Lenalidomide plus R-CHOP21 in newly diagnosed diffuse large B-cell lymphoma (DLBCL): long-term follow-up results from a combined analysis from two phase 2 trials.

Lenalidomide-RCHOP (R2-CHOP21) has been shown to be safe and effective in patients with untreated diffuse large B-cell lymphoma (DLBCL). The aim of this analysis is to report long-term outcome and toxicities in newly diagnosed DLBCL patients who received R2-CHOP21 in two independent phase 2 trials, conducted by Mayo Clinic (MC) and Fondazione Italiana Linfomi (FIL). All patients received R-CHOP21 plus lenalidomide. Long-term progression-free survival (PFS), time to progression (TTP), overall survival (OS) and late toxicities and second tumors were analyzed. Hundred and twelve patients (63 MC, 49 FIL) were included. Median age was 69 years, 88% were stage III-IV. At a median follow-up of 5.1 years, 5y-PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%; according to cell of origin (COO): 5y-PFS 52.8% vs 64.5%, 5y-TTP 61.6% vs 69.6% and 5y-OS 68.6% vs 74.1% in germinal center (GCB) vs non-GCB respectively. Four patients experienced grade 4-5 late toxicities. Grade ≤ 3 toxicities were infections (N = 4), thrombosis (N = 1) and neuropathy (N = 3). Seven seconds tumors were observed. Long-term follow-up demonstrates that R2-CHOP21 efficacy was maintained with high rates of PFS, TTP, and OS. Lenalidomide appears to mitigate the negative prognosis of non-GCB phenotype. Incidence of therapy-related secondary malignancies and late toxicities were low.

Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib.

This phase 2 trial was designed to evaluate ixazomib, an orally bioavailable proteasome inhibitor, in patients with myeloma who have limited prior exposure to bortezomib. Thirty-three patients with relapsed multiple myeloma were enrolled. Ixazomib was given at 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added for lack of a minor response (MR) by end of cycle 2 or lack of a partial response (PR) by end of cycle 4 or for disease progression at any time. Median age was 69 years; patients had a median of two prior therapies (range 1-7). A grade 3 or 4 adverse event considered at least possibly related to drug was seen in 19 (59%) and 6 (19%) patients, respectively. The most common adverse events were thrombocytopenia, fatigue, nausea and diarrhea. Dexamethasone was initiated in 22 (67%) patients, 17 for not reaching the desired response and 5 for progression. Response (⩾PR) to single agent was seen in five patients within four cycles of therapy including three patients with PR, one patient with complete response (CR) and one patient with stringent CR. Six additional patients with either an MR (2) or SD (4) achieved a PR after addition of dexamethasone, translating to an overall response rate of 34%.

[Septic knee arthritis caused by Pseudomonas aeruginosa after anterior cruciate ligament reconstruction in an adolescent athlete]. / Artritis de rodilla por Pseudomonas aeruginosa posterior a reconstrucción de ligamento cruzado anterior en un adolescente deportista.

Anterior cruciate ligament reconstruction is a very frequent procedure. Postoperative infection after this procedure is a catastrophic, although infrequent, complication. According to the literature, it occurs in less than 1% of all reconstructions done in the United States. We present herein a case report of septic arthritis of the posterior knee associated with anterior cruciate ligament reconstruction.

Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study.

Lenalidomide was shown to have significant single-agent activity in relapsed aggressive non-Hodgkin's lymphoma (NHL). We conducted a phase I trial to establish the maximum tolerated dose of lenalidomide that could be combined with R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone). Eligible patients were adults with newly diagnosed, untreated CD20 positive diffuse large cell or follicular grade III NHL. Patients received oral lenalidomide on days 1-10 with standard dose R-CHOP every 21 days. All patients received pegfilgrastim on day 2 of the cycle and aspirin prophylaxis. The lenalidomide dose levels tested were 15, 20 and 25 mg. A total of 24 patients were enrolled. The median age was 65 (35-82) years and 54% were over 60 years. Three patients received 15 mg, 3 received 20 mg and 18 received 25 mg of lenalidomide. No dose limiting toxicity was found, and 25 mg on days 1-10 is the recommended dose for phase II. The incidence of grade IV neutropenia and thrombocytopenia was 67% and 21%, respectively. Febrile neutropenia was rare (4%) and there were no toxic deaths. The overall response rate was 100% with a complete response rate of 77%. Lenalidomide at the dose of 25 mg/day administered on days 1 to 10 of 21-day cycle can be safely combined with R-CHOP in the initial chemotherapy of aggressive B-cell lymphoma.

A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia.

Patients with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF) have limited therapeutic options. The farnesyltransferase-inhibitor tipifarnib inhibits in vitro proliferation of myeloid progenitors from such patients. In the current phase II clinical trial, single-agent oral tipifarnib (300 mg twice daily x 21 of 28 days) was given to 34 symptomatic patients with either PMF (n=28) or post-PV/ET MF (n=6). Median time to discontinuation of protocol therapy was 4.6 months; reasons for early termination (n=19; 56%) included disease progression (21%) and adverse drug effects (18%). Toxicities (>/=grade 3) included myelosuppression (n=16), neuropathy (n=2), fatigue (n=1), rash (n=1) and hyponatremia (n=1). Response rate was 33% for hepatosplenomegaly and 38% for transfusion-requiring anemia. No favorable changes occurred in bone marrow fibrosis, angiogenesis or cytogenetic status. Pre- and post-treatment patient sample analysis for in vitro myeloid colony growth revealed substantial reduction in the latter. Clinical response did not correlate with either degree of colony growth, measurable decrease in quantitative JAK2(V617F) levels or tipifarnib IC(50) values (median 11.8 nM) seen in pretreatment samples. The current study indicates both in vitro and in vivo tipifarnib activity in PMF and post-PV/ET MF.

Plasma ascorbate in a population of children: influence of age, gender, vitamin C intake, BMI and smoke exposure

The objective of this study is to determine the influence of several personal and lifestyle factors on the levels of circulating vitamin C in a population of children. To accomplish this objective, blood samples were collected from 511 healthy children residing in the Greater San Juan area. The population was stratified into 4 percentile groups (approaching quartiles) according to plasma ascorbate levels from lowest to highest concentrations. Comparisons were made between percentile groups on the basis of age, gender, body mass index (BMI), dietary intake of vitamin C (corrected and uncorrected for energy intake) and exposure to environmental tobacco smoke (ETS). Smoke exposure was determined using urinary cotinine, which is a highly sensitive bioindicator for ETS. Dietary vitamin C was determined via one 24hr recall questionnaire. When all 4 percentile groups were used as a basis of comparison, no differences were noted for any of the factors between groups, however when comparing percentile group 1 (lowest blood ascorbate) to an aggregate value of percentile, groups 2-4, it was found that vitamin C intake (corrected for energy intake) paralleled blood values with a statistically significant association. Among personal and environmental factors only exposure to ETS showed a significant difference in blood levels between groups 2-4 and group 1. No differences between percentile groups were noted for age gender or BMI. These results emphasize that ETS is strongly associated with lowered blood ascorbate levels with the obvious implication of reduced antioxidant protection and increased risk of adverse health consequences.

Improving access to liver transplantation: the University of Puerto Rico experience

Liver transplantation is the only treatment for end-stage liver disease. It is costly, difficult, and not performed in Puerto Rico. For these reasons, it has been a limited option for Puerto Ricans with advanced cirrhosis, especially for those with no medical insurance to cover for the procedure. In an effort to improve access to the procedure and offer this chance of life to more Puerto Ricans facing death from complications of advanced liver disease, the Gastroenterology and Liver Diseases Division of the University of Puerto Rico, in collaboration with LifeLink Transplant Institute in Tampa, Florida and the Office of Catastrophic Funds of the Commonwealth of Puerto Rico, opened a clinic for liver transplant evaluation at the Medical Sciences Campus. The purpose of this clinic is to coordinate the pre-transplant evaluation of candidates for this therapy, provide the evaluation by the transplant surgeon in Puerto Rico, expedite the process in seriously ill patients, and offer post-transplant follow-up upon the patient's return to Puerto Rico. The purpose of this article is to describe the experience in this clinic from 1999 to 2003. One hundred ninety-three patients were seen from September 1999 to January 2003. The most common causes for liver disease were hepatitis C and alcohol, alone or in combination. One hundred thirty four were accepted as candidates for evaluation. Of these, 63 had completed the process, 33 were listed for transplantation and 21 had been transplanted by January 2003. Neither education level, marital status, health insurance nor Child score were associated with successful outcome. This clinic offers Puerto Ricans, especially those with limited resources, with a viable access to liver transplantation.

Comparative study of the effectiveness of thyroxine and steroids on reduction of neonatal morbidity: outcome at 20 months follow-up

This study analyzes health, growth and neurodevelopmental outcome of infants who received prenatal corticosteroids with or without thyroxine for fetal lung maturation. During a 12 month period infants from a prospective double blind study who received either steroids or steroids combined with thyroxine for pulmonary maturation and who had reached 18 months of age were recalled for evaluation of health status, growth parameters and neurodevelopmental outcome using the Bayley Scales 2nd edition (BSID-II). Mental developmental index (MDI), psychomotor developmental index (PDI), language developmental age (LDA), cognitive developmental age (CDA), and behavioral rating scales (BRS) were compared for the two treatment groups. The Hollingshead Socioeconomic Status Index was determined for each infant. Of a total of 134 patients enrolled during the study period, 66 patients return for follow up. Data from 60 patients was included in the final analysis. Of these, 32 had received the combination regimen and 28 had solely received only steroids. Demographics and neonatal morbidity were similar in both groups. No statistical differences in growth parameters, hospital admissions, respiratory problems, surgical procedures or frequency of infections were found. Neurodevelopmental parameters (MDI, PDI) were similar in both treatment groups, although, below normal in both groups. Language delay was more common in infants who received prenatal corticosteroids. There were no difference in the incidence of neurologic abnormalities. The addition of thyroxine to steroids did not affect growth or neuro-developmental outcome of the infants at 18 to 22 postnatal age.

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome.

Many autoimmune diseases are associated with HLA alleles, and such a relationship also has been reported for aplastic anemia (AA). AA and paroxysmal nocturnal hemoglobinuria (PNH) are related clinically, and glycophosphoinositol (GPI)-anchored protein (AP)-deficient cells can be found in many patients with AA. The hypothesis was considered that expansion of a PNH clone may be a marker of immune-mediated disease and its association with HLA alleles was examined. The study involved patients with a primary diagnosis of AA, patients with myelodysplastic syndrome (MDS), and patients with primary PNH. Tests of proportions were used to compare allelic frequencies. For patients with a PNH clone (defined by the presence of GPI-AP-deficient granulocytes), regardless of clinical manifestations, there was a higher than normal incidence of HLA-DR2 (58% versus 28%; z = 4.05). The increased presence of HLA-DR2 was found in all frankly hemolytic PNH and in PNH associated with bone marrow failure (AA/PNH and MDS/PNH). HLA-DR2 was more frequent in AA/PNH (56%) than in AA without a PNH clone (37%; z = 3.36). Analysis of a second cohort of patients with bone marrow failure treated with immunosuppression showed that HLA-DR2 was associated with a hematologic response (50% of responders versus 34% of nonresponders; z = 2.69). Both the presence of HLA-DR2 and the PNH clone were independent predictors of response but the size of PNH clone did not correlate with improvement in blood count. The results suggest that clonal expansion of GPI-AP-deficient cells is linked to HLA and likely related to an immune mechanism.

A new genetic isolate of gray platelet syndrome (GPS): clinical, cellular, and hematologic characteristics.

Gray platelet syndrome (GPS) is a disorder characterized by thrombocytopenia and large platelets that lack alpha granules and their contents. We describe two siblings with GPS who are members of a Moslem Bedouin genetic isolate. The children, an 8-year-old girl and a 5-year-old boy, had characteristic pale blue platelets lacking alpha granules on electron microscopy. Platelet aggregation studies were normal. The girl underwent a bone marrow aspiration and biopsy which showed mild myelofibrosis and extensive emperipolesis, i.e., the passage of other hematopoietic cells through megakaryocytes. Both children lacked high-molecular-weight multimers of von Willebrand factor (vWF) and had reduced activity and antigens of vWf. Platelet activation was approximately normal when ADP was employed as agonist, but significantly impaired using the thrombin receptor-activating peptide (TRAP). These findings are explained in light of the mechanism of action of each agonist. In addition, we propose that the emperipolesis was caused by increased P-selectin in megakaryocytes, and resulted in release of fibroblastic growth factors, explaining the myelofibrosis. The detailed description of these cases provides a basis for future differentiation of the various types of GPS, and for our current attempts to isolate the gene causing GPS in this genetic isolate.

Plasma ascorbic acid concentrations in a population of rhesus monkeys (Macaca mulatta).

Although monkeys frequently are used as animal models for ascorbic acid studies whose results are extrapolated to humans, little information is available on the normal levels of this vitamin in large populations of animals classified by sex, age, or physiologic state such as pregnancy or lactation. The purpose of this report is to provide these values and compare them to the same parameters in humans, pointing out similar and dissimilar trends. Plasma samples were obtained from a troop of 167 rhesus monkeys (Macaca mulatta) and analyzed for ascorbic acid by using the 2,4-dinitrophenyl hydrazine method. Results obtained for ascorbic acid concentrations in plasma showed no differences between sexes. A significant (P< 0.0001) lowering effect was observed in aging versus young animals. Pregnant and nonpregnant females had similar ascorbate values, and lactating monkeys had slightly elevated levels. We conclude that rhesus monkeys and humans exhibit some of the same characteristics of ascorbic acid metabolism, such as an age-related decrease in ascorbate and the maintenance of these levels during lactation. However, a difference between species was noted with gender. Women maintain higher ascorbate concentrations than do men, whereas no differences in concentrations of this vitamin were observed between female and male monkeys.

Determinants of environmental tobacco smoke in a population of Puerto Rican children.

This study was designed to determine among various personal, socioeconomic, and environmental factors those which had the greatest influence on exposure to environmental tobacco smoke (ETS) in a population of children residing in a tropical environment and to compare these results with those obtained in the literature of tobacco exposed children in temperate climates. Urine specimens were collected from 606 healthy Puerto Rican children (2-12 years) living in an industrial area and analyzed for cotinine, a quantitative biomarker for exposure to ETS. Parents completed a questionnaire covering smoking habits and socioeconomic information. Seventy per cent of the children were reported to be exposed to ETS, 50% resulting from exposure to smoke from either or both parents. Major determinants to ETS exposure were found to be presence of smoker, number of smokers, identity of smoker, number of cigarettes smoked in the household and child age with the youngest children suffering twice the exposure of older children. Non-determinants were exposure to smoke other than from the parent, sex of the child, season of the year and several socioeconomic factors including civil and employment status of the mother, mother's age and educational background and whether food stamps were being received. Results of a multiple regression analysis showed that our predictors accounted for 40% of cotinine appearing in the urine. Reasons for this relatively low value may be due in part to precision of our analytic method and lower levels of ambient smoke in our population vs. others that reported higher R(2) values. Predictions from questionnaire information for high ETS exposure were not always the same as those indicated by urinary cotinine emphasizing that the bioindicator, which indicates the actual inhalation of ETS, is a better predictor of exposure than responses from a questionnaire.

Identification of a new mutation in platelet glycoprotein IX (GPIX) in a patient with Bernard-Soulier syndrome.

We describe a new mutation in glycoprotein IX (GPIX) in a patient with Bernard-Soulier syndrome (BSS). Sequencing of GPIX revealed a homozygous (T-->C) transition at nucleotide 1717 (GenBank/HUMGPIX/M80478), resulting in a Cys(8) (TGT)-->Arg (CGT) replacement in the mature peptide. DNA restriction enzyme analysis using BsaAI revealed that the patient was homozygous and that his parents were heterozygous for the defect. This mutation disrupts a putative disulphide bond between the Cys(8) and Cys(12) that would alter the secondary structure of GPIX and which probably accounts for the absence of the GPIb/IX/V complex from the platelet surface in this patient.

Surgical versus interventional procedures in patients with multivessel coronary artery disease.

OBJECTIVE: This study examined the clinical characteristics, risk factors, indications and post-intervention complications of patients with multivessel coronary artery disease (CAD) submitted to either percutaneous transluminal coronary angioplasty (PTCA) and/or stent placement versus isolated coronary artery bypass grafting (CABG). BACKGROUND: Several studies have examined the relative safety and outcome of patients submitted to those interventional procedures compared to CABG. Limited information is available regarding that subject in Puerto Rico. METHODS: We performed a retrospective analysis of the clinical, angiographic, operative, interventional, post-operative and post-interventional data of patients submitted to those procedures in our institution from January 1998 to August 1998. There were 53 patients in the interventional group and 206 patients in the CAGB group. Comparison of quantitative variables by procedure was based on Student t test or Mann-Whitney-Wilcoxon test; categorical variables were compared using Pearson's chi-square or Fisher's exact test. RESULTS: There were no significant differences in age, body surface area, or cardiac risk factors. The most common pre-existing cardiovascular diagnosis was unstable angina. Three-vessel disease was the most common angiographic finding among CABG patients (61.7%). Two-vessel disease without left anterior descending coronary artery obstruction was significantly more common in the PTCA/Stent patients (58.5%). The vast majority (97.6%) of patients in the PTCA/Stent group and 52.4% of the CABG group had two-vessel intervention. A significantly higher frequency of complications occurred in the CABG group. However, the incidence of major complications, in both groups was not statistically different. Atrial arrhythmias were significantly more frequent in the CABG group. CONCLUSION: A larger prospective study should be conducted in order to corroborate these preliminary findings and seek effective solution to any identifiable problem.

Overexpression of GATA-2 inhibits erythroid and promotes megakaryocyte differentiation.

GATA-1 and GATA-2 transcription factors are required for effective hematopoiesis. These regulatory proteins present overlapping yet distinct patterns of expression in hematopoietic cells. Absence of GATA-2 leads to defective hematopoiesis and an embryonic lethal phenotype. Disruption of GATA-1 results in a compensatory increase in GATA-2 in early erythroid cells and incomplete erythropoiesis with embryos dying at 11.5 days. We examine the specific role of GATA-2 later in hematopoiesis, during erythroid differentiation. Stable K562 cell lines expressing various levels of GATA-2 were generated using a GATA-2 expression plasmid. Overexpression of GATA-2 transcripts was determined by quantitative polymerase chain reaction (PCR). Cytospin smears, growth curve analysis, PCR, and flow cytometry were used to examine the effects of increased levels of GATA-2 in altering cell phenotype and activation of megakaryocytic markers. Human progenitor erythroid cells also were transfected with a GATA-2 expression vector. Growth curve analysis, benzidine staining, and high-performance liquid chromatographic analysis were used to study the effects of GATA-2 on erythroid maturation and proliferation.K562/GATA-2 cell lines expressing high levels of GATA-2 mRNA showed a marked decrease in proliferation and a shift in phenotype toward the megakaryocyte lineage. Ploidy analyses showed that these cell lines developed a multinuclear phenotype, including tetraploids and octaploids. PCR analysis showed activation of megakaryocyte-specific genes including thrombopoietin receptor (c-mpl). Surface expression of platelet glycoprotein receptors Ib/IX (CD42b/CD42a) and IIb/IIIa (CD41/CD61) also was demonstrated by flow cytometry. In primary human adult erythroid cultures transfected with a GATA-2 expression vector, production of total hemoglobin and cell proliferation decreased in a dose-dependent manner.GATA-2 plays an important role in deciding cell lineage throughout hematopoiesis, and increased expression of GATA-2 determines megakaryocytic differentiation. Downregulation of GATA-2 is required for erythroid differentiation.

CCR5 and beta-chemokines in HIV-1 infected children.

The duration from initial infection with HIV-1 to CD4 lymphocyte depletion and progression to AIDS varies among infected individuals. Despite treatment with highly active antiretroviral therapy (HAART), patients still show different stages of disease progression. We examined the role of beta-chemokines and its receptor, CCR5 in HIV-1 infected children in order to define determinants of HIV progression among treated individuals. Population was divided in two groups: Group 1--Long Term Non Progressors (LTNP) includes 10 patients with B1-B2 CDC disease classification and with a less aggressive therapy (only 2 in HAART); Group 2--Rapid Progressors (RP) includes 9 patients with C3 disease classification. All the patients had a CCR5 wild type (wt) genotype indicating that they do not have the 32 base-pair deletion associated with slower progression. There was an increased production of MIP 1-beta in 8/10 LTNP but only in 4/9 Progressors (Paired t-test/Wilcoxon Sign test, p-value < 0.05). The change in the levels of MIP-1 beta after PHA stimulation was statistically significant in both groups. The levels of RANTES increased in LTNP and RP and the change of the levels after mitogen stimulation was statistically significant for both groups included. The production of RANTES and MIP-1 beta in response to stimulation between both groups was not statistically significant. The production of MIP-1 alpha was variable in both groups and the difference in the levels after mitogen stimulation between the groups was not statistically significant. These results suggest that beta-chemokines do not play an important role in HIV-1 progression in children undergoing HAART.

Patient noncompliance and overcompliance. Behavior patterns underlying a patient's failure to 'follow doctor's orders'.

The vicissitudes of medical treatment are affected in large part by patient compliance. Noncompliance can be caused by a variety of psychological, somatic, and socioeconomic factors. Overcompliance would seem on the surface to be less of a problem, but it too can have serious consequences in terms of treatment success. Several psychological factors account for overcompliance. The physician's best defenses against both noncompliance and overcompliance are to listen carefully to the patient for clues to one of these impending behaviors and to establish good rapport with the patient. An individualized approach is important, and in some cases participation in organized self-help groups is of benefit.