Treatment of refractory and relapsed Hodgkin's lymphoma: Facts and perspectives

The most effective salvage strategy for patients with Hodgkin's lymphoma relapsed or refractory to front-line therapy has yet to be conclusively defined. This problem has evolved in the last years and it is time to reconsider its dimension and to comment on mature data, new facts and perspective

Metabolic Disorders in Elderly Patients with Hematologic Malignancies. A Review

Over recent decades, due to the gradual rise in life expectancy and the consequent aging of the population, the incidence of some hematological malignancies most common in the elderly is expected to increase. In elderly cancer patients, the older age is an adverse prognostic factor because of specific age-related conditions, such as changes in cellular biology and reduced functional reserve in multiple organ systems, as well as in consequence of comorbidities. Some age-related pathological conditions, such as diabetes mellitus, renal failure, chronic obstructive pulmonary disease, cardiovascular dysfunction, liver disease and other disorders may predispose the elderlies to develop metabolic abnormalities. In the elderly, the occurrence of hematological malignancies can cause some metabolic disorders or worsen pre-existing dysmetabolic conditions that increase the outcomes of these patients. Hyperuricemia is the most common metabolic abnormality; hyperuricemia less commonly may be associated with hyperkalemia, hyperphosphatemia and hypocalcemia, in the framework of oncologic emergency that is the Tumor lysis syndrome. Hypercalcemia is relatively common in patients with multiple myeloma and adult T-cell Lymphoma. Cases of Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in patients with hematological malignancies have also been reported. Idiopathic hyperammonemia may occur in oncohematological patients after receiving intensive chemotherapy or following bone marrow transplantation. Moreover, there is evidence that patients with lymphoma, leukemia and multiple myeloma can develop Type B lactic acidosis. Non–islet cell tumor hypoglycemia and Hyperglycemia are other potential metabolic abnormalities occurring in patients with hematological malignancies. The pathogenesis of these metabolic disorders is often unclear and several theories have been postulated; possible mechanisms include: increase in neoplastic cell turnover and apoptosis, blast crisis, cytotoxic effects of chemotherapy, tumor secretion of hormones, peptides or cytokines, immune cross-reactivity between malignant and normal tissues, malignancy-induced enzyme dysfunction. Parenteral nutrition, sarcopenia, cachexia, stress, immune deficiency and infections could contribute. Although successful treatment of the underlying tumor often improves metabolic disorders, these conditions often worse prognosis and are associated with poor survival; thus it is important to consider early detection and effective treatment

Neuroendocrine Mediators, Food Intake and Obesity: A Narrative Review

Obesity is a chronic multifactorial disease caused by imbalance between caloric intake and energy expenditure. The Neuroendocrine system is one of the main factors regulating energy intake in humans. The Neuroendocrine system is made up of cells able to synthesize and secrete amines, peptides, growth factors and biological mediators, known as neurohormones, which modulate various biological functions by interacting with the nervous and immune system. In the central nervous system, neurosecretory elements are mainly located in the hypothalamus which is the anatomical site of the hunger (lateral nucleus) and satiety (ventromedial nucleus) centers; thus it plays a key role in chemical coding of food intake. Dopamine, Noradrenaline and Serotonin are historically considered key points in the regulation of feeding behavior. However, other neurohormones have been identified; these substances, also synthesized in peripheral tissues (especially adipose tissue and digestive tract), influence food intake. Some of these hormones have orexigenic activity; conversely, other substances have anorexigenic activity. A constant balance between orexigenic and anorexigenic neurohormones is essential to ensure a smooth feeding behavior, whereas a subtle and progressive disruption of neurochemical transmission is sufficient to induce hyperphagia or anorexia. Several factors affect the synthesis and release of neuropeptides: genetic, hormonal, psychological, environmental, receptorial, type of feeding and meal frequency. In the recent past some drugs, as Sibutramine and Rimonabant, modulating the activity of several neuroendocrine mediators (Serotonin, Noradrenaline, Endocannabinoids), have proven to be effective in reducing weight excess, even if they were withdrawn because of serious side effects. Recently, promising results in this way have been obtained with Glucagon like Peptide-1 analogs, showing significant efficacy in counteracting weight excess without side effects. Further knowledge developments on these complex neuroendocrine circuits and their hypothalamic interactions in food intake regulation could open new frontiers for effective pharmacological therapeutic approach to Obesity and other nutritional disorders

Focus on Pitavastatin

Currently, different statins are available for the treatment of dyslipidemia: Atorvastatin, Simvastatin, Rosuvastatin, Lovastatin, Pravastatin, and Fluvastatin; the newest entry in this class of drugs is Pitavastatin.The purpose of the present study was to examine the latest evidences on Pitavastatin, more than 10 years after its first marketing and focuses on the most recent evidence regarding its differences with other available statins. A literature review of the last 3 years (January 2013 - January 2016) has been carried out via Pub Med. 193 obtained items were analysed.Pitavastatin has been studied against other drugs in its class and has demonstrated high potency in reducing LDL-Cholesterol levels and increasing HDL-Cholesterol. Pitavastatin has demonstrated a significant reduction in atherosclerotic plaque volumes and several pleiotropic effects, which suggest its potential benefits in reducing cardiovascular risk.At present, Pitavastatin don’t seem to have adverse effects on glucose metabolism; it has no adverse effects on renal function and currently there is no clinical evidence of Pitavastatin-induced hepatotoxicity. Pitavastatin has favorable pharmacokinetic and safety profiles and its characteristic structure provides significant efficacy at low doses

High Specificity of Quantitative Methylation-Specific PCR Analysis for MGMT Promoter Hypermethylation Detection in Gliomas

Normal brain tissue from 28 individuals and 50 glioma samples were analyzed by real-time Quantitative Methylation-Specific PCR (QMSP). Data from this analysis were compared with results obtained on the same samples by MSP. QMSP analysis demonstrated a statistically significant difference in both methylation level (P = .000009 Mann Whitney Test) and frequencies (P = .0000007, Z-test) in tumour samples as compared with normal brain tissues. Although QMSP and MSP showed similar sensitivity, the specificity of QMSP analysis was significantly higher (93%; CI95%: 84%–100%) as compared with MSP (64%; 95%CI: 46%–82%). Our results suggest that QMSP analysis may represent a powerful tool to identify glioma patients that will benefit from alkylating agents chemotherapy

A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: Results from the Fondazione Italiana Linfomi MCL-0208 trial

Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By analyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell receptor pathway (B-cell receptor low and B-cell receptor high ) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes (AKT3, BCL2, BTK, CD79B, PIK3CD, and SYK), was used to classify the 83 cases (43 B-cell receptor low and 40 B-cell receptor high ). The B-cell receptor high signature associated with shorter progression-free survival (P=0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival (P=0.0014 and P=0.029, respectively) in combination with high ( extgreater30%) Ki-67 staining, and was an independent predictor of short progression-free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6-gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homoge-nously treated with different schedules. In conclusion, this 6-gene signature associates with a poor clinical response in the context of the MCL-0208 clinical trial. (clinicaltrials.gov identifier: 02354313)

Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts

We studied 459 consecutive patients with hematologic malignancies, median age 44 years (range, 15 to 71 years), who underwent transplantation with grafts from identical sibling donors (SIB; n = 176), matched unrelated donors (MUD; n = 43), mismatched unrelated donors (mmUD; n = 43), unrelated cord blood (UCB; n = 105) or HLA-haploidentical family donors (HAPLO; n = 92). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in the SIB recipients; antithymocyte globulin for the MUD, mmUD, and UCB recipients; and post-transplantation cyclophosphamide, cyclosporine, and mycophenolate in the HAPLO recipients. Conditioning regimens were mostly myeloablative (69%). Advanced disease phase was more frequent, but not significantly so, in the HAPLO and mmUD groups (P = .08). Acute GVHD grade II-IV was significantly less frequent in the HAPLO, UCB, and MUD groups (14% to 21%) compared with the SIB (31%) and mmUD (42%) groups (P < .001), and there was a trend toward less moderate-severe chronic GVHD in the HAPLO and UCB groups (P = .053). The proportion of patients off cyclosporine at 1 year ranged from 55% for the SIB group to 81% for the HAPLO group (P < .001). Transplantation-related mortality at 2 years was lower in the HAPLO and SIB groups (18% to 24%) compared with the MUD, mmUD, and UCB groups (33% to 35%; P = .10). Relapse rate was comparable in the 5 groups (P = .80). The 4-year actuarial survival was 45% in the SIB group, 43% in the MUD group, 40% in the mmUD group, 34% in the UCB group, and 52% in the HAPLO group (P = .10). In multivariate analysis, advanced disease was a negative predictor of survival (hazard ratio [HR], 2.4; P < .0001), together with a diagnosis of acute leukemia (HR, 1.8; P = .0001); HAPLO grafts were comparable to SIB (P = .80), whereas UCB had inferior survival (P = .03). In conclusion, unmanipulated haploidentical family donor transplants are an additional option for patients lacking a matched sibling donor

R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lmphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi

PURPOSE Although rituximab (R) is commonly used for patients with advanced follicular lymphoma (FL) requiring treatment, the optimal associated chemotherapy regimen has yet to be clarified. PATIENTS AND METHODS We conducted an open-label, multicenter, randomized trial among adult patients with previously untreated stages II to IV FL to compare efficacy of eight doses of R associated with eight cycles of cyclophosphamide, vincristine, and prednisone (CVP) or six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or six cycles of fludarabine and mitoxantrone (FM). The principal end point of the study was time to treatment failure (TTF). Results There were 534 patients enrolled onto the study. Overall response rates were 88%, 93%, and 91% for R-CVP, R-CHOP, and R-FM, respectively (P=.247). After a median follow-up of 34 months, 3-year TTFs were 46%, 62%, and 59% for the respective treatment groups (R-CHOP v R-CVP, P=.003; R-FM v R-CVP, P=.006; R-FM v R-CHOP, P=.763). Three-year progression-free survival (PFS) rates were 52%, 68%, and 63% (overall P=.011), respectively, and 3-year overall survival was 95% for the whole series. R-FM resulted in higher rates of grade 3 to 4 neutropenia (64%) compared with R-CVP (28%) and R-CHOP (50%; P< .001). Overall, 23 second malignancies were registered during follow-up: four in R-CVP, five in R-CHOP, and 14 in R-FM. CONCLUSION In this study, R-CHOP and R-FM were superior to R-CVP in terms of 3-year TTF and PFS. In addition, R-CHOP had a better risk-benefit ratio compared with R-FM