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PubMed1997

Role of neutrophils in lung vascular injury and edema after premature birth in lambs.

To investigate the role of neutrophils in the pathogenesis of respiratory distress after premature birth, we assessed the relationship between circulating neutrophil concentration and neutrophil accumulation in the lung, lung lymph and pleural liquid flow, and extravascular lung water in 10 chronically catheterized preterm lambs (127 +/- 1 days gestation) that were mechanically ventilated for 8 h after birth. Circulating neutrophil concentration transiently decreased within 2 h after birth and then returned to prenatal values by 6-8 h. The decrease in circulating neutrophil concentration was related directly to the accumulation of neutrophils in the air spaces, drainage of liquid and protein from the lung 6-8 h after delivery, and postmortem extravascular lung water. In additional studies, we intravenously administered mechlorethamine to 5 fetal lambs to reduce circulating neutrophils before delivery (neutrophil concentration before birth: 9 +/- 11 cells/microl). Compared with control lambs, neutrophil-depleted lambs had significantly less drainage of liquid (7.8 +/- 5.9 vs. 2.6 +/- 1.9 ml/h, respectively) and protein (116 +/- 74 vs. 42 +/- 27 mg/h, respectively) from the lung 6-8 h after birth and significantly less extravascular lung water at postmortem (6.5 +/- 0. 8 vs. 4.8 0.6 g/g dry lung, respectively). Thus neutrophils contribute to the pathogenesis of respiratory distress after premature birth by increasing lung vascular protein permeability and promoting lung edema.

Alkylating Agents↗
PubMed1999

Cutaneous T cell lymphoma: update of treatment.

The state-of-the art therapy of cutaneous T cell lymphoma (CTCL) is reviewed. Commonly used treatments for early-stage (patch/plaque) mycosis fungoides (MF) include topical corticosteroids, mechlorethamine, carmustine, ultraviolet light B and PUVA. Total skin electron beam (TSEB) therapy is indicated for widespread infiltrated plaque and tumor stage disease. Low-dose methotrexate is often useful for resistant patch/plaque MF and erythrodermic CTCL. Interferon alpha (IFN-alpha) is indicated for methotrexate failures and recurrent tumors following TSEB therapy. Photopheresis may be helpful for early-stage erythrodermic CTCL but is very costly. Retinoids may be of value for early and moderately advanced CTCL particularly in combination with other agents such as IFN-alpha and PUVA. Systemic disease usually requires combination chemotherapy such as that used for non-Hodgkin's lymphoma; however, responses are usually short lived.

Administration, Topical↗
PubMedDate not supplied

Low doses of endotoxin potentiate venous thrombosis in the rabbit.

Procoagulant activity of the endothelium and of monocytes was induced by an intravenous administration of a low dose of endotoxin in the rabbit. Venous thrombosis induced by a 45-min stasis of the jugular vein was dramatically increased after the administration of endotoxin. Endotoxin enhanced venous thrombosis in a dose-dependent manner which was the highest after the administration of 1 microgram/kg. This effect increased with time but was optimal when endotoxin was injected 4 h before stasis induction. Leukocytes appear to play a key role in this process since mechlorethamine-induced leukopenia totally inhibited thrombus formation. Hirudin and heparin, administered intravenously 5 min before stasis, were both potent inhibitors of endotoxin-induced venous thrombosis exhibiting ED50 values of 3.8 +/- 1.0 and 2.3 +/- 1.1 microgram/kg, respectively.

Animals↗
PubMed1981

Leukocytes are required for increased lung microvascular permeability after microembolization in sheep.

We studied the effects of uneven pulmonary artery obstruction by microemboli on steady state transvascular fluid and protein exchange in normal and leukopenic sheep. We measured pulmonary artery and left atrial pressures, cardiac output, lung lymph flow, and lymph plasma protein concentrations. Sheep were made profoundly leukopenic by administration of intra-arterial mechlorethamine hydrochloride (0.4 mg/kg, two doses) and colchicine (0.1-0.2 mg/kg, anesthetized sheep only). In anesthetized sheep, we injected glass beads 200 micrometers in diameter via the right atrium to raise pulmonary vascular resistance to 2-3 times baseline values. With normal levels of circulating leukocytes, sheep developed an increased protein-rich lymph flow from the lung characteristic of increased permeability edema. Leukopenic sheep had a significantly attenuated response after embolization for equivalent degrees of vascular obstruction. In unanesthetized sheep, we continuously infused air bubbles 1 mm in diameter via the right atrium to raise pulmonary vascular resistance to about 2 times baseline values. Each sheep served as its own control. With normal circulating leukocyte levels, there was an increase in protein-rich lymph flow from the lung during embolization. When the air infusion ended, the sheep recovered to the baseline condition in 24 hours. We induced emboli with the same amount of air when the sheep were profoundly leukopenic; lymph and protein flow from the lung were significantly less for equivalent degrees of obstruction. We conclude that circulating leukocytes are essential for the microvascular injury that results in increased permeability in the lungs of sheep after microembolization.

Animals↗
PubMed2002

Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study.

Although numerous reports indicate that patients receiving autotransplants for lymphoma are at increased risk for myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), the separate contributions of pretransplantation- and transplantation-related therapy are not well characterized. We conducted a case-control study of 56 patients with MDS/AML and 168 matched controls within a cohort of 2 739 patients receiving autotransplants for Hodgkin disease or non-Hodgkin lymphoma at 12 institutions (1989-1995). Detailed abstraction of medical records was undertaken to determine all pre- and posttransplantation therapy, and transplantation-related procedures. In multivariate analyses, risks of MDS/AML significantly increased with the intensity of pretransplantation chemotherapy with mechlorethamine (relative risks [RRs] = 2.0 and 4.3 for cumulative doses < 50 mg/m2 and > or = 50 mg/m,2 respectively; trend over dose categories, P =.04) or chlorambucil (RRs = 3.8 and 8.4 for duration < 10 months or > or = 10 months, respectively; trend, P =.009), compared with cyclophosphamide-based therapy. Transplantation-conditioning regimens including total-body irradiation (TBI) at doses 12 Gy or less did not appear to elevate leukemia risk (RR = 1.3; P =.48) compared with non-TBI regimens; however, a statistically significant increased risk was found for TBI doses of 13.2 Gy (RR = 4.6; P =.03). Peripheral blood stem cells were associated with a nonsignificant increased risk of MDS/AML (RR = 1.8; P =.12) compared with bone marrow grafts. Our data show that type and intensity of pretransplantation chemotherapy with alkylating agents are important risk factors of MDS/AML following autotransplantation. Transplantation-related factors may also modulate this risk; however, the apparent contribution of high-dose TBI requires confirmation.

Acute Disease↗
PubMed2006

Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA).

From 1989 to 1996, 533 eligible patients with stage IIIB/IV Hodgkin lymphoma (HL) were randomly assigned to receive 6 cycles of hybrid MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone/Adriamycin [doxorubicin], bleomycin, vinblastine; n = 266) or ABVPP (doxorubicin, bleomycin, vinblastine, procarbazine, prednisone; n = 267). Patients in complete remission (CR) or partial response of at least 75% after 6 cycles received 2 cycles of consolidation chemotherapy (CT) (n = 208) or subtotal nodal irradiation (RT) (n = 210). A better survival probability was observed after ABVPP alone: the 10-year overall survival (OS) estimates were 90% for ABVPP x 8, 78% for MOPP/ABV x 8, 82% for MOPP/ABV with RT, and 77% for ABVPP x 6 with RT (P = .03); and the 10-year disease-free survival (DFS) estimates were 70%, 76%, 79%, and 76%, respectively (P = .09). The 10-year DFS estimates for patients treated with consolidation CT or RT were 73% and 78% (P = .07), and OS estimates were 84% and 79%, respectively (P = .29). These results showed that RT was not superior to consolidation CT after a doxorubicin-induced CR in patients with advanced HL. An analysis of competing risks identified age more than 45 years as a significant risk factor for death, relapse, and second cancers. Prospective evaluation of late adverse events may improve the management of patients with HL.

Adolescent↗
PubMed1983

Long-term follow-up with ABDIC salvage chemotherapy of MOPP-resistant Hodgkin's disease.

Thirty-six consecutive patients with advanced recurrent Hodgkin's disease resistant to chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) were treated with doxorubicin (Adriamycin), bleomycin, (dacarbazine) DTIC, (lomustine) CCNU, and prednisone (ABDIC). Among the 34 patients evaluable for response, complete remission occurred in 35% and partial remission in 35%. The achievement of complete remission during primary MOPP induction was a statistically significant prognostic factor that predicted complete remission with ABDIC (p less than 0.01). The median time to complete remission was 2 months (range 1-11 mo). The median relapse-free survival time for complete responders is 47 months, and an estimated 53% of all patients who achieve complete remission are projected to be alive, free of disease off therapy at 3 years from initiation of ABDIC. The median survival of all patients is 24 months. The median survival of complete responders, partial responders, and nonresponders is 70, 17, and 4 months, respectively. The survival curve for complete responders is significantly different from that for partial responders (p less than 0.01); the survival curve for partial responders is also significantly different from that of nonresponders (p less than 0.01). Toxicity of ABDIC was acceptable; only one patient died from complications of myelosuppression. Our results indicate that ABDIC is a potentially curative regimen for a fraction of patients with MOPP-resistant Hodgkin's disease who achieve complete remission with prior MOPP therapy. It also prolongs the survival of patients who do not achieve complete remission with prior MOPP therapy.

Adult↗
PubMed1984

Recovery of spermatogenesis after treatment for Hodgkin's disease: limiting dose of MOPP chemotherapy.

The sperm production of 25 patients with Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy was studied retrospectively. All but two patients also received radiotherapy treatment to pelvic and/or non-pelvic fields. Sperm counts were obtained from patients treated either with three or fewer (MOPP-2 group) or with five or more (MOPP-6 group) chemotherapy cycles. Recovery of spermatogenesis following treatment-induced azoospermia was significantly higher among the MOPP-2 patients (Mann-Whitney rank sum test, p = 0.001). Patients in this group who did not receive pelvic irradiation appeared to have greater recovery rates (p = 0.06). The results suggest that three cycles of MOPP chemotherapy represent a maximum exposure compatible with the recovery of spermatogenesis.

Adolescent↗
PubMed1985

Allogeneic marrow transplantation in the treatment of MOPP-resistant Hodgkin's disease.

Eight patients with disseminated Hodgkin's disease resistant to MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) chemotherapy were treated with high-dose chemoradiotherapy and marrow transplantation from an HLA-identical sibling. Two patients remain alive in unmaintained complete remission (CR) at 38 and 39 months after transplant. In the other six patients, reasons for failure included relapse of lymphoma (two patients), or death due to complications of the transplant procedure, including Legionnaire's disease, disseminated zoster, graft-v-host disease, and aspiration pneumonia secondary to severe mucositis. These results demonstrate that some patients with MOPP-resistant Hodgkin's disease can obtain prolonged CR following intensive chemoradiotherapy and allogeneic marrow transplantation.

Adult↗
PubMed1985

Hodgkin's disease in childhood and adolescence: results of chemotherapy-radiotherapy in clinical stages IA-IIB.

From April 1972 to May 1980, 72 children and adolescents (aged 5 to 19 years old, median 16) with Hodgkin's disease, clinical stages IA-IIB (IA, 18; II2A, two areas involved on the same side of the diaphragm, 23; II3+A, three areas or more, 16; IIB, 15) were prospectively treated in two successive clinical trials (H 72 and H 77). Clinical stages IA and II2A received three courses of mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP) and supradiaphragmatic radiotherapy (40 Gy), and no laparotomy was performed. Clinical stages II3+A and IIB received either six cycles of MOPP (H 72), three cycles of MOPP, or three cycles of CCNU, vinblastine, procarbazine, and prednisone (CVPP) (H 77) and subsequently had a laparotomy followed by supradiaphragmatic radiotherapy and a lumboaortic field if results of laparotomy were positive. Patients without evidence of mediastinal involvement did not have mediastinal radiotherapy. At the completion of therapy, the disease in 70 of 72 patients was in complete remission (one failure, one death during treatment). Eight patients relapsed (in situ, 1; marginal, 1; nonirradiated subdiaphragmatic area, 6) after three to 57 months of complete remission (median 20 months); one patient died after relapse. There were three deaths after complete remission of the disease (infection, two; acute nonlymphocytic leukemia [ANLL], one). As of June 1984 the median follow-up was 82 months (range, 49 to 145 months), the actuarial probabilities for survival and freedom from relapse for all patients being 91.6% and 87.6%, respectively. There was no statistical difference according to clinical stage, age (greater than 15 or less than 15 years), sex, or number of cycles of chemotherapy (six or three). Bone growth defects related to radiotherapy were reduced particularly in the 29 patients who did not receive mediastinal radiotherapy. None of these patients had a mediastinal relapse. Azoospermia was the rule for the male patients studied, but young girls and young women retained reproductive integrity.

Actuarial Analysis↗
PubMed1986

Combined modality treatment of cutaneous T cell lymphoma: results of a 6-year follow-up.

Thirty-nine patients with cutaneous T cell lymphoma (CTCL; including mycosis fungoides or the Sezary syndrome) with no previous treatment other than topical therapy or oral corticosteroids, received total skin electron beam irradiation (TSEB) and either sequential or simultaneous systemic chemotherapy. Median follow-up, measured from the time of initiation of therapy to the time of analysis, is in excess of 6 years and extends to 100+ months. Thirteen patients with stage I disease (limited to skin with no adenopathy) received 3,000 rad total skin electron beam irradiation followed by three 2-week courses of daily intravenous (IV) mechlorethamine. Twenty-six patients with advanced disease (stage II-IV) received 2,400 rad of TSEB and simultaneous chemotherapy with two alternating three-drug regimens: vinblastine, doxorubicin, and bleomycin (VAB) alternating with cyclophosphamide, methotrexate, and prednisone (CMP) administered over 54 weeks. The overall response rate was 92% with 16 of 39 patients (41%) achieving a histologically documented complete response (CR). Stage I patients had a significantly increased CR rate (77%) compared with stage II-IV (P less than .01). The overall 6-year survival was 92% for stage I patients and 26% for stage II-IV patients (23%) (P less than .001). Among ten completely responding stage I patients, six remain alive and disease-free in excess of 72 months. The median disease-free survival is 26 months for completely responding stage II-IV patients (P = .04), but none are continuous disease-free survivors after protocol treatment. We conclude that combined modality treatment can be safely administered and produces prolonged disease-free survival in some stage I patients, but not in more advanced stage patients.

Adult↗
PubMed1986

Twenty years of MOPP therapy for Hodgkin's disease.

The results of treatment of 198 patients with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) for Hodgkin's disease were analyzed after a median of 14 years of follow-up. Throughout the period of follow-up, 103 patients have remained continuously free of disease. Review of biopsy specimens of 43 patients originally classified as Hodgkin's disease, lymphocyte-depleted type, revealed that ten of these patients actually had diffuse immunoblastic or large cell non-Hodgkin's lymphomas. Of the 188 patients with Hodgkin's disease, 157 achieved a complete response (CR) (84%), and 66% of them (101 patients) have remained disease-free more than 10 years from the end of treatment. Absence of B symptoms and receiving higher doses of vincristine were factors associated with a higher CR rate and longer survival. Patients entering complete remission in five cycles or less had significantly longer remissions than those requiring six or more cycles. Forty-eight percent of the Hodgkin's disease patients have survived between 9 and 21 years (median, 14 years) from the end of treatment. Nineteen percent of the CRs have died of intercurrent illnesses, free of Hodgkin's disease.

Adolescent↗
PubMed1987

Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy.

In an attempt to reduce some of the delayed sequelae associated with combined modality therapy in Hodgkin's disease, we randomly tested stages IIB, IIIA, and IIIB MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) v ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine). In 232 previously untreated patients, three cycles of either combination preceded and followed extensive irradiation. The complete remission rate was 80.7% following MOPP and 92.4% following ABVD (P less than .02). The 7-year results indicated that ABVD was superior to MOPP in terms of freedom from progression (80.8% v 62.8%; P less than .002), relapse-free survival (87.7% v 77.2%; P = .06), and overall survival (77.4% v 67.9%; P = .03). Moreover, the comparative iatrogenic morbidity showed that irreversible gonadal dysfunction as well as acute leukemia occurred only in patients subjected to MOPP, while cardiopulmonary studies failed to document significant laboratory differences between the two treatment groups. Present findings indicate that ABVD followed by extensive irradiation represents a valid therapeutic alternative to the widely used alkylating agent-containing regimens plus radiotherapy.

Adult↗
PubMed1988

Treatment with MOPP or ChlVPP chemotherapy only for all stages of childhood Hodgkin's disease.

Fifty-three children with Hodgkin's disease were clinically staged and treated with chemotherapy alone. Forty-six received mechlorethamine (Mustargen; Merk Sharpe & Dohme, West Point, PA), vincristine (Oncovin; Eli Lilly and Company, Indianapolis), procarbazine, and prednisolone (MOPP) and 7 chlorambucil, vinblastine, prednisolone, and procarbazine (ChlVPP). There were four events in the 38 children with stage I and II disease. One patient with massive mediastinal disease failed to remit and subsequently failed mantle irradiation and changes of chemotherapy. Another relapsed at the site of local disease and was salvaged with involved field irradiation and further courses of MOPP. Two other children died as a result of acute graft-v-host disease (GVHD) following transfusion. At autopsy there was no evidence of Hodgkin's disease. Fifteen children had stage III and IV disease and 14 achieved complete remission (CR) and none have relapsed. The child who failed to achieve remission died of virus infections. A mediastinal mass greater than 1/3 the thoracic width was present in 19 children of whom 18 achieved remission and none relapsed. An infradiaphragmatic presentation occurred in eight, all achieved remission and none relapsed. Overall at a median follow-up time of 45 months survival was 94%; the percent of patients without treatment failure was 92; and the percent without relapse was 98.

Adolescent↗
PubMed1988

Combined modality therapy for tumor stage mycosis fungoides: results of a 10-year follow-up.

Twenty-one patients with tumor stage mycosis fungoides (MF) with or without lymph node (LN) involvement, were treated with total skin electron beam irradiation (TSEB) followed by six monthly cycles of systemic chemotherapy (CT) of either mechlorethamine (HN2) or cyclophosphamide (CTX) with vincristine (VCR), procarbazine, and prednisone (PRD) (COPP or MOPP). All patients had complete clearing of the skin after TSEB. However, while receiving chemotherapy, two patients developed visceral involvement and eight patients relapsed with limited cutaneous plaques (LCP). The median duration of remission was 12 months from the completion of TSEB, and all patients relapsed with cutaneous plaques within 25 months. Complete remission was again achieved using additional electron irradiation and maintenance therapy in all but one patient. Multiple cutaneous recurrences occurred in all patients. Median survival from the initiation of TSEB is 6 years. Five patients are living beyond 8 years (four off treatment without disease for 1 to 7 years). LN involvement did not influence initial response or survival. Combined modality therapy for tumor stage MF using TSEB followed by systemic CT and subsequent maintenance therapy may lead eventually to prolonged disease-free survival (DFS) in selected patients.

Adult↗
PubMed1988

Two cycles of MOPP and radiotherapy for stage III1A and stage III1B Hodgkin's disease.

One hundred two adult patients with stage III1A (76 patients) and stage III1B (26 patients) Hodgkin's disease were treated with two cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and radiotherapy (XRT) between 1970 and 1984. Sixty-four of the patients were treated between 1970 and 1978 with two cycles of MOPP and XRT to the mantle, upper abdomen, and pelvis. The remaining 38 patients were treated from 1978 to 1984 with a modification of the protocol in which pelvic XRT was omitted and low-dose whole-lung XRT was administered to patients with unfavorable mediastinal disease. The 10-year actuarial freedom-from-progression (FFP) and determinate survival rates at a mean follow-up of 93 months were 84% and 86% for stage III1 disease, 86% and 84% for stage III1A disease, and 78% and 91% for stage III1B disease. Three patients died of treatment-related toxicities without evidence of Hodgkin's disease, two died of complications of myelosuppression and one of acute nonlymphocytic leukemia (ANLL). Neither FFP nor determinate survival rates were significantly influenced by B symptoms, unfavorable mediastinal disease, histologic subtype, extent of abdominal disease, the omission of pelvic XRT, the use of whole-lung XRT, or the number of splenic nodules. Patients 40 years of age or older had a 73% determinate survival rate at 10 years compared with 88% for patients younger than 40 years (P = .01). This survival difference was due to treatment-related toxicity in the older group. This study indicates that two cycles of MOPP and XRT to the mantle and upper abdomen is as effective as more intensive treatment for all patients with stage III1 Hodgkin's disease. This treatment program can preserve fertility and has had only a 1% actuarial incidence of ANLL at 15 years.

Adolescent↗
PubMed1988

High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin's disease patients: an Italian study group report.

Fifty patients with recurrent Hodgkin's disease have been treated with high-dose therapy followed by autologous bone marrow transplantation. Forty-one patients had extranodal sites of relapse and 31 patients had constitutional symptoms. Two patients had been treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), lomustine, vinblastine, procarbazine, and prednisone (CcVPP), and radiation; 16 patients with MOPP, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), radiation, and lomustine, etoposide, and prednisone (CEP); 20 patients with alternating MOPP/ABVD, and 12 patients with alternating MOPP/ABVD followed by CEP and radiation. Eighteen patients had progressive disease during alternating MOPP/ABVD protocol alone or during conventional salvage therapy; 32 patients had had a complete remission with first-line therapy but later relapsed, 25 of them having received conventional salvage therapy; 12 achieved no response or progression ("resistant-relapse" patients); and 13 responded partially or completely ("sensitive-relapse" patients). Complete remission occurred in 24 patients (48%) with a median duration of 24 months and 16 patients (32%) achieved partial response with a median duration of 9 months, for an overall response rate of 80%. Ten patients failed to respond and died in progressive disease 1 to 10 months (median, 6 months) after transplantation. Toxicity was significant including infections (20%), liver enzymes and alkaline phosphatase elevations (100%), and carmustine lung toxicity (7%). There were two treatment-related deaths; one patient died of Pseudomonas aeruginosa septicemia and another patient died of cerebral hemorrhage. These results validate the procedure of high-dose therapy followed by autologous bone marrow transplantation in inducing remission in these advanced, highly-treated patients. Clearly, the question of whether high-dose therapy and transplantation will eventually supersede new conventional salvage therapies will be addressed after controlled clinical studies.

Adult↗
PubMed1989

MOPP chemotherapy versus extended-field radiotherapy in the management of pathological stages I-IIA Hodgkin's disease.

In order to assess whether mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy (CT), which is less expensive and more easily available than radiotherapy (RT), is at least as effective as RT in terms of cure rate and has less iatrogenic damage, 89 consecutive patients with Hodgkin's disease (HD) (pathological stage I-IIA) were randomly allocated to receive mantle plus lumbar bar RT (36-45 Gy) or CT (six courses of MOPP). Forty-five patients were entered in the RT group and 44 in the CT group. The median follow-up was 60 months. Complete remission (CR) was obtained in all patients in the RT group and in 40 of 44 patients in the CT group. Overall survival (OS) and disease-free survival (DFS) were, respectively, 87.2% and 72.7% in the CT group and 93.5% and 74% in the RT group. Survival probability of relapsing patients was 76% for the patients in the RT group and 45% in the CT group. Treatment-related complications were more severe in the CT group as compared with the RT group.

Adolescent↗