Rehabilitation of exacerbated case of oral mucositis associated with renal failure following bone marrow transplantation.

Inflammation of oral mucosa induced by anti neoplastic drugs is an important, dose limiting and costly side effect of cancer therapy. Here is presented an exacerbated case of oral mucositis associated with renal failure in a patient who underwent bone marrow transplantation. The clinical aspects and an integrated rehabilitation program are discussed below.

Criopreservaçäo de medula óssea e células pluripotentes periféricas utilizando um congelador programável: experiência em 86 congelamentos / Cryopreservation of bone marrow and peripheral blood stem cells using a controlled rate freezing system: experience on 86 procedures

A infusao de células hematopoéticas totipotentes criopreservadas permite a recuperaçao da hematopoese após quimioterapia mieolblativa. Objetivo. A formaçao de cristais de gelo durante o processo de congelamento é o fator principal que causa ruptura das estruturas celulares. A criopreservaçao dessas células a uma taxa constante preveniria os danos causados pelo congelamento brusco. Métodos. Vinte e três pacientes com mediana de 25 anos (variaçao 3-57) tiveram a medula óssea e/ou células-tronco periféricas (CTP) coletadas no período de março de 1993 a outubro de 1994, totalizando 86 congelamentos. Os pacientes apresentavam as seguintes neoplasias: linfoma nao-Hodgkin (n=5), leucemia mielóide aguda (n=8), leucemia linfóide aguda (n=6), doença de Hodkin (n=3) e mieloma múltiplo (n=1). O congelamento foicontrolado por um computador, acoplado ao sistema, às seguintes temperaturas: -1 graus Celsius/min até -45 graus Celsius e depois a -10 graus Celsius/min até -80 graus Celsius. Após o congelamento, as células foram mantidas em freezer a -110 graus Celsius até o momento da infusao. Para obtençao das CTP, empregou-se o fator de crescimento estimulante de granulócitos (G-CSF). Resultados. Uma mediana de 3,16 x 10(8) céls./kg (variaçao 0,86-24,22) de CTP e 2,03 x 10(8) céls./kg (variaçao 0,19-12,21) de medula óssea foi congelada. A mediana para atingir granulócitos maior ou igual a 500/muL e plaquetas maior que 20.000/muL foi de 12 dias (variaçao 8-40) e 31 dias (variaçao 8-80), respectivamente. Todos os pacientes tiveram recuperaçao hematopoética após a infusao das células criopreservadas. Conclusao. A criopreservaçao em congelador program vel permite o armazenamento de células hematopoéticas e, potencialmente, pode causar menor dano celular.

[Cryopreservation of bone marrow and peripheral blood stem cells using a controlled rate freezing system: experience with 86 procedures]. / Criopreservação de medula óssea e células pluripotentes periféricas utilizando um congelador programável: experiência em 86 congelamentos.

UNLABELLED: The cryopreservation of hematopoietic stem cells can be used for rescuing the hematopoiesis after high dose chemotherapy. PURPOSE: The ice crystal formation during the freezing procedure is the key point that can be harmful to the cells. The cryopreservation of hematopoietic stem cells in a controlled-rate freezer could decrease the cell damage. METHODS: Twenty-three patients with a median age of 26 years (range 03-57) had bone marrow and/or peripheral blood stem cells harvested from March 1993 through October 1994, ending up to 86 freezing procedures. The patient's diagnoses are as follows: Non-Hodgkin's Lymphoma (n = 5); Acute Myelogenous Leukemia (n = 8); Acute Lymphocytic Leukemia (n = 6); Hodgkin's disease (n = 3); Multiple Myeloma (n = 1). The cells were frozen away in a controlled-rate freezer chamber at the following rate: -1 degree C/min from room temperature to -45 degrees C and then, at -10 degrees C/min down to -80 degrees C. After freezing, the cells were kept into mechanical freezers until the marrow infusion. To mobilize PBSC (peripheral blood stem cells), G-CSF (granulocyte colony stimulating factor) was given. RESULTS: A median of 3.16 x 10(8) cells/kg (range 0.86-24.22) of PBSC and 2.03 x 10(8) cells/kg (0.19-12.21) of bone marrow cells were frozen. The median time to reach granulocytes greater than 500/microL and platelets greater than 20,000/microL was 12 days (range 8-40) and 31 days (range 8-80), respectively. All patients had marrow engraftment after infusion of hematopoietic stem cells. CONCLUSION: The cryopreservation procedure using a controlled-rate freezer can store hematopoietic stem cells and potentially, cause less damage to the cells.

Herpes Simplex Virus Shedding in Bone Marrow Transplant Recipients During Low-Dose Oral Acyclovir Prohylaxis.

A 400mg dose twice-a-day oral acyclovir prophylaxis regimen was evaluated in 50 allogeneic transplant recipients. Twenty (40%) patients experienced 24 episodes of herpes simplex virus (HSV) shedding; l7 (70.8%) occurring during prophylaxis. Thirteen of such episodes were asymptomatic and, in three, it was difficult to differentiate severe mucositis from viral lesions. In the remaining one, HSV pneumonia was suspected after a bronchoalveolar lavage (BAL) procedure performed in an attempt to early detection of cytomegalovirus (CMV). All cases responded to acyclovir therapy or dose adjustment suggesting that acyclovir resistance did not account for the occurrence of infection in our patients. These data demonstrated that oral acyclovir prophylaxis, 400mg dose twice-a-day, was inadequate to suppress viral shedding. The bronchoalveolar lavage procedure in a patient with HSV shedding could precipitate HSV spread to the lungs and the occurrence of pneumonia.

Unrelated peripheral blood stem cell transplantation for Fanconi anemia.

The Brazilian unrelated bone marrow donor program began in 1993 and an unrelated matched donor was found for a Fanconi anemia patient without a sibling match. An 11-year-old female recipient received FTBI (6.0 Gy) and cyclophosphamide (40 mg/kg) as conditioning. The 41-year-old female unrelated donor received G-CSF at 5 micrograms/kg x 5 days, and on day 6 and 7 postmobilization, peripheral blood stem cells were harvested. Engraftment was seen on day 19 post-BMT and she remains alive and well on day 191+. This case supports the potential role of harvesting G-CSF-stimulated PBSC for unrelated bone marrow transplantation.

Clinical features and successful recovery from disseminated nocardiosis after BMT.

Nocardiosis has rarely been described after BMT. When the doses of immunosuppressive therapy were tapered, a 46-year-old BMT recipient developed chronic graft-versus-host disease (GVHD) and immunosuppresive drugs were increased. Sixteen days later the patient developed nocardiosis diagnosed by lung biopsy. Trimethoprim/sulfamethoxazole (TMP/SMZ) was initiated but the doses were reduced because of rising creatinine levels. Skin and cerebral dissemination of nocardiosis was observed and TMP/SMZ doses were increased. After 4 months, the brain lesion was unaltered despite resolution of pulmonary lesions. Clinical improvement was observed after drainage of the brain abscess.

Close simulation of acute graft-versus-host disease by interleukin-2 administered after autologous bone marrow transplantation for hematologic malignancy.

The high relapse rate of hematologic malignancy treated with autologous bone marrow transplantation (ABMT) may reflect the absence of a graft-versus-leukemia (GVL) effect usually associated with graft-versus-host disease (GVHD). The purpose of this study was to determine whether administration of interleukin-2 (IL-2) early after ABMT might induce or exacerbate acute skin GVHD. Fourteen patients at high risk for post-transplant relapse, eight with NHL and six with AML > or = first relapse, were conditioned with chemotherapy and total body irradiation (13) or chemotherapy alone (1), and received purged (10) or unpurged (4) marrow. A median of 35 days (range 25-58) after ABMT, they received a 5-day induction course of Roche IL-2 (9 x 10(6) U/m2/day) followed by apheresis, reinfusion of LAK cells, and a 10-day maintenance course of IL-2 (0.9 x 10(6) U/m2/day), all by continuous i.v. infusion. Serial skin biopsies were obtained before and after IL-2 therapy and were read blindly. Patients were studied prospectively for the development of acute cutaneous GVHD as reflected by rash ( > or = 25% body surface area), skin biopsy ( > or = grade II histologic changes) and T cell infiltration as assessed by staining of the biopsy with antibodies UCHL-1 and TIA-1. No patient had a rash before IL-2 therapy, but 12 of 14 (85%) developed a rash during the IL-2 induction course. Before IL-2 therapy, biopsies from three of 10 patients (30%) revealed histologic GVHD; after induction IL-2, biopsies from 11 of 14 patients (79%) revealed grade II acute GVHD. Biopsies from all patients with histologic GVHD after IL-2 therapy contained TIA-1 positive T cells. HLA-DR was negative in the keratinocytes of these paraffin-embedded sections. One patient died early of sepsis, one patient required and responded to topical corticosteroids and 12 had spontaneous resolution of the rash. Six patients relapsed at 3-13 months, while seven remain in complete remission 32+ to 41+ months after ABMT. The results demonstrate that IL-2 therapy after ABMT can induce effects which histologically and clinically mimic cutaneous acute GVHD in most patients. Prospective, randomized trials of IL-2 vs observation after transplantation of autologous marrow or stem cells for high-risk NHL and AML have been initiated which may allow us to determine whether this phenomenon is associated with a clinical GVL effect as reflected by a decreased relapse rate.

Relevance of marrow fibrosis in bone marrow transplantation: a retrospective analysis of engraftment.

A retrospective study compared posttransplant engraftment parameters in 203 patients with myelofibrosis (MF) with those in a population of 203 matched controls without MF. There were no significant differences between these groups in the proportions of patients who died without achieving engraftment and in the disease-free survival distributions. Furthermore, comparisons between the two groups of patients reaching the respective endpoints showed no differences in the time distributions for reaching 0.5 or 1.0 x 10(9)/L granulocytes, but the time to platelet transfusion independence was 3 days longer in patients with MF. In further analysis, results for 33 patients with severe MF were compared with those of their respective controls. The proportions of patients with severe MF who died without reaching these engraftment endpoints and the disease-free survival distributions in the two groups were similar. Among patients who reached the respective engraftment endpoints, there was no statistically significant difference in the pace of granulocyte recovery. In patients with severe MF, there was a 7-day delay in the time to reach platelet transfusion independence and a 2-day delay in the time to reach red blood cell independence, but the differences were not statistically significant. The present results do not substantiate concerns raised by earlier studies. MF may delay the time to reach platelet independence by approximately 3 days and may increase platelet transfusion requirements, but no other perturbation of hematopoietic reconstitution was apparent.

Induction by interleukin-7 of lymphokine-activated killer activity in lymphocytes from autologous and syngeneic marrow transplant recipients before and after systemic interleukin-2 therapy.

Therapy with recombinant lymphokines after autologous bone marrow transplantation (ABMT) is being explored as a way to prevent relapse. Lymphokine therapy may exert an antitumor effect through a variety of mechanisms, including the induction of lymphokine-activated killer (LAK) cell cytotoxicity. We tested the ability of interleukin-7 (IL-7) to induce LAK cytotoxicity in peripheral blood mononuclear cells (PBMC) from healthy subjects and from patients early after ABMT. LAK activity was defined as lysis of Daudi by PBMC after incubation with IL-7 at 10 to 100 ng/mL or IL-2 at 1000 U/mL. PBMC from four healthy subjects were cultured with either IL-7 or IL-2. IL-7 induced LAK activity in two of the four, whereas IL-2 induced LAK activity in all four. The median percent lysis (effector-to-target ratio [E:T] 40:1) with IL-7 (23%) was lower than with IL-2 (67%). PBMC were obtained from 15 patients 27 to 84 days after autologous (n = 13) or syngeneic (n = 2) bone marrow transplantation (BMT) and tested for IL-7-induced LAK activity. Eleven exhibited significant activity (10% to 77% lysis at E:T 40:1). In contrast to the results in PBMC from normal subjects, in PBMC from ABMT patients IL-7 induced LAK activity of a magnitude similar to that induced by IL-2. Studies were also performed on PBMC from eight patients who had received IL-2 after ABMT (3.0 x 10(6) U/m2/d) for 4 days by continuous intravenous (IV) infusion. In seven of the eight patients, IL-7 induced significant LAK activity, which was higher than that seen in PBMC from ABMT patients who had not received IL-2. Thus, IL-7 reproducibly induced significant LAK activity in cells obtained early after autologous or syngeneic BMT. Indeed, such LAK activity was comparable quantitatively to that induced by IL-2. Finally, IL-7 induced an even greater LAK activity in vitro in PBMC obtained after ABMT and preactivated in vivo by IL-2 therapy. The results suggest that IL-7 may have a potential immunotherapeutic role, alone or with IL-2, after ABMT.

Interleukin-2 with or without lymphokine-activated killer cells as consolidative immunotherapy after autologous bone marrow transplantation for acute myelogenous leukemia.

IL-2 with or without autologous lymphokine-activated killer (LAK) cells, administered early after ABMT for AML may eradicate residual disease and reduce relapses. This paper reports 14 patients who received IL-2 or IL-2 plus LAK cells after ABMT for AML in first relapse or at a later stage, in two separate trials. Patients with AML in first relapse (n = 9), second CR (n = 3) or second relapse (n = 2) underwent ABMT after busulfan (BU), CY and total body irradiation (n = 11) or BU/CY alone (n = 3), with marrow that was (n = 6) or was not (n = 8) purged with 4-HC. In a previously-reported Phase I trial, eight patients received IL-2 (Roche) by continuous infusion at 0.3-3.0 x 10(6) U/m2/day x 5 days and, after 6 days of rest, 0.3 x 10(6) U/m2/day x 10 days. In a subsequent trial, five patients received IL-2 at 3.0 x 10(6) U/m2/day x 5 days, underwent leukapheresis for 3 days and received their LAK cells plus IL-2 (0.3 x 10(6) U/m2/day x 10 days). A sixth patient received only 2 days of IL-2, developed sepsis and died of multiorgan failure. All other patients had mild to moderate toxicity which was reversible. All patients developed neutrophilia, lymphocytosis and thrombocytopenia. IL-2 with or without LAK therapy was initiated 21-91 days (median 51 days) after ABMT. Severe thrombocytopenia (< 10 x 10(9)/l) occurred during the apheresis days.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-2 +/- lymphocytes as consolidative immunotherapy after autologous bone marrow transplantation for hematologic malignancies.

Patients who undergo autologous bone marrow transplantation (ABMT) for advanced hematologic malignancies experience a high relapse rate. Therapy with interleukin-2 (IL-2) +/- lymphokine-activated killer (LAK) cells has induced clinical responses in some patients with advanced malignant lymphoma (ML) or acute myelogenous leukemia (AML). It is postulated that IL-2 +/- LAK cells represents a potentially non-cross-resistant therapeutic modality which might prevent or delay relapses if used as consolidative immunotherapy after ABMT, at a time of minimal residual disease. Therefore, we first studied the reconstitution of IL-2-responsive LAK precursor cells after ABMT and found them in the circulation as early as 3 weeks after ABMT. A phase Ib clinical trial was then performed which identified a tolerable IL-2 regimen which could be administered early after ABMT and which could induce immunomodulatory effects. We then initiated a clinical trial to determine the feasibility of generating and administering autologous LAK cells using this IL-2 regimen after ABMT for 16 patients with ML. The results show that IL-2+LAK therapy early after ABMT is feasible but is more toxic than IL-2 alone. Patients with AML on the phase I IL-2 trial and with ML on the IL-2+LAK protocol were evaluated for tumor status. Of 8 patients with AML in first relapse or at a later stage who underwent ABMT and received IL-2, 2 have relapsed, while 6 remain in complete remission 26+ to 40+ (median 28+) months after ABMT. Of 16 patients with ML considered at high risk for relapse who were treated with ABMT+IL-2+LAK, 5 have relapsed, while 11 remain in complete remission at 6+ to 21+ (median 10+) months after ABMT. The results in both trials are quite encouraging and appear to be better than those in nonrandomized historical controls at our institution. Prospectively randomized trials of IL-2 versus no IL-2 after ABMT in such patients are being initiated to assess definitively the effect, if any, on the relapse rate.

[Plasminogen activators as thrombolytic agents in myocardial infarction]. / Ativadores do plasminogênio como agentes trombolíticos no infarto do miocárdio.

Administration of thrombolytic agents can determine recanalization of thrombosed coronary arteries. Apparently, the earlier reperfusion is performed the better the prognosis of myocardial infarction. Streptokinase was administered to 117 patients with myocardial infarction at the "Instituto do Coração da Universidade de São Paulo" and angiographic patency of the vessel was restored in as many as 87% of them. New thrombolytic agents, such as tissue plasminogen activator (tPA), single chain urokinase-type Plasminogen Activator (scuPA) and Anisoylated Plasminogen Streptokinase Activator Complex (APSAC) have been evaluated in clinical trials. Recent advances in thrombolytic therapy and comparative aspects of the various agents currently available are reviewed.

[Etiopathogenesis of aplastic anemia and of the severe form treated with immunosuppression and bone marrow transplantation]. / Etiopatogênese da anemia aplástica e tratamento da forma severa com imunossupressão e transplante de medula óssea.

Aplastic anemia is a condition characterized by bone marrow hipoplasia and pancytopenia. Various etiologic agents are related to the acquired form of this disease but in many cases the causative agents remain obscure. Severe aplastic anemia has been treated by immunosuppression and allogeneic marrow transplantation.

Deficient release of prostacyclin-like activity by rat stomach under stress.

It is known that a confinement procedure will promote histological alterations in the gastric mucosa of rats. It is our hypothesis that, under these conditions, there should be an alteration in prostacyclin metabolism. Our findings corroborate this idea, which makes us suppose that the deficient release of prostacyclin-like activity by the rat's stomach may play an important role in gastric mucosa vitality and in its consequent damage.

[Use of the combination of a nitrofurazone derivative with polyethylene glycols in the prevention of the formation of peritoneal adhesions - experimental study]. / Utilização da associação do derivado da nitrofurazona com o polietileno-glicol (NPG)+ para prevenção da formação de aderências peritoneais--estudo experimental.

The authors studied the effectiveness of the association of Nitrofurazone derivates with Polyethylene glycol (NPG) on peritoneal adhesions prevention. Despite the fact of constitutional characteristics may elicit or not the formation of adhesions and bands, they concluded that, although the drugs have not demonstrated the capacity of avoiding such phenomena, they could block this process at a fibrinous stage, which is relatively safe concerning the possibility of intestinal obstruction.

Utilizacao da associacao do derivado da nitrofurazona com o polietileno-glicol (NPG) para prevencao da formacao de aderencias peritoneais - estudo experimental. / Use of the association of nitrofurazone with polyethylene glycols (NPG) for prevention of formation of peritoneal adhesions - experimental study

Os autores estudaram em caes, a efetividade da associacao do derivado da nitrofurazona com o polietileno-glicol (NPG), na prevencao de aderencias peritoneais traumaticas (poscirurgicas). A partir dos resultados obtidos, concluem que, a despeito da constituicao do animal, como fator influenciador na capacidade de formacao de aderencias e bridas, a droga, de modo geral, mostrou-se capaz de prevenir o estabelecimento de aderencias fibrosas, bloqueando este processo evolutivo em um estagio fibrinoso, que nao acarreta maiores preocupacoes no que concerne a possibilidade de obstrucao intestinal