A Rare Case of Coexisting Breast Cancer and Refractory Acute Myeloid Leukemia.

The occurrence of acute myeloid leukemia (AML) within six months from a diagnosis of breast cancer (BC) is rarely reported in the literature, and it is associated with a poor prognosis. We report herein the case of a 40-year-old woman referred to our centre affected by BC and simultaneous AML. The patient proved refractory to first line therapy and achieved complete remission (CR) with a clofarabine-based regimen followed by allogeneic stem cell transplantation (ASCT). Both during salvage chemotherapy and after ASCT, the patient presented severe infectious complications ( acute cholecistytis and Nocardia pneumonia, respectively) treated with surgery, and currently she is alive in CR for both diseases after 29 months of follow-up. The case highlights the importance of a diagnostic assessment of any unexplained cytopenia in association with solid neoplasia under treatment, underlining the feasibility and priority of a timely treatment of the haematological neoplasm in order to achieve long-term survival.

Experiencia argentina en la etapa final de erradicación de la polio: cambio de vacuna oral trivalente a bivalente / Argentinian experience to finish polio eradication: switch from trivalent to bivalent oral poliovirus vaccine

Entre el 17 de abril y el 1 de mayo de 2016, 155 países en todo el mundo cambiaron el uso de la vacuna oral trivalente, que protege contra los tres tipos de poliovirus (1, 2 y 3), por la vacuna oral bivalente, que protege contra los poliovirus tipo 1 y 3. Este cambio señala el mayor esfuerzocoordinado globalmente en la historia de las vacunas. En Argentina se realizó el pasado 29 de abril, con una intensa planificación previa y una posterior validación.

Complete remission obtained with azacitidine in a patient with concomitant therapy related myeloid neoplasm and pulmonary mucormycosis.

Mucormycosis is the third cause of invasive mycosis after candidiasis and aspergillosis in AML patients, representing a poor prognostic factor associated with a high rate of fatal outcome. We report a case of a patient with AML and a concomitant pulmonary mucormycosis at diagnosis, who obtained a complete remission both of her AML and of the fungal infection. The incidence of the infection at the onset of leukemia is extremely unusual, and, to our knowledge, the sporadic cases reported in the literature are included in heterogeneous series retrospectively examined. In our case, Liposomal Amphotericin B as single agent appeared incapable of controlling the infection, so anti-infective therapy was intensified with posaconazole and simultaneously antileukemic treatment with 5-azacitidine was started, with the understanding that the only antifungal treatment would not have been able to keep the infection under control for a long time if not associated with a reversal of neutropenia related to the disease. We observed a progressive improvement of the general conditions, a healing of pneumonia and a complete remission of the leukemic disease, suggesting that a careful utilization of the new compounds available today, in terms of both antifungal and antileukemic treatment, may offer a curative chance a patient who would have otherwise been considered unfit for a potentially curative therapeutic strategy.

The outcome of reduced intensity allogeneic stem cell transplantation and autologous stem cell transplantation when performed as a first transplant strategy in relapsed follicular lymphoma: an analysis from the Lymphoma Working Party of the EBMT.

Both auto-SCT and reduced intensity allo-SCT (RIST) are employed in the treatment of relapsed follicular lymphoma (FL). We have analysed the outcome of these two transplant procedures when used as a first transplant in this setting. We conducted a retrospective comparison of 726 patients who underwent an auto-SCT and 149 who underwent a RIST as a first transplant procedure for relapsed FL as reported to the Lymphoma Working Party of the European Bone Marrow Transplant. The non-relapse mortality (NRM) was significantly worse for patients undergoing a RIST (relative risk (RR) 4.0, P<0.001). The 1-year NRM was 15% for those undergoing a RIST compared with 3% for those undergoing an auto-SCT. Disease relapse or progression were significantly worse for those receiving an auto-SCT (RR 3.1, P<0.001). Patients undergoing a RIST had a 5-year relapse rate of 20% compared with 47% for those undergoing an auto-SCT. The PFS at 5 years was 57% for patients receiving a RIST compared with 48% for those receiving an auto-SCT. There was no significant difference in OS between the two groups. RIST is associated with a higher NRM and lower relapse rate in patients with relapsed FL.

Spatial and temporal analysis of the distribution of hantavirus pulmonary syndrome in Buenos Aires Province, and its relation to rodent distribution, agricultural and demographic variables.

We studied the spatial and temporal distribution of Hantavirus Pulmonary Syndrome (HPS) cases from 1998 to 2001 in the Buenos Aires Province, Argentina. HPS is a severe viral disease whose natural reservoir are rodents of the subfamily Sigmodontinae (Muridae) and which occurs in many countries of South and North America. We considered two spatial arrangements: cells of 18.5 x 18.5 km(2); and departments, the political subdivisions of the province, as spatial units. We tested the departure from a Poisson distribution of the number of cases per cell and per month with the Variance/Mean index, while the interaction between spatial and temporal clustering was tested by means of the Knox and Mantel tests. We constructed probability maps in which the HPS rates per department were considered Poisson variates according to population, area and the product of population and area. We analysed the relation between rodent distribution, environmental and demographic variables and HPS cases conducting preliminary univariate analysis from which we selected variables to enter in general linearized models. We found that both the spatial and temporal distribution of cases is strongly aggregated. The spatiotemporal interaction appears to be related to a strong seasonality and the existence of particular ecological conditions rather than epidemic transmission of the disease. The main explanatory variables for the distribution of HPS cases among the departments of the Buenos Aires Province were human population, the distribution of the rodent Oxymycterus rufus and evapotranspiration. The last two variables are probably indicators of favourable ecological conditions for the reservoirs, which encompass other variables not taken into account in this study.

Neutropenic enterocolitis in acute leukemia: diagnostic and therapeutic dilemma.

The main purpose of this report is to focus on the importance of an accurate etiologic diagnosis of gastrointestinal complications during chemotherapy for acute myeloid leukemia, taking into account that a syndrome characterized by bowel wall thickening associated with diarrhea and abdominal pain may have etiologies different from neutropenic enterocolitis (NE) and in such a case necessitate a different treatment approach. We describe a case of a 46-year-old woman affected by acute myeloid leukemia presenting the onset of a syndrome with clinical features of NE. Supportive therapy for NE was instituted, but during treatment the patient presented a life-threatening gastrointestinal bleeding and was submitted in emergency to hemicolectomy. Following surgery, the patient recovered completely and she is currently alive in complete remission after receiving allogeneic bone marrow transplantation. Histological examination of the surgical specimens showed that the acute abdominal syndrome was related to massive infiltration of the bowel by leukemia cells. A correct baseline evaluation and a prompt diagnosis of the complication may help in making the therapeutic decision, which in our case led necessarily to a surgical procedure, because the bleeding was due to post-chemotherapy necrosis of the leukemic infiltrating tissue. A close collaboration between the hematologist and the surgeon may provide guidelines for behavior in such cases, giving these patients the possibility of survival and the opportunity to carry on the treatment planned for the primary disease.

How long can we give interleukin-2? Clinical and immunological evaluation of AML patients after 10 or more years of IL2 administration.

We have treated 20 patients, affected by acute myelogenous leukemia in advanced phase of the disease, with intravenous high-dose recombinant interleukin-2 (IL2) as induction treatment, achieving a complete remission (CR) in 11/20 of patients (55%). All CR patients were planned to receive a maintenance program with lower subcutaneous doses of IL2 until relapse. Currently, 5/11 patients are alive in continuous complete remission with a minimum follow-up of 9 years from IL2 induction. In the aim to investigate the treatment's side-effects during or after prolonged IL2 therapy, we decided to submit these patients to a clinical and immunological evaluation. Four patients have been evaluated as one, who independently stopped IL2 after 6 years, refused the check-up. No organ-specific treatment sequelae that may decrease the quality of life or may be life-threatening were found, concerning renal, liver and cardiovascular function. Endocrine abnormalities were detected in three patients, the most serious being a severe hypothyroidism, which prompted cessation of IL2 maintenance after 6 years and required thyroid supplementation treatment. Immunological studies were carried out prior to the last IL2 cycle and showed high levels of CD3-positive T cells expressing the IL2 receptor alpha chain (CD25), both in the peripheral blood and in the bone marrow. Our study shows that low-dose IL2 can be given for a prolonged period of time without serious organ-specific late sequelae and with a good quality of life.

Thrombotic thrombocytopenic purpura and pregnancy: a case report and a review of the literature.

Thrombotic thrombocytopenic purpura (TTP) is a severe disorder affecting the microcirculation of multiple organ systems. Plasma therapy has significantly reduced the mortality rate. Infections, pregnancy, cancers, drugs, and surgery were frequently associated with the initial episodes and relapses. Women who are either pregnant or in the postpartum period make up 10-25% of TTP patients, suggesting the interrelationship between TTP and pregnancy. The introduction of aggressive treatment with plasma transfusion or plasmapheresis improved maternal and fetal survival rates. We describe a case of a first successful pregnancy concomitant to a late relapse of TTP, in which the identification of important risk factors for both TTP and pregnancy allowed us easier hematological and obstetrical management. Proposed guidelines for pregnancy-related TTP management and a brief review of current treatment options for this rare condition are also included.

Thrombotic thrombocytopenic purpura: prospective neurologic, neuroimaging and neurophysiologic evaluation.

BACKGROUND AND OBJECTIVES: Neurologic symptoms are present in 60% of patients with thrombotic thrombocytopenic purpura (TTP) on initial examination and ultimately develop in about 90% of cases during the course of the disease. Despite central nervous system involvement being frequent, abnormalities in the brain of patients with TTP are infrequent on neuroimaging (CT/MRI) and neurophysiologic (EEG) evaluation, often reversible and mainly limited to symptomatic stages of the disease. The aim of our study was to establish the value of a complete neurologic screening as part of the work up of TTP. DESIGN AND METHODS: We prospectively evaluated 16 TTP patients, performing serial neurologic, neuroimaging and EEG examinations, independently of the presence of an objective central nervous system involvement. RESULTS: Our study shows that a complete neurologic evaluation is of modest help in improving the diagnosis of TTP, but may be useful for the neurologic management. INTERPRETATION AND CONCLUSIONS: Accurate neuroimaging and, especially, EEG evaluation and monitoring allowed us to identify patients who could benefit from anticonvulsive therapy, avoiding the unnecessary administration of the latter. The prognostic utility of complete neurologic screening in TTP remains to be conclusively demonstrated in larger prospective neurologic studies.

Obesity and autologous stem cell transplantation in acute myeloid leukemia.

In the bone marrow transplant setting, several authors hypothesized that severely overweight patients are at increased risk of transplant-related toxicity, but different definitions of obesity, different body weight groupings and heterogeneous samples of patients were analyzed. To overcome these limitations, we retrospectively considered a homogeneous group of 54 patients (median age 36.5 years), with a diagnosis of de novo acute myeloid leukemia (AML), autografted in first complete remission (CR) with the Bu-Cy2 conditioning regimen, dosed on actual body weight. Patients were classified into three groups (obese, non-obese, underweight) using body mass index (BMI = kg/m(2)); for each group we analyzed transplant-related toxicity and mortality, overall survival and disease-free survival (OS/DFS). In spite of the relatively small number of patients, in our results high BMI appears a predictive factor for an increase of treatment-related toxicity and mortality. Moreover, 30 (55%) patients are currently alive in continuous CR, and after a median follow-up of 76.5 months (range 14-137) statistically significant differences in OS and DFS were detected between obese and non-obese groups (P = 0.012 and 0.021, respectively). Our study suggests that obesity may represent an independent risk factor for autograft in AML and further investigations are warranted.

Ten-year follow-up of a single center prospective trial of unmanipulated peripheral blood stem cell autograft and interferon-alpha in early phase chronic myeloyd leukemia.

BACKGROUND AND OBJECTIVES: The potential role of autologous stem cell transplantation (ASCT) as an alternative therapeutic strategy in chronic myelogenous leukemia (CML) has been widely explored in pilot studies, but the clinical results in terms of survival have so far been evaluated only retrospectively and in heterogeneous groups of patients. The goal of our prospective study was to evaluate the feasibility and long-term efficacy of unmanipulated ASCT followed by low-dose interferon-alpha in a homogeneous group of patients affected by CML in a very early phase of disease. DESIGN AND METHODS: Twenty-six unselected consecutive patients with CML in chronic phase underwent stem cell collection at diagnosis, then received cytoreductive treatment with hydroxyurea and, subsequently, a busulphan-melphalan myeloablative regimen followed by unmanipulated stem cell graft within one year of diagnosis. Interferon was given a median of 6.5 months after transplant at escalating doses, starting from 0.5 x 10(6) IU 3 times/week, on the basis of the clinical and hematologic tolerance. RESULTS: Median chronic phase duration from diagnosis is 9 years. The ten-year projected probability of overall survival from diagnosis is 55% with a median follow-up of surviving patients of 9.5 years (8-10.5); median survival has not been reached after ten years. INTERPRETATION AND CONCLUSIONS: Our experience suggests that high-dose therapy followed by unmanipulated peripheral blood stem cell transplantation and low-dose interferon-alpha is a feasible approach, which results in long-term survival in newly diagnosed CML patients. These data need to be confirmed in controlled trials comparing ASCT with other therapeutic approaches, such as the use of interferon-alpha alone or in combination with other agents.

High-dose idarubicine, busulphan and melphalan as conditioning for autologous blood stem cell transplantation in multiple myeloma. A feasibility study.

Extensive studies have tested the clinical impact of double and triple sequential transplants as front-line therapy in MM, following the suggestion that dose escalation can overcome the marked drug resistance characteristic of this disease, but the superiority of such approaches vs one single transplant has still to be demonstrated. The aim of our study was to evaluate the feasibility and efficacy of high-dose idarubicine intensification of a standard busulphan-melphalan conditioning regimen in MM. Twenty-eight patients (median age 55 years) with sensitive disease received PBSCT after high-dose idarubicine combined with busulphan and melphalan and followed by s.c. rhG-CSF until PMN recovery. The most severe toxicity was represented by oral mucositis which resolved with hemopoietic reconstitution. Overall response and CR rate were 52% and 40%, respectively. Currently, 36 patients are alive and 19 are progression-free a median of 20 months (12-36) from transplant. The 3-year projected probability of progression-free survival for patients transplanted after first-line treatment is 60%. The combination of Ida/Bu/Melph appears a promising alternative regimen for PBSCT in myeloma, with low transplant-related toxicity and fast hematological recovery. Long-term follow-up and a prospective randomized study, now ongoing, will probably clarify whether an idarubicine-intensified regimen will result in superior outcomes to conventional conditioning and even be comparable to a double consecutive transplant program.

Unmanipulated peripheral blood stem cell autograft in chronic lymphocytic leukemia: clinical findings and biological monitoring.

BACKGROUND AND OBJECTIVES: To investigate the feasibility of peripheral blood stem cell (PBSC) transplantion in patients with high-risk chronic lymphocytic leukemia (CLL) in remission after fludarabine therapy, the clinical impact of minimal residual disease (MRD) monitoring and the immunologic reconstitution after transplantation. DESIGN AND METHODS: Twenty CLL patients, in clinical complete remission (CR) after fludarabine, were offered an unmanipulated PBSC transplant and were longitudinally monitored for MRD and immunologic reconstitution. RESULTS: Due to unsatisfactory PBSC collection, 4 patients received bone marrow cells. All patients engrafted. Two patients died, one due to infection and one because of another neoplasia. Thirteen patients are at present in clinical CR after a median follow-up of 17 months and 18 patients are alive with a survival probability of 0.87 (+/-0.04) at 52 months after transplant. Fifteen patients had a molecular remission. Three of them showed a molecular relapse 16-28 months after autograft, followed by a clinical relapse 10-16 months later. Three of the four patients who remained persistently rearranged could be revaluated over time and showed an immunologic relapse 11-26 months after transplant; two of these had a clinical relapse 12 and 7 months later. A marked and persistent impairment of both the B- and T-immunologic compartments was recorded in the horizontal follow-up. INTERPRETATION AND CONCLUSIONS: Unmanipulated PBSC autograft is a feasible procedure that produces prolonged molecular remissions in high-risk CLL patients. Persistence or reappearance of a molecular signal after engraftment is predictive of subsequent immunologic and clinical CLL recurrence. The long -lasting impairment of the host immune repertoire after fludarabine followed by autograft has to be taken into account in the patients' management.

Use of interleukin-2 in the management of haematological malignancies: focus on minimal residual disease.

Interleukin (IL)-2 is a glycoprotein lymphokine which induces proliferation of all subclasses of T-lymphocytes, natural killer cells and lymphokine activated killer cells, differentiation of cytotoxic cells and secretion of other cytokines, especially interferon-gamma. A fundamental property of IL-2 activated effector cells is to selectively lyse freshly isolated tumour cells. Work carried out on animal tumour models and application in human therapeutics has suggested the potential value of an immunotherapeutic approach in haematological malignancies, especially in the setting of minimal residual disease. Extensive phase I/II trials have been conducted in all haematological diseases, but the most interesting results have been obtained in acute myeloid leukaemia and non-Hodgkin's lymphoma, where the possibility of achieving partial and complete responses in patients with advanced disease has been reported. The feasibility and immunomodulatory effects of IL-2 treatment in patients with minimal residual disease after high-dose chemotherapy have also been explored. However, the heterogeneity of cases treated and administration schedules used does not allow definitive conclusions to be drawn about the true impact of IL-2 treatment on the prognosis of these patients. The clearly encouraging results reported in the literature deserve further investigation from a biological and clinical point of view; until the role of IL-2 in haematological malignancies has been identified, it should be used only in the investigative setting of clinical trials.

Clinical and metabolic effects of different parenteral nutrition regimens in patients undergoing allogeneic bone marrow transplantation.

BACKGROUND: Nutrients may interfere with physiological and pathophysiologic mechanisms. The present study was aimed at evaluating whether the differences in the quality of energy substrates administered with total parenteral nutrition (TPN) after cytoreductive therapy may influence the clinical outcome of patients undergoing bone marrow transplantation (BMT). METHODS: Sixty-six consecutive allogeneic BMT patients with hematologic malignancies were randomized to receive either a glucose-based (100% glucose) or a lipid-based (80% lipid, using an omega-6 long-chain triacylglycerol emulsion + 20% glucose) TPN, providing 146.3 kJ/kg body weight, 1.4 g of protein/kg of body weight, administered from day +1 to day +15 after BMT. Time to engraftment (EGT), incidence of sepsis and metabolic complications (hyperglycemia and hypertriglyceridemia), incidence of acute graft-versus-host-disease (A-GVHD) and relapse, survival at 18 months, incidence of deaths for A-GVHD and relapse were evaluated. RESULTS: Six patients dropped out before completing the study period. Thirty-one patients in the glucose-based TPN group and 29 patients in the lipid-based TPN group were evaluated. The incidence of hyperglycemia was significantly lower in the lipid-based TPN group than in the glucose-based TPN group (3.4% vs. 32%, respectively; P=0.004). Five patients in the glucose group and none in the lipid group died for A-GVHD (P<0.05). Survival at 18 months tended to be higher in the lipid group than in the glucose group (62% vs. 42%, P=NS). Rate of bone-marrow EGT, time to EGT, incidence of sepsis and fungal infections during TPN, incidence of A-GVHD, and rate of relapse at 18 months were not different in the two groups. CONCLUSIONS: The results obtained suggest that the use of lipid-based TPN after allogeneic BMT is associated with lower incidence of lethal A-GVHD and hyperglycemia, without negatively affecting the EGT of infused cells. Intravenously administered lipids might have influenced the severity of A-GVHD likely via modulation of immune response and synthesis of cytokines, prostaglandins, and leukotrienes that participate in the pathogenesis of graft-versus-host disease.

Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene.

Reverse-transcription polymerase chain reaction (RT-PCR) of the PML/RAR alpha fusion gene may predict relapse in acute promyelocytic leukemia (APL) patients in hematologic complete remission (CR). We have prospectively studied by RT-PCR 15 PML/RAR alpha+ APL patients undergoing autologous bone marrow transplantation (ABMT) in second CR. The median time of first CR duration was 12 months (range, 6 to 40). All patients were reinduced with all-trans retinoic acid (ATRA), followed in 12 of 15 cases by mitoxantrone and Ara-C as consolidation. Fourteen patients received the BAVC (BCNU, Ara-C, m-AMSA, and VP-16) schedule as conditioning regimen. Unpurged marrows were collected immediately before conditioning treatment, analyzed by RT-PCR, and reinfused at median of 2 months (range, 2 to 7) from the achievement of second CR. Seven patients were PCR+ and eight PCR for PML/RAR alpha in their pretransplant marrows. All seven patients of the former group remained PCR+ during the follow-up and relapsed at a median time of 5 months (range, 2 to 9) from ABMT and 9 months (range, 4 to 14) from second CR. Of the eight PCR- patients, all remained PCR- during the follow-up controls. One patient relapsed at 10 months from ABMT, one died of a secondary (PML/RAR alpha-) leukemia, and six are in hematologic and molecular remission at a median time of 28 months (range, 15 to 60) after ABMT and 32 months (range, 17 to 62) from second CR. Our results indicate that, in APL patients in second CR, ABMT with PML/RAR alpha- marrow cells is likely to result in prolonged clinical and molecular remissions. Conversely, patients who test PCR+ after reinduction necessitate the use of alternative aggressive approaches, including unrelated allogeneic transplant.