Efficacy of two different ProMACE-CytaBOM derived regimens in advanced aggressive non-Hodgkin's lymphoma. Final report of a multicenter trial conducted by GISL

Background and Objective. To compare the efficacy of ProME(Epidoxorubicin)CE-CytaBOM (PE-C) and ProMI(Idarubicin)CE-CytaBOM (PIG) in the treatment of adult patients with aggressive non Hodgkin's lymphoma in a multicenter randomized controlled trial performed by 18 centers of the Italian Lymphoma Study Group (GISL). Design and Methods. One hundred and twenty-eight and 122 patients were randomly assigned to receive either 6 courses of PE-C or PI-C, respectively. Some patients achieving complete remission with induction therapy participated in another randomized study comparing no further therapy versus maintenance therapy consisting of four blocks of two drugs. Results. The rate of CRs was 62% and 64% for patients treated with PE-C and PI-C, respectively (p=0.51). The 5-year relapse-free survival was 60% for PE-C and 53% for PI-C (p=0.29). The estimated relapse-free disease survival rates at 4 years were 75% for patients in the consolidation group and 57% for those in the observation group (p=0.11). Patients alive In first complete remission 4 years after study entry were estimated to be 39% in the PE-C arm and 38% in the PI-C arm (p=0.90). The 3-year and 5-year estimated survival rates were 61% and 55% for the PE-C group and 56% and 47% for the PI-C group (p=0.26). Fatal toxicities occurred in 7 patients (2.9%) with active disease and in 4 patients (1.7%) in complete remission. Stage (p=0.04), bulky disease (p=0.02), serum LDH (p=0.0006), serum albumin (p=0.0051), hemoglobin (p=0.0011), performance status (p=0.0001), International prognostic index (p<0.0001) and the index proposed by the French group G.E.L.A. (p<0.0001) were of prognostic value. In a multivariate analysis (Cox regression model) alternatively IPI alone or G.E.L.A, index plus performance status emerged as independent prognostic factors. Interpretation and Conclusions. The present study indicates that epirubicin and idarubicin in a combined chemotherapy regimen, have similar activities. The toxic profile also indicates the safety of both anthracyclines at the dosages employed, suggesting their possible dose escalation in a combined chemotherapy setting. PE-C and PI-C were both effective and feasible regimens in an outpatient setting, with acceptable cardiovascular toxicity. The trend toward a better outcome in patients undergoing consolidation therapy after the achievement of a complete remission, warrants further investigation. (C)1998, Ferrata Storti Foundation

Successful Treatment With Omalizumab in a Child With Asthma and Urticaria: A Clinical Case Report.

Urticaria of childood is rare and more uncommon is its persistence.Comorbidities are associated with CSU in children, among these asthma, allergic rhinitis or atopic dermatitis, while many children with CSU have a family history of atopy. Therapeutic approach to CSU in children is the same recommended in international guidelines for management of chronic urticaria in adults. In the European Union, according to European Medicine Agency, Omalizumab is indicated as add-on therapy for the treatment of chronic spontaneous urticaria in adult and adolescent (12 years and above) patients with inadequate response to H1 antihistamine treatment. Furthermore in children (6 to &lt;12 years of age) is indicated as add-on therapy to improve asthma control.The treatment of children with urticaria under the age of 12 represents a therapeutic “limbo”, being possible to administer omalizumab only “off label”

CD20 and CD19 targeted vectors induce minimal activation of resting B lymphocytes

B lymphocytes are an important cell population of the immune system. However, until recently it was not possible to transduce resting B lymphocytes with retro- or lentiviral vectors, making them unsusceptible for genetic manipulations by these vectors. Lately, we demonstrated that lentiviral vectors pseudotyped with modified measles virus (MV) glycoproteins hemagglutinin, responsible for receptor recognition, and fusion protein were able to overcome this transduction block. They use either the natural MV receptors, CD46 and signaling lymphocyte activation molecule (SLAM), for cell entry (MV-LV) or the vector particles were further modified to selectively enter via the CD20 molecule, which is exclusively expressed on B lymphocytes (CD20-LV). It has been shown previously that transduction by MV-LV does not induce B lymphocyte activation. However, if this is also true for CD20-LV is still unknown. Here, we generated a vector specific for another B lymphocyte marker, CD19, and compared its ability to transduce resting B lymphocytes with CD20-LV. The vector (CD19ds-LV) was able to stably transduce unstimulated B lymphocytes, albeit with a reduced efficiency of about 10% compared to CD20-LV, which transduced about 30% of the cells. Since CD20 as well as CD19 are closely linked to the B lymphocyte activation pathway, we investigated if engagement of CD20 or CD19 molecules by the vector particles induces activating stimuli in resting B lymphocytes. Although, activation of B lymphocytes often involves calcium influx, we did not detect elevated calcium levels. However, the activation marker CD71 was substantially up-regulated upon CD20-LV transduction and most importantly, B lymphocytes transduced with CD20-LV or CD19ds-LV entered the G1b phase of cell cycle, whereas untransduced or MV-LV transduced B lymphocytes remained in G0. Hence, CD20 and CD19 targeting vectors induce activating stimuli in resting B lymphocytes, which most likely renders them susceptible for lentiviral vector transduction

Interplay between neuroendocrine biomarkers and gut microbiota in dogs supplemented with grape proanthocyanidins: Results of dietary intervention study

Several studies on the interaction between gut microbiota and diets, including prebiotics, have been reported in dogs, but no data are available about the effects of dietary administration of grape proanthocyanidins. In the study, 24 healthy adult dogs of different breeds were recruited and divided in 3 groups of 8 subjects each. A group was fed with a control diet (D0), whilst the others were supplemented with 1 (D1) or 3 (D3) mg/kg live weight of grape proanthocyanidins. Samples of feces were collected at the beginning and after 14 and 28 days for microbiota, short chain fatty acid, and lactic acid analysis. Serotonin and cortisol were measured in saliva, collected at the beginning of the study and after 28 days. A significantly higher abundance (p < 0.01) of Enterococcus and Adlercreutzia were observed in D0, whilst Escherichia and Eubacterium were higher in D1. Fusobacterium and Phascolarctobacterium were higher (p < 0.01) in D3. Salivary serotonin increased (p < 0.01) at T28 for D1 and D3 groups but cortisol did not vary. Proanthocyanidins administration influenced the fecal microbiota and neuroendocrine response of dogs, but a high variability of taxa was observed, suggesting a uniqueness and stability of fecal microbiota related to the individual

Investigating Safety and Technological Traits of a Leading Probiotic Species: Lacticaseibacillus paracasei

Lacticaseibacillus spp. are genetically close lactic acid bacteria species widely used in fermented products for their technological properties as well as their proven beneficial effects on human and animal health. This study, the first to include such a large collection of heterogeneous isolates (121) obtained from international collections belonging to Lacticaseibacillus paracasei, aimed to characterize the safety traits and technological properties of this important probiotic species, also making comparisons with other genetically related species, such as Lacticaseibacillus casei and Lacticaseibacillus zeae. These strains were isolated from a variety of heterogeneous sources, including dairy products, sourdoughs, wine, must, and human body excreta. After a preliminary molecular characterization using repetitive element palindromic PCR (Rep-PCR), Random Amplification of Polymorphic DNA (RAPD), and Sau-PCR, particular attention was paid to safety traits, evaluating antibiotic resistance profiles, biogenic amine (BA) production, the presence of genes related to the production of ethyl carbamate and diaminobenzidine (DAB), and multicopper oxidase activity (MCO). The technological characteristics of the strains, such as the capability to grow at different NaCl and ethanol concentrations and different pH values, were also investigated, as well as the production of bacteriocins. From the obtained results, it was observed that strains isolated from the same type of matrix often shared similar genetic characteristics. However, phenotypic traits were strain-specific. This underscored the vast potential of the different strains to be used for various purposes, from probiotics to bioprotective and starter cultures for food and feed production, highlighting the importance of conducting comprehensive evaluations to identify the most suitable strain for each purpose with the final aim of promoting human health

Breast cancer patients receiving denosumab during adjuvant aromatase inhibitors treatment: Who are the “inadequate responders” patients to denosumab?

Purpose: Adjuvant hormone therapy with aromatase inhibitors (AIs) through the induction of tissue hypo-estrogenism induces an increase in osteoclast activity and inhibition of osteoblast activity through the production of RANKL. This is a relevant cause of comorbility in women affected by breast cancer with negative impact on quality of life. We conducted an observational study on patients treated with AIs and denosumab to compare responders and inadequate responders. Methods: The study design was a historical cohort survey that represented a 42-month follow-up period for patients on hormone treatment with AI for breast cancer and concomitant denosumab (Prolia®) at 60 mg subcutaneously every 6 months. Sixty-eight patients treated consecutively at our Medical Oncology Unit were studied. The comparison was carried out by stratifying on the basis of age, body mass index (BMI), weight, carboxy-terminal collagen crosslink (CTX), lumbar spine and femoral T-scores, FRAX 10-year probability of a fracture, FRAX 10-year probability of a major osteoporotic fracture at baseline and at the end of follow-up. Results: Calculating and comparing the FRAX 10-year probability of hip fragility fracture at baseline in the subgroup of responders and in the inadequate responders subgroup, we found a statistically significant difference (p=0.039). Similarly, a statistically significant difference was found between the two subgroups of patients in terms of FRAX 10-year probability of hip fragility at the end of follow-up (p=0.014) and FRAX 10-year probability of a mayor osteoporotic fracture at the end of follow-up (p=0.043). Conclusion: This study suggests the need to control weight in breast cancer survivors and adjuvant AIs treatment in order not only to reduce the incidence of disease relapse but also to safeguard bone health undergoing treatment with denosumab. Indeed, patients tend to respond inadequately to denosumab if they are not careful to control their body weight

Studies on the aetiology of kiwifruit decline: interaction between soil-borne pathogens and waterlogging

Aims: In 2012, Italian kiwifruit orchards were hit by a serious root disease of unknown aetiology (kiwifruit decline, KD) that still causes extensive damage to the sector. While waterlogging was soon observed to be associated with its outbreak, the putative role of soil microbiota remains unknown. This work investigates the role of these two factors in the onset of the disease. Methods: Historical rainfall data were analysed to identify changes that might explain KD outbreak and mimic the flooding conditions required to reproduce the disease in a controlled environment. A greenhouse experiment was thus designed, and vines were grown in either unsterilized (U) or sterilized (S) soil collected from KD-affected orchards, and subjected (F) or not (N) to artificial flooding. Treatments were compared in terms of mortality rate, growth, and tissue modifications. Results: KD symptoms were only displayed by FU-treated vines, with an incidence of 90%. Ultrastructural observations detected tyloses and fibrils in the xylem vessels of all plants, irrespective of the treatment. Phytopythium vexans and Phytopythium chamaehyphon, isolated from roots of FU plants, emerged as the associated microorganisms. Conclusions: We succeeded in reproducing KD under controlled conditions and confirmed its association with both waterlogging and soil-borne microorganism(s)

Real-life use of denosumab 120 mg every 12 weeks in prolonged treatment over 2 years of patients with breast cancer bone metastases

Purpose: To analyze the activity and safety of denosumab (DNS) 120 mg every 3 months over 2 years of standard treatment (120 mg SC every 4 weeks) of patients with breast cancer bone metastases in real life. Methods: We prospectively analyzed the activity and safety of denosumab 120 mg every 3 months and 120 mg every 4 weeks in the treatment of 22 patients with breast cancer bone metastases over 2 years of standard treatment. All patients received specific concomitant antineoplastic treatment, chemotherapy or endocrine therapy and/or target therapy. Oral daily calcium (≥500 mg) and vitamin D (≥1000 U) supplement was recommended. Results: Of the 22 patients treated with denosumab, 4 (18.1%) had at least 1 skeletal related event (SRE); 3 (13.6%) had 1 SRE and 1 patient (4.5%) had 2 SRE, all 10% treated with radiotherapy. Overall, no denosumab-related G3 adverse events occurred; in particular, no cases of osteonecrosis of the jaw have been recorded. The decrease in serum calcium levels was mild (G1, 2 patients, 9%), and recovered in a short time (within 2 weeks) with an increase in the oral support of calcium and vitamin D. Conclusions: Denosumab confirms a good activity profile in terms of delaying and preventing SREs in breast cancer patients and a good safety profile. It represents an optimal treatment resource which doesn’t necessitate renal function monitoring and has the convenience of a subcutaneous administration

Age-related differences in integrin expression in peripheral blood lymphocytes

Alpha integrins play an important role in cell to cell and cell to extra-cellular matrix interactions required for an effective T-lymphocyte-mediated immune response, however little is known about age related differences in expression of alpha integrins on T-cells in humans. We here measured alpha-4 (α4) integrin (CD49d) expression on T-lymphocytes via peripheral blood sampling, comparing parameters between cohorts of young and old adults. No age-related differences were found for the absolute numbers of T-cells, although the percentage of CD4+ T-cells in older adults was significantly greater and the percentage of CD8+ T-cells lower than in younger cohorts. Percentage and absolute numbers of CD3+ T-cells co-expressing CD49d were significantly lower in older adults compared to younger cohorts, and the percentage of gated CD4+ and CD8+ cells that co-labelled positively for CD49d was also reduced in this group. There were no age-related differences in circulating levels of cytokines (Type I interferons) that are known to regulate cell surface integrin expression. Reduced expression of alpha integrins on T-cells may be an early indicator of the loss of homeostatic control that occurs with ageing, contributing to diminished effector T-cell responses during senescence

An unusual case of chronic meningitis

BACKGROUND: Chronic meningitis is defined as symptoms and signs of meningeal inflammation and persisting cerebrospinal fluid abnormalities such as elevated protein level and pleocytosis for at least one month. CASE PRESENTATION: A 62-year-old woman, of unremarkable past medical history, was admitted to hospital for investigation of a four-week history of vomiting, malaise an associated hyponatraemia. She had a low-grade pyrexia with normal inflammatory markers. A CT brain was unremarkable and a contrast MRI brain revealed sub-acute infarction of the right frontal cortex but with no evidence of meningeal enhancement. Due to increasing confusion and patient clinical deterioration a lumbar puncture was performed at 17 days post admission. This revealed gram-negative coccobacilli in the CSF, which was identified as Neisseria meningitidis group B. The patient made a dramatic recovery with high-dose intravenous ceftriaxone antibiotic therapy for meningococcal meningitis. CONCLUSIONS: 1) Chronic bacterial meningitis may present highly atypically, particularly in the older adult. 2) There may be an absent or reduced febrile response, without a rise in inflammatory markers, despite a very unwell patient. 3) Early lumbar puncture is to be encouraged as it is essential to confirm the diagnosis.4) Despite a delayed diagnosis appropriate antibiotic therapy can still lead to a good outcome