Y-90-Ibritumomab Tiuxetan (Zevalin (R)) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin's Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients

The FIT trial was conducted to evaluate the safety and efficacy of 90Y-ibritumomab tiuxetan (0.4 mCi/kg; maximum dose 32 mCi) when used as consolidation of first complete or partial remission in patients with previously untreated, advanced-stage follicular lymphoma (FL). Patients were randomly assigned to either 90Y-ibritumomab treatment (n = 207) or observation (n = 202) within 3 months (mo) of completing initial induction therapy (chemotherapy only: 86%; rituximab in combination with chemotherapy: 14%). Response status prior to randomization did not differ between the groups: 52% complete response (CR)/CR unconfirmed (CRu) to induction therapy and 48% partial response (PR) in the 90Y-ibritumomab arm vs 53% CR/CRu and 44% PR in the control arm. The primary endpoint was progression-free survival (PFS) of the intent-to-treat (ITT) population. Results from the first extended follow-up after a median of 3.5 years revealed a significant improvement in PFS from the time of randomization with 90Y-ibritumomab consolidation compared with control (36.5 vs 13.3 mo, respectively; P < 0.0001; Morschhauser et al. JCO. 2008; 26:5156-5164). Here we report a median follow-up of 66.2 mo (5.5 years). Five-year PFS was 47% in the 90Y-ibritumomab group and 29% in the control group (hazard ratio (HR) = 0.51, 95% CI 0.39-0.65; P < 0.0001). Median PFS in the 90Y-ibritumomab group was 49 mo vs 14 mo in the control group. In patients achieving a CR/CRu after induction, 5-year PFS was 57% in the 90Y-ibritumomab group, and the median had not yet been reached at 92 months, compared with a 43% 5-year PFS in the control group and a median of 31 mo (HR = 0.61, 95% CI 0.42-0.89). For patients in PR after induction, the 5-year PFS was 38% in the 90Y-ibritumomab group with a median PFS of 30 mo vs 14% in the control group with a median PFS of 6 mo (HR = 0.38, 95% CI 0.27-0.53). Patients who had received rituximab as part of induction treatment had a 5-year PFS of 64% in the 90Y-ibritumomab group and 48% in the control group (HR = 0.66, 95% CI 0.30-1.47). For all patients, time to next treatment (as calculated from the date of randomization) differed significantly between both groups; median not reached at 99 mo in the 90Y-ibritumomab group vs 35 mo in the control group (P < 0.0001). The majority of patients received rituximab-containing regimens when treated after progression (63/82 [77%] in the 90Y-ibritumomab group and 102/122 [84%] in the control group). Overall response rate to second-line treatment was 79% in the 90Y-ibritumomab group (57% CR/CRu and 22% PR) vs 78% in the control arm (59% CR/CRu, 19% PR). Five-year overall survival was not significantly different between the groups; 93% and 89% in the 90Y-ibritumomab and control groups, respectively (P = 0.561). To date, 40 patients have died; 18 in the 90Y-ibritumomab group and 22 in the control group. Secondary malignancies were diagnosed in 16 patients in the 90Y-ibritumomab arm vs 9 patients in the control arm (P = 0.19). There were 6 (3%) cases of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) in the 90Y-ibritumomab arm vs 1 MDS in the control arm (P = 0.063). In conclusion, this extended follow-up of the FIT trial confirms the benefit of 90Y-ibritumomab consolidation with a nearly 3 year advantage in median PFS. A significant 5-year PFS improvement was confirmed for patients with a CR/CRu or a PR after induction. Effective rescue treatment with rituximab-containing regimens may explain the observed no difference in overall survival between both patient groups who were - for the greater part - rituximab-naïve.

Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials.

PURPOSE: Several studies observed a female advantage in the prognosis of cutaneous melanoma, for which behavioral factors or an underlying biologic mechanism might be responsible. Using complete and reliable follow-up data from four phase III trials of the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, we explored the female advantage across multiple end points and in relation to other important prognostic indicators. PATIENTS AND METHODS: Patients diagnosed with localized melanoma were included in EORTC adjuvant treatment trials 18832, 18871, 18952, and 18961 and randomly assigned during the period of 1984 to 2005. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for women compared with men, adjusted for age, Breslow thickness, body site, ulceration, performed lymph node dissection, and treatment. RESULTS: A total of 2,672 patients with stage I/II melanoma were included. Women had a highly consistent and independent advantage in overall survival (adjusted HR, 0.70; 95% CI, 0.59 to 0.83), disease-specific survival (adjusted HR, 0.74; 95% CI, 0.62 to 0.88), time to lymph node metastasis (adjusted HR, 0.70; 95% CI, 0.51 to 0.96), and time to distant metastasis (adjusted HR, 0.69; 95% CI, 0.59 to 0.81). Subgroup analysis showed that the female advantage was consistent across all prognostic subgroups (with the possible exception of head and neck melanomas) and in pre- and postmenopausal age groups. CONCLUSION: Women have a consistent and independent relative advantage in all aspects of the progression of localized melanoma of approximately 30%, most likely caused by an underlying biologic sex difference.

Effect of precocene II, ecdysone and juvenile Hormone on the glicogen concentration in pupae of Stomocys calcitram (Diptera muscidae)

Third instar larvae of Stomoxys calcitrans (L.) were treated with precocene II, ecdysone and juvenile hormone. The larvae were allowed to develop until pupation and when it occurred, determination of glycogen levels was assayed. The administration of those three substances have interfered on the clycogen concentration. the precocene II causing a decrease whereas the ecdysone and juvenile hormone causing an increase. The ecdysone administered together withprecocene II reverses the effect of the latter. This does not happen when precocene II is administered together with the juvenile hormone. Ecdysone administered together with juvenilehormone causes reduction of the glycogen concentration.

The PRINTO criteria for clinically inactive disease in juvenile dermatomyositis.

OBJECTIVES: To develop data-driven criteria for clinically inactive disease on and off therapy for juvenile dermatomyositis (JDM). METHODS: The Paediatric Rheumatology International Trials Organisation (PRINTO) database contains 275 patients with active JDM evaluated prospectively up to 24 months. Thirty-eight patients off therapy at 24 months were defined as clinically inactive and included in the reference group. These were compared with a random sample of 76 patients who had active disease at study baseline. Individual measures of muscle strength/endurance, muscle enzymes, physician's and parent's global disease activity/damage evaluations, inactive disease criteria derived from the literature and other ad hoc criteria were evaluated for sensitivity, specificity and Cohen's κ agreement. RESULTS: The individual measures that best characterised inactive disease (sensitivity and specificity >0.8 and Cohen's κ >0.8) were manual muscle testing (MMT) ≥78, physician global assessment of muscle activity=0, physician global assessment of overall disease activity (PhyGloVAS) ≤0.2, Childhood Myositis Assessment Scale (CMAS) ≥48, Disease Activity Score ≤3 and Myositis Disease Activity Assessment Visual Analogue Scale ≤0.2. The best combination of variables to classify a patient as being in a state of inactive disease on or off therapy is at least three of four of the following criteria: creatine kinase ≤150, CMAS ≥48, MMT ≥78 and PhyGloVAS ≤0.2. After 24 months, 30/31 patients (96.8%) were inactive off therapy and 69/145 (47.6%) were inactive on therapy. CONCLUSION: PRINTO established data-driven criteria with clearly evidence-based cut-off values to identify JDM patients with clinically inactive disease. These criteria can be used in clinical trials, in research and in clinical practice.

Mass migration of juvenile Biomphalaria glabrata snails bred under semi-natural conditions

For the development of studies on snail interspecific competition special in-door laboratory channels were built. In the all five channels seeded with adult specimens of Biomphalaria glabrata mass migration of juvenile snails outside the water was observed. Most of the migrant snails presented apertural lamellae. Data collected during the period of two years, showed the regression of the migration phenomenon and the disappearance of the lamellate snails.

First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma.

PURPOSE: To evaluate the efficacy of first-line chemotherapy (CT) in preventing external-beam radiotherapy (EBR) and/or enucleation in patients with retinoblastoma (Rbl). PATIENTS AND METHODS: Twenty-four patients with newly diagnosed unilateral or bilateral Rbl received CT associated with local treatment (LT). Two to five courses of etoposide and carboplatin were administered at 3- to 4-week intervals, depending on tumor response, and were completed each time by LT. RESULTS: Tumor response was observed in all eyes. Twenty-one of 24 patients showed a complete response (CR) that persisted at a median follow-up (FU) of 31 months (range, 4 to 41 months). Among the three patients who relapsed, two were lost to FU and one died of progressive disease. CR was achieved by CT and LT alone in 15 (71.4%) of 21 patients with less advanced disease (groups I to III). Six other patients with advanced disease (groups IV and V) experienced treatment failure and needed salvage treatment by EBR and/or enucleation. The difference between the two patient groups with regard to disease stage was statistically significant (P <.0001). EBR could be avoided in 13 (68.4%) of 19 patients, who presented with groups I to III (15 eyes) and group V (one eye) disease, whereas enucleation could be avoided in only two (40%) of five. CONCLUSION: CT combined with intensive LT is effective in patients with groups I to III Rbl, permitting the avoidance of EBR in the majority of these young children and, thus, reducing the risk of long-term sequelae. This is in contrast with the disappointing results for patients with groups IV and V Rbl, in whom EBR and/or enucleation was needed.

Juvenile hormone III and nutrition effects on spermatogenesis in the 4th instar nymphs of Panstrongylus megistus (Hemiptera: Reduviidae)

When 4th instar nymphs of Panstrongylus megistus are fed with a saturant blood meal, there is an intense proliferation of the spermatogonia. At the end of the intermoult, the older spermatogonial cysts differentiate into 1st primary spermatocyte cysts. In the nymphs deprived of the blood meal this evolution is not observed, but a small growth of the testicular follicles occurs, due to a few mitotic divisions. This growth is observed at least, until 25 days after ecdysis. Since day 15, an autolytic process starts in the older spermatogonial cysts. The presence of exogenous juvenile hormone III (JH III) does not promote the development of the germ cells in the fasting insects. There is only a small growth of the testicular follicles and the autolytic process is also observed. In the precocious adults obtained by allatectomy or precocene II treatment, germ cells are observed in all development stages, except packed and elongated spermatozoa bundels.

Partial Knowledge Restrictions on theTwo-Stage Threshold Model of Choice

In the context of the two-stage threshold model of decision making, with the agent’s choices determined by the interaction Of three “structural variables,” we study the restrictions on behavior that arise when one or more variables are xogenously known. Our results supply necessary and sufficient conditions for consistency with the model for all possible states of partial Knowledge, and for both single- and multivalued choice functions.

Personality traits and behavioral and psychological symptoms in patients at an early stage of Alzheimer's disease.

OBJECTIVE: The origins of behavioral and psychological symptoms (BPS) in Alzheimer's disease (AD) are still poorly understood. Focusing on individual personality structure, we explored the relationship between premorbid personality and its changes over 5 years, and BPS in patients at an early stage of AD. METHOD: A total of 54 patients at an early stage of AD according to ICD-10 and NINCDS-ADRDA criteria and 64 control subjects were included. Family members filled in the Neuropsychiatric Inventory Questionnaire to evaluate their proxies' current BPS and the NEO Personality Inventory Revised twice, the first time to evaluate the participants' current personality and the second time to assess personality traits as they were remembered to be 5 years earlier. RESULTS: Behavioral and psychological symptoms, in particular apathy, depression, anxiety, and agitation, are frequent occurrences in early stage AD. Premorbid personality differed between AD patients and normal control, but it was not predictive of BPS in patients with AD. Personality traits clearly change in the course of beginning AD, and this change seems to develop in parallel with BPS as early signs of AD. CONCLUSIONS: Premorbid personality was not associated with BPS in early stage of AD, although complex and non-linear relationships between the two are not excluded. However, both personality and behavioral changes occur early in the course of AD, and recognizing them as possible, early warning signs of neurodegeneration may prove to be a key factor for early detection and intervention. Copyright © 2012 John Wiley & Sons, Ltd.

A recombinant hybrid protein as antigen for an anti-blood stage malaria vaccine: a study on the conservation of a protective component

Recently we have shown that two hybrid proteins expressed in Escherichia coli confer protective immunity to Aotus monkeys against an experimental Plasmodium falciparum infection (Knapp et al., 1992). Both hybrid proteins carry a sequence containing amino acids 631 to 764 of the serine stretch protein SERP (Knapp et al., 1989b). We have studied the diversity of this SERP region in field isolates of P. falciparum. Genomic DNA was extracted from the blood of six donors from different endemic areas of Brazil and West Africa. The SERP region encoding amino acids 630 to 781 was amplified by polymerase chain reaction (PCR) and sequenced. Only conserved amino acid substitutions in maximally two positions of the analyzed SERP fragment could be detected which supports the suitability of this SERP region as a component of anti-blood stage malaria vaccine.

Heterogeneity of Ia antigen expression on myeloblastic leukaemias: correlation with stage of maturation defined by cytochemical markers.

The expression of Ia-like antigen (Ia) has been studied in 55 cases of acute myeloid leukaemia (AML) in correlation with the expression of both Sudan Black (SB) and naphthol AS-D chloroacetate esterase (NCAE) stains. Operationally the AML cases were divided into three groups using only NCAE expression on the leukaemic cells: the first group with early maturation stage (MS1) consisted of 30 cases with less than 10% NCAE positive cells (SB: 15-100%): the MS2 group of 14 cases with 10-70% NCAE positive cells (SB: 65-100%) and the MS3 group of 11 cases with 70-100% NCAE positive cells (SB: 89-100%). Ia expression was determined by complement-dependent cytotoxicity, immunofluorescence and immunoperoxidase methods. A similar high percentage (80%) of patients from both group MS1 and MS2 expressed Ia on the surface of 32-100% of the cells. Furthermore, individual comparison of all cases from these two groups showed no correlation between Ia, NCAE and SB expression. Only in the 11 cases from the MS3 group, which included nine cases of promyelocytic leukaemias, was there a correlation between very low expression of Ia antigen with the high NCAE expression. Thus, for AML with a low degree of differentiation the expression of Ia seems to be independent of conventional cytochemical markers of cell maturation.