleviation of nausea, perhaps like the alleviation of pain by endogenous opiates. However, aversions produced by intraperitoneal copper sulfate were not attenuated by lithium-conditioned pentobarbital.

Animals↗
PubMed1987

Further studies on the response of intestinal crypt cells of different hierarchical status to eighteen different cytotoxic agents.

Adult male mice were treated with one or two different doses of each of 18 different cytotoxic agents. They were sampled at various times (3-12h) thereafter, and the spatial distributions of cell death in the small intestinal crypts were studied. Dead or dying cells or cells carrying dead cell fragments were examined histologically, and all of these were recorded (for convenience as apoptotic fragments), relative to the cell position in the crypt. Thus, distributions of apoptotic fragments against cell position were determined. A regression analysis of the data obtained at different times after administration of each agent was undertaken and the position of the median of the spatial distribution of presumptive target cells was deduced for each cytotoxic agent. The accuracy of this median value was determined to be +/- 0.5 cell positions. From these median values, the different cytotoxic agents could be divided roughly into three groups: [3H]thymidine, isopropyl-methane-sulphonate, gamma-rays, bleomycin and adriamycin all have their median values (susceptible cells) at cell positions 4 to 6; bischlorethylnitrosourea, actinomycin D, cyclophosphamide and cycloheximide at cell positions 6-8; mechlorethamine, triethylenethiophosphoramide, vincristine, 5-fluorouracil, hydroxyurea and methotrexate at cell positions 8-11. The position of these medians was considered in relation to the killing of clonogenic cells. Preliminary studies on the distributions of dead cells after myleran, cis-platinum and heat (hyperthermia) were also reported. There is a general tendency for antibiotics and radiation to attack the lower cell positions in the crypt. Alkylating agents on the other hand have a somewhat broad spectrum of action. Antimetabolites and a microtubule dissociating agent act on higher cell positions. No difference could be detected between two different forms (sources) of actinomycin D. The changes in the yields of apoptotic and mitotic cells with time and the migration velocities of cells in the crypts carrying apoptotic fragments after exposure to cytotoxics are also presented.

Animals↗
PubMed2003

Secondary myelodysplastic syndrome and acute myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma.

Secondary myelodysplastic syndrome (sMDS) and acute myelogenous leukemia (AML) have been recognized with increasing frequency following autologous stem cell transplantation (ASCT). A retrospective analysis of 230 consecutive patients with Hodgkin's lymphoma (HL, 64) and non-Hodgkin's lymphoma (NHL, 166) who underwent ASCT was conducted to assess the incidence and risk factors for the development of sMDS/AML. At a median follow up of 41 months (range 0.1-177 months), 10 of 230 patients (4.3%) developed sMDS/AML. The 5-year-actuarial incidence of sMDS/AML was 13.1% and 5-year cumulative incidence by competing risk analysis was 4.2%. The median time to development of sMDS/AML was 39.9 months from the time of ASCT (range 12.1-62.0 months). Complex karyotypes at diagnosis of sMDS/AML included structural anomalies and/or loss of chromosome 5 (eight patients), 7 (five patients), 17 (two patients) and 20 (two patients). All patients subsequently died, at a median of 6.8 months (range 0-39.9) from diagnosis of sMDS/AML. Fluorescent in situ hybridization (FISH) analysis for -5/5q- and -7/7q- were normal in all six patients whose pre-ASCT bone marrow was available for testing. Five of the six had samples available for testing at diagnosis of sMDS/AML and all had abnormal FISH results. By univariate statistical analysis, male gender (P=0.01), prior alkylating agents (mechlorethamine for HL, P=0.001 and cyclophosphamide for NHL, P=0.05) and the number of prior treatment regimens (P=0.04) were significantly associated with the development of sMDS/AML. Given the relatively low incidence rate of sMDS/AML, these analyses are primarily exploratory in nature but provide some insight into relevant risk factors and illustrate the risk of developing sMDS/AML after myeloablative conditioning and ASCT for lymphoma.

Adult↗
PubMed2006

Clinical experience: practical management of five patients with cutaneous T-cell lymphoma (CTCL)-related symptoms.

There are now a wide variety of therapeutic options for managing patients with cutaneous T-cell lymphoma-related symptoms. These include skin-directed therapies such as psoralen with UVA irradiation (PUVA), topical chemotherapies such as mechlorethamine (nitrogen mustard) and carmustine (BCNU), electron beam radiation, and systemic therapies such as chemotherapy, photopheresis, and interferons. Although treatment algorithms exist for patients with early stage disease, often treatments are individualized, based on patient specific factors, cost, and accessibility of referral centers for specialized therapies. This article provides details of five real-life case studies to illustrate how cutaneous T-cell lymphoma management can be tailored to the needs of each individual patient.

Aged↗
PubMed2000

Evaluation and treatment of chemotherapy extravasation injuries.

Extravasation of chemotherapeutic vesicant agents can result in significant tissue damage, alteration in limb function, and pain. Quality of life for long-term survivors can be severely impacted by negative sequelae from vesicant extravasation. Currently, there is no known preventive therapy. Early detection and intervention are paramount to halt tissue damage and reduce the chance of permanent disability or disfigurement. This article provides an overview of known chemotherapeutic vesicants (mechlorethamine, mitomycin-C, doxorubicin, daunomycin, vincristine and vinblastine), associated theories of tissue destruction, assessment techniques for peripheral intravenous sites, vascular access devices and central venous lines, current treatment strategies, and investigational therapies. A brief discussion of the legal implications of extravasation injuries and recommended key points for medical record documentation are included.

Antineoplastic Agents↗
PubMed1996

Combined Modality Treatment for Poor Prognosis Stages I and II Hodgkin's Disease.

Recommendations for the treatment of "poor prognosis" stages I and II Hodgkin's disease (HD) depend on the extent of staging. For centers that favor exploratory laparotomy and splenectomy, the standard treatment after negative surgical staging remains subtotal lymphoid irradiation. However, most centers recommend excluding selected patients from surgical staging. In particular, most specialists agree that patients with bulky mediastinal disease (large mediastinal adenopathy) should receive combined chemotherapy and radiotherapy without surgical staging. Centers that have eliminated staging laparotomy rely on clinical staging and have identified a number of poor prognostic factors that influence treatment recommendations. In 1995, the following factors were considered to be associated with an unfavorable prognosis in clinical stages (CS) I and II HD: advanced age, systemic symptoms, high erythrocyte sedimentation rate, large number of individual sites, and presence of bulky disease. For example, these factors have been used in the H7 and H8 European Organization for the Research and Treatment of Cancer trials and have been adopted by almost 100 participant groups. For CS I and II patients with unfavorable presentations, the literature suggests that the optimal treatment is a combination of chemotherapy and radiotherapy. Nevertheless, the optimal delivery of chemotherapy and radiotherapy is still debated and a number of the questions listed below are awaiting answers: 1. The chemotherapy schedule: Mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alone can no longer be recommended (for toxicity reasons) for the routine treatment of poor prognosis CS I and II HD. Many centers, on theoretical arguments, favor seven or eight drug combinations (MOPP/ABV hybrid), although the advantage of these combinations in toxicity and efficacy over doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone has not been demonstrated. 2. The number of chemotherapy courses: Most groups use six cycle regimens, but reduction to three to four cycles is currently being investigated both in pilot and randomized studies. 3. Timing of chemotherapy: Chemotherapy is given first in most instances. Whether or not a "sandwiched" scheme is better than all the chemotherapy given upfront remains to be answered. 4. Volumes to be irradiated: Data suggest that the irradiated volumes can be safely limited to initially involved lymph node regions after effective chemotherapy. The question is presently being addressed in a few ongoing randomized trials. 5. Radiation dose to be delivered: The decrease of the radiation dose to 35 to 36 Gy after effective chemotherapy has gained a wide acceptance. Further dose reduction is being investigated. In conclusion, except for selected CS I and II patients still referred for surgical staging, combined modality therapy appears to be the treatment of choice for poor prognosis CS I and II HD.

Journal Article↗
PubMed1990

Leukemia following Hodgkin's disease.

To investigate the effect of different treatments for Hodgkin's disease on the risk of leukemia, we used an international collaborative group of cancer registries and hospitals to perform a case-control study of 163 cases of leukemia following treatment for Hodgkin's disease. For each case patient with leukemia, three matched controls were chosen who had been treated for Hodgkin's disease but in whom leukemia did not develop. The use of chemotherapy alone to treat Hodgkin's disease was associated with a relative risk of leukemia of 9.0 (95 percent confidence interval, 4.1 to 20) as compared with the use of radiotherapy alone. Patients treated with both had a relative risk of 7.7 (95 percent confidence interval, 3.9 to 15). After treatment with more than six cycles of combinations including procarbazine and mechlorethamine, the risk of leukemia was 14-fold higher than after radiotherapy alone. The use of radiotherapy in combination with chemotherapy did not increase the risk of leukemia above that produced by the use of chemotherapy alone, but there was a dose-related increase in the risk of leukemia in patients who received radiotherapy alone. The peak in the risk of leukemia came about five years after chemotherapy began, and a large excess persisted for at least eight years after it ended. After adjusting for drug regimen, we found that patients who had undergone splenectomy had at least double the risk of leukemia of patients who had not, and an advanced stage of Hodgkin's disease carried a somewhat higher risk of leukemia than Stage I disease. We conclude that chemotherapy for Hodgkin's disease greatly increases the risk of leukemia and that this increased risk appears to be dose-related and unaffected by concomitant radiotherapy. In addition, the risk is greater for patients with more advanced stages of Hodgkin's disease and for those who undergo splenectomy.

Antineoplastic Agents↗
PubMed1998

Overexpression of DNA polymerase beta in cell results in a mutator phenotype and a decreased sensitivity to anticancer drugs.

DNA polymerase beta (pol beta) is the most error prone of all known eukaryotic DNA polymerases tested in vitro. Here, we show that cells overexpressing pol beta cDNA have acquired a spontaneous mutator phenotype. By measuring the appearance of mutational events using three independent assays, we found that genetic instability increased in the cell lines that overexpressed pol beta. In addition, these cells displayed a decreased sensitivity to cancer chemotherapeutic, bifunctional, DNA-damaging agents such as cisplatin, melphalan, and mechlorethamine, resulting in enhanced mutagenesis compared with control cells. By using cell-free extracts and modified DNA substrates, we present data in support of error-prone translesion replication as one of the key determinants of tolerance phenotype. These results have implications for the potential role of pol beta overexpression in cancer predisposition and tumor progression during chemotherapy.

Animals↗
PubMedDate not supplied

Paucity of hematological neoplasia after treatment of Hodgkin disease: observation after long-term follow-up at Cancer Institute, Chennai, south India.

The purpose of the study was to evaluate the incidence of second malignancies in childhood Hodgkin disease treated with COPP and COPP/ABV (replacing mechlorethamine by cyclophosphamide) chemotherapy. In 212 children with Hodgkin disease who were under 14 years of age and treated at Cancer Institute during the 25-year period of 1970-1994, the occurrence of second malignant neoplasms was analyzed as on 31 December 1999. Eighty-two percent attained complete response. The 5- and 10-year overall survival rate was 91 and 83%, respectively. In this interm report 5 cases of second malignancies were documented. All 5 were solid tumors: one each of soft tissue sarcoma, dermatofibrosarcoma, micropapillary carcinoma of thyroid, malignant phylloides tumor of breast, and chondrosarcoma of ilium. All patients had received combination chemotherapy and radiotherapy. Interestingly, all were splenectomized. All these patients had advanced stage of cancer and were 7-14 years of age at the time of diagnosis of first primary Hodgkin disease. It is significant that there were no secondary hematological malignancies. COPP and COPP/ABV are effective therapeutic regimens. The paucity of secondary hematological malignancies is unique in this series and may be attributed to the substitution of nitrogen mustard with cyclophosphamide in the chemotherapy combination. This is an initial observation, and further follow-up is needed for a firm conclusion.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) for advanced-stage Hodgkin's disease: CALGB 8856.

Successful treatment of advanced-stage Hodgkin's disease (HD) may critically depend on dose intensity. Because mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP), and Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) are not suitable for major dose escalation, we evaluated the activity and toxicity of combined cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) in advanced HD, here used at conventional dose intensity, as a preparatory study prior to using this regimen at higher dose intensity. Ninety-two patients were treated with CHOPE (cyclophosphamide, 750 mg/m2, day 1; doxorubicin, 50 mg/m2, day 1; vincristine, 1.4 mg/m2, days 1 and 8; prednisone, 100 mg/day, days 1-5; and etoposide, 80 mg/m2, days 1, 2, and 3) every 21 days. All had advanced HD with no prior chemotherapy with 46% stage IV, 63% with B symptoms, and 57% with bulky disease (> 5 cm). Radiation and growth factor support were not permitted. Full-dose vincristine (not capped at maximum 2 mg/dose) was used in the first 33 patients. An initial cohort of 41 patients was treated with four cycles of CHOPE to evaluate safety and efficacy followed by four cycles of ABVD. A second cohort of 51 patients was treated with 6-8 cycles of CHOPE alone. Toxicity was generally acceptable and primarily hematologic, with neutrophils < 500 in 63% of cohort I and 90% of cohort II, and platelets < 25,000 in 7% of cohort I and 8% of cohort II. The long-term neurotoxicity of full-dose, high-intensity vincristine was acceptable and largely reversible. In cohort I, 92% of patients achieved a complete response (CR) or partial response (PR) with four cycles of CHOPE and 85% were in CR after four additional cycles of ABVD. In cohort II, 77% achieved a CR with 6-8 cycles of CHOPE alone. FFS was 76% in cohort I and 59% in cohort II, with a median follow-up of 8.2 and 5.7 years, respectively. CHOPE, at conventional dose intensity as used here, is an effective first-line regimen for the treatment of advanced-stage HD and may warrant evaluation using higher doses of cyclophosphamide and etoposide with granulocyte colony stimulating factor (G-CSF) support.

Adult↗
PubMed1961

Studies on bacteriemia. V. The effect of simultaneous leukopenia and reticuloendothelial blockade on the early blood stream clearance of staphylococci and Escherichia coli.

Observations are presented on the course of experimental bacteriemia in rabbits modified by thorotrast reticuloendothelial "blockade" and mechlorethamine induced leukopenia, given singly and together. The production of severe granulocytopenia did not impair the clearance of staphylococci from the blood stream and did not enhance the impairment of clearance produced by thorotrast reticuloendothelial "blockade." Neither severe granulocytopenia nor thorotrast blockade alone produced consistent impairment in the removal of circulating E. coli from the blood stream, whereas when these conditions were present together, the early phases of clearance in these animals were virtually prevented. These results indicate that the host mechanisms operative in the control of bacteriemia differ for staphylococci and E. coli. It is suggested that the fate of bacteria within polymorphonuclear leukocytes may in part determine the importance of these cells in the removal of bacteria from the blood stream.

Animals↗