Double-blind placebo-controlled randomized clinical trial evaluating doxycycline effects on chemotherapy-induced oral mucositis.

WHAT IS KNOWN AND OBJECTIVE: Chemotherapy (CT)-associated oral mucositis (OM) is one of the most debilitating and painful side effects in oncology patients, with limited effective management options. During CT, matrix metalloproteinases (MMPs) are upregulated, causing damage in mucosal and submucosal tissues, and playing a key role in OM; therefore, the use of subantimicrobial doxycycline as a MMP inhibitor may represent a potential approach for OM management. The aim of this clinical trial was to evaluate the efficacy and safety of low doses of doxycycline in OM development in individuals with acute leukaemia (AL) during CT. METHODS: Randomized controlled clinical trial (Registration No. NCT01087476) performed in adult AL patients scheduled to receive CT (September 2010-October 2014). Individuals were stratified by leukaemia type and assigned randomly to receive doxycycline hyclate (50 mg/d) (doxycycline group: DG) or placebo (placebo group: PG) before and during CT. Included subjects had a baseline oral examination and thereafter 3 times a week during 21 days. The primary outcome was OM development. RESULTS AND DISCUSSION: One hundred and forty-seven AL subjects were enrolled: 74 in DG and 73 in PG; baseline characteristics between groups were comparable. During follow-up, 15 (10.2%) individuals developed OM; no differences between treatment groups were found (DG:8.1%, PG:12.3%; P = .59). The mean OM Assessment Scale score was 2.51, without differences between groups (DG:2.7, PG:2.4; P = .65). Low baseline blood albumin levels in the OM-affected individuals were identified, revealing the effect of systemic deterioration as a predisposing factor for OM development. No adverse effects were observed. WHAT IS NEW AND CONCLUSION: Subantimicrobial doses of doxycycline did not reduce the incidence, onset, duration or severity of OM.

[Lymphoma. Current status and treatment]. / Linfomas. Estado actual y tratamiento.

The use of single-cell polymerize chain reaction analysis has allowed for a better understanding of the origin of Hodgkin's disease, Burkitt. The study of the mechanisms regulating apoptosis and the survival of neoplastic clones have opened a whole area of research. The Revised European-American List of lymphoid neoplasms must be presented in a form that facilitates the understanding, learning, and teaching of these disorders. There is a great need for a better definition of the new category of lymphoplasmacytic lymphoma, the variants of mantle cell lymphoma and marginal zone B-cell lymphomas, and the coming of age of the NK-cell lymphomas. Based on current data, it is difficult to determine the site of transplantation in the management of follicular, low-grade non-Hodgkin's lymphoma. These patients remain at risk of relapse after transplantation, mirroring results with conventional therapy. The treatment of aggressive lymphomas remains an area of significant controversy. The Intergroup Study concluded that none of the more recent regimens was superior to CHOP. Recent data suggest that high-dose therapy with consolidative autologous or allogenic transplant may benefit patients with aggressive histology lymphoma who have poor prognostic features.

Refractory anemia with excess of blasts: increased survival when treated with cyclophosphamide, methotrexate and 6-mercaptopurine.

Owing to the lack of efficacious treatments for refractory anemia with an excess of blasts (RAEB), evaluation of other therapeutic strategies is necessary, especially in elderly patients. We report herein our experience with an oral triple drug regimen with cyclophosphamide 200 mg/m2 and methotrexate 20 mg/m2 once a week, and 6-mercaptopurine 50 mg/m2 daily for the treatment of RAEB. Eighteen patients with a median age of 62 yr (range 17-80) received a triple drug regimen (TDR), and they were compared with 6 patients who received oxymetholone (2 mg/m2/d) and 9 who received supportive therapy only. Partial response was achieved in 45% of patients receiving TDR. In 77% of patients treated with TDR the number of bone marrow blasts decreased to <5%; however, they persisted with trilineage dyspoietic morphologic changes. Median survival for TDR was 23 months (range 1-96), which was longer than that for the other groups. A slight rise in liver enzymes was the only side effect of TDR. TDR seems to be a useful alternative in patients with RAEB, a finding to be confirmed in further prospective studies.

Hemophagocytic syndrome associated with hematological neoplasias.

Hemophagocytic syndrome (HPS) is a reactive process that complicates several diseases including hematological neoplasias (HN). It has been suggested that HPS may be a negative prognosis factor for neoplastic diseases. In this retrospective analysis, 13 cases with HPS associated to HN were compared with two age, sex, diagnosis, disease stage and treatment matched controls in order to determine the impact of this syndrome on the survival. Cases with HPS were adult patients with a male:female ratio of 1:1 and their clinical picture was characterized by fever, lymphadenopathy, hepatosplenomegaly, and pancytopenia. Median survival since HN diagnosis was 7 and 48 months for the HPS and control groups, respectively (P = 0.0001). In ten patients who died, median survival after HPS presentation was 1 month. These results suggest that the presence of HPS is a negative prognosis factor in patients with HN. Due to its high mortality rate, an individualized, early, and intensive chemotherapeutic regimen may be required for HN complicated with this syndrome.

The incidence of protein C deficiency in thrombosis-related portal hypertension.

OBJECTIVE: To know the incidence of protein C deficiency associated with noncirrhotic, thrombosis-related portal hypertension. METHODS: Thirty-six patients were studied who had thrombosis-related portal hypertension diagnosed by means of hepatic venography or abdominal echocardiography or during abdominal surgery. Liver disease was excluded in 20 patients based on normal liver function tests and normal histology on liver biopsy. At the time of protein C assays, these patients were not receiving oral anticoagulation, and, in those recently diagnosed, the assays were performed more than 14 days after the last thrombotic event. Antigenic and functional assays for protein C were performed by ELISA and chromogenic assay, respectively. RESULTS: We found 11 patients with protein C deficiency who had a median age of 28 yr (range 19-55 yr) at time of diagnosis. Five patients had a history of systemic thromboembolism, and upper GI bleeding was the most frequent symptom related to portal hypertension (six cases). Antigenic protein C levels were measured in nine of the 11 patients (mean 31.88%, range 10-49%). Functional protein C level was assayed for all 11 patients (mean 40.90%, range 15-58%). After diagnosis, all patients received oral anticoagulants (ideally International Normalized Ratio: 2-3). CONCLUSION: We suggest that protein C screening should be performed in patients with thrombosis-related portal hypertension.

[Essential thrombocythemia: a 35-year experience and review of the literature]. / Trombocitemia esencial: experiencia de 35 años y revisión de la literatura.

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by an uncontrolled rise in peripheral blood platelet count. The aim of this report was to determine the clinical and laboratory data of this disease in a 35 years revision. Of the patients with the diagnosis of ET, we selected those who fulfilled five of the six diagnostic criteria proposed by the Poli Vera Study Group. We found 14 cases (10 female and 4 male) with a median age of 54.5 years (range 29-74). The most frequent initial clinical finding was hemorrhage and in four cases the diagnosis was preoperative. Median platelet count was 1,355 x 10(9)/L (range 600 to 3,750). One case had iron deficiency which was corrected before ET was diagnosed. None has evolved to acute leukemia. Initially, most of the cases were treated with busulphan and two received alpha-interferon which was promptly changed to busulphan because of secondary effects. Three patients have died due to hemorrhagic complications and one due to thrombosis. ET has a low frequency in our country and must be considered an exclusion diagnosis. Iron deficiency may mask the diagnosis specially in the cases with a platelet count not very high. Treatment can provide in general a long survival of good quality of life.

[Reference values for protein C activity in healthy adults in Mexico]. / Valores de referencia de la activadad de proteína C en adultos sanos en México.

Protein C (pC) is a natural-occurring anticoagulant and its acquired or hereditary deficiency has been associated with thrombosis. For its screening, technics that appraise both its plasmatic concentration and biological activity are used. The quantitative deficiency is important, but some characteristics of pC activity (pCA) suggest an essential role of the functional deficiency. Because reference levels have not been previously described in Mexico, we report here the results of a pCA assessed by a chromogenic assay in 88 adult healthy mexican people between 15 and 69 years of age. The pCA values at the 2.5 and 97.5% percentiles in our population were 75 and 137% in normal plasma. Functional disorders of this protein have been described in the presence of normal pC quantitative levels and, therefore, there are individuals with low pC concentrations and a normal pCA without thrombosis. These data suggest that the pCA could be a more important screening test than the quantitative determination as the first step in the study of a possible deficiency state of protein C.

Drug-induced agranulocytosis treated with granulocyte-macrophage colony stimulating factor.

Drug induced agranulocytosis (DIA) is a potentially lethal disorder characterized by selective neutropenia. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been utilized for its treatment. We report four cases of DIA treated with GM-CSF at the dose of 5 micrograms/kg/day. The patients presented infectious diseases at diagnosis. Median days to obtain 1 x 10(9)/L neutrophils and a normal neutrophil count (NNC), were 7(5-9) and 7.5 (6-10) days, respectively. The infectious disease at diagnosis improved and all patients are alive at the moment of this report. No other adverse effects than thrombocytosis (two cases) and thrombocytopenia (one case) were observed. We consider that GM-CSF could be a safe and effective alternative in the treatment of DIA.

[The international normalization ratio in the monitoring of oral anticoagulant therapy]. / El cociente de normalización internacional en la vigilancia de la terapia anticoagulante oral.

Oral anticoagulants are employed very frequently in the prophylaxis and treatment of several diseases. For their optimal effectiveness, many vigilance schedules have been proposed but none has proved to be 100% effective. The international normalization ratio (INR) can be a safer way to monitor oral anticoagulation, and our objective was to determine its clinical usefulness. A prothrombin time test (PT) was carried out by means of either a chromogenic or a coagulometric method, and an INR was obtained using the ratio of the PT patient/PT control elevated to an exponential given by the international sensitivity index (ISI) of our thromboplastin. Our objective was to maintain our patients in a therapeutical INR range between two and three. We present our experience with 77 patients and 810 results during an 18 months period. We observed 26 cases of hemorrhage and three of thrombosis. In all these cases, the INR was out of the desired therapeutical range. No deaths occurred in our patients. Our analysis showed a significative disagreement between the INR and the prothrombin time ratio (PTR) but a better correlation with hemorrhage and thrombosis was seen with the INR than with the PTR. Our experience supports the use of INR in the clinical vigilance of oral anticoagulation as a useful method.

[Treatment of chronic refractory idiopathic thrombocytopenia purpura. 10 years experience at the Salvador Zubiran National Institute of Nutrition]. / Tratamiento de la púrpura trombocitopénica idiopática crónica refractaria. Experiencia de diez años en el Instituto Nacional de la Nutrición Salvador Zubirán.

A total of 126 patients with chronic idiopathic thrombocytopenic purpura were diagnosed from January 1980 to January 1990 in our institute. In this group of patients, 21 were refractory to prednisone therapy, splenectomy or both, or had had a relapse after a good response with these treatments. They were given other therapies. There was enough information for evaluation in 16 of the 21 patients. The treatment responses were classified according to the post-therapy platelet counts: complete response (CR) = > 150 x 10(9)/L for more than three months; partial response (PR) = 50-150 x 10(9)/L for more than three months; any response (AR) = CR + PR; no response (NR) = < 50 x 10(9)/L. There were 15 women and one male. The median age was 41 years (range 11 to 65). 6-mercaptopurine was given in all patients with CR = 31.2%, PR = 18.8%, AR = 50% and NR = 50%. Seven patients received cyclophosphamide with CR = 28.6%, PR = 14.3%, AR = 42.9% and NR = 57%. Vincristine was given in four patients with only one PR. Interferon alpha 2B was given in four patients with two transitory PR. One patient received colchicine and vitamin C without response. It is concluded that 6-mercaptopurine and cyclophosphamide are useful drugs in refractory thrombocytopenic purpura.

[Comparison of 2 chemotherapy protocols in adult acute myeloblastic leukemia. Results of the Instituto Nacional de la Nutrición Salvador Zubirán cooperative group]. / Comparación de dos esquemas de quimioterapia en la leucemia aguda mieloblástica del adulto. Resultados del grupo cooperativo INNSZ.

Up to now, the best treatment for patients with acute myelogenous leukemia (AML) is the induction of bone marrow hypoplasia by ablative combined chemotherapy; the prototype of these schedules is the so-called 7 + 3 (seven days of continuous infusion of cytarabine and three days of one-hour infusion of any anthracycline); these schedules require the support of both platelet transfusions and antibiotics. Other non-ablative schedules have also been tried in the treatment of such patients. Here we analyze the results of the treatment of 76 adult patients with AML; 43 were treated with the classical 7 + 3 schedule, whereas 33 were treated with a combination of chemotherapy used in non-ablative doses (TADOP: thioguanine, arabinosyl-citosine, doxorrubicin, vincristine and prednisone). The results were as follows, respectively, for 7 + 3 and TADOP: complete remission (CR) was achieved in 60 and 48% of patients (p NS); the number of cycles to achieve CR had a median of 1 and 5 months (p less than 0.001); the median duration of the CR was 21 and 10 months (p less than 0.05); fatal myelotoxicity was 30 and 42% (p NS), one-year disease free survival (DFS) was 45 and 46% (p NS) and three-year survival was 22% and 15% (p NS). Additionally, patients treated with 7 + 3 were divided into two groups according to the type of platelet transfusion support; those supported with apheresis equipment and those with centrifugation-derived platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term treatment and prognostic factors in adult acute myeloblastic leukemia. Experience of the INNSZ group Puebla-Monterrey-Mexico)]. / Tratamiento a largo plazo y factores pronósticos en leucemia aguda mieloblástica del adulto. Experiencia del grupo INNSZ (Puebla-Monterrey-México).

The results of the treatment in a group of 43 adult patients with acute myelogenous leukemia (AML) are analyzed. All patients were induced to remission with a 7/3 schedule: cytarabine in continuous infusion during seven days and an anthracycline in push during three days; consolidation was done with the same regimen and no maintenance therapy was used. Complete remission (CR) was achieved in 60%, median survival of those achieving CR was 21 months. Mortality during induction was 30%; relapses occurred in 61% of those achieving CR. Twelve and 78 months overall-survival was 50 and 18% respectively, whereas 12 and 78 months disease-free-survival was 46 and 16% respectively. Fourteen variables were analyzed in their impact in both CR achievement and long term survival. Four variables were found to be associated with CR achievement: hemoglobin levels, major bleeding and infection at diagnosis, and site of treatment (private practice vs city hospital). All variables were associated with the 78 months survival, but two variables were related to 12 months survival: time of recovery of the bone marrow after ablative chemotherapy and amount of platelets transfused during the chemotherapy-induced hypoplasia. With regard to the first variable, the 12 months survival was 90 and 55% for patients recovering a normal bone marrow, before or after 25 days of initiation of chemotherapy (p less than 0.05). On the other hand, the hemorrhage-associated-mortality during induction was 9 and 36% for patients receiving more or less than 20 units of platelets during hypoplasia respectively (p = 0.038).(ABSTRACT TRUNCATED AT 250 WORDS)

[Dyshemopoietic anemias (AD) (myelodysplastic syndromes). Retrospective analysis of 40 cases from the Instituto Nacional de la Nutrición Salvador Zubirán (INNSZ)]. / Anemias dishemopoyéticas (AD) (síndromes mielodisplásicos). Análisis retrospectivo de 40 casos del Instituto Nacional de la Nutrición "Salvador Zubirán" (INNSZ).

40 patients with DMPS were studied and diagnosed at the INNSZ during 1980-1985. Eighteen were males and twenty two females; age average of 55.7 years (17-82), with 72.5% over 50 years old. Their distribution according to the FAB classification was: 55% type I, 10% type II, 27.5% type III, 2.5% type IV and 5% type V. All of them had an anemic syndrome and 47.5% had bled, 52.5% had pancytopenia; there was anemia and thrombocytopenia in 32.5%, anemia and leukopenia in 7.5%, and anemia only in 7.5%. The bone marrow was normocellular in 42.5%, hypercellular in 40% and hypocellular in 17.5%, 45% of the patients survived; 22% achieved a complete remission (CR) and 9 patients (22.5%) died of causes related to DMPS. The rest was lost to follow up.