The impact of inflammation on the obesity paradox in coronary heart disease.

BACKGROUND: Despite the well-known adverse effects of obesity on almost all aspects of coronary heart disease, many studies of coronary heart disease cohorts have demonstrated an inverse relationship between obesity, as defined by body mass index (BMI), and subsequent prognosis: the 'obesity paradox'. The etiology of this and the potential role of inflammation in this process remain unknown. PATIENTS AND METHODS: We studied 519 patients with coronary heart disease before and after cardiac rehabilitation, dividing them into groups based on C-reactive protein ((CRP)⩾3 mg l-1 and CRP<3 mg l-1 after cardiac rehabilitation). BMI was calculated and body fat was measured using the skin-fold method. Lean mass index (LMI) was calculated as (1-%body fat) × BMI. The population was divided according to age- and gender-adjusted categories based on LMI and body fat and analyzed by total mortality over >3-year follow-up by National Death Index in both CRP groups. RESULTS: During >3-year follow-up, all-cause mortality was higher in the high inflammation and in the low BMI group. In proportional hazard analysis, even after adjusting for ejection fraction and peak O2 consumption, higher BMI was associated with lower mortality in the entire population (hazard ratio (HR) 0.38; confidence interval 0.15-0.97) and a trend to lower mortality in both subgroups (HR 0.45 in low CRP, P=0.24 vs HR 0.32, P=0.06 in high CRP). High body fat, however, was associated with significantly lower mortality in the high CRP group (HR 0.22; P=0.03) but not in the low CRP group (HR 0.73; P=0.64). Conversely, high LMI was associated with markedly lower mortality in the low CRP group (HR 0.04; P=0.04). CONCLUSIONS: The obesity paradox has multiple underlying etiologies. Body composition has a different role in different populations with an obesity paradox by BMI. Especially in the subpopulation with persistently high CRP levels, body fat seems protective.

A prognostic regulatory pathway in stage I epithelial ovarian cancer: new hints for the poor prognosis assessment.

BACKGROUND: Clinical and pathological parameters of patients with epithelial ovarian cancer (EOC) do not thoroughly predict patients' outcome. Despite the good outcome of stage I EOC compared with that of stages III and IV, the risk assessment and treatments are almost the same. However, only 20% of stage I EOC cases relapse and die, meaning that only a proportion of patients need intensive treatment and closer follow-up. Thus, the identification of cell mechanisms that could improve outcome prediction and rationalize therapeutic options is an urgent need in the clinical practice. PATIENTS AND METHODS: We have gathered together 203 patients with stage I EOC diagnosis, from whom snap-frozen tumor biopsies were available at the time of primary surgery before any treatment. Patients, with a median follow-up of 7 years, were stratified into a training set and a validation set. RESULTS AND CONCLUSIONS: Integrated analysis of miRNA and gene expression profiles allowed to identify a prognostic cell pathway, composed of 16 miRNAs and 10 genes, wiring the cell cycle, 'Activins/Inhibins' and 'Hedgehog' signaling pathways. Once validated by an independent technique, all the elements of the circuit resulted associated with overall survival (OS) and progression-free survival (PFS), in both univariate and multivariate models. For each patient, the circuit expressions have been translated into an activation state index (integrated signature classifier, ISC), used to stratify patients into classes of risk. This prediction reaches the 89.7% of sensitivity and 96.6% of specificity for the detection of PFS events. The prognostic value was then confirmed in the external independent validation set in which the PFS events are predicted with 75% sensitivity and 94.7% specificity. Moreover, the ISC shows higher classification performance than conventional clinical classifiers. Thus, the identified circuit enhances the understanding of the molecular mechanisms lagging behind stage I EOC and the ISC improves our capabilities to assess, at the time of diagnosis, the patient risk of relapse.

Phloridzin derivatives inhibiting pro-inflammatory cytokine expression in human cystic fibrosis IB3-1 cells.

Cystic Fibrosis (CF) is the most diffuse autosomal recessive genetic disease affecting Caucasians. A persistent recruitment of neutrophils in the bronchi of CF patients contributes to exacerbate the airway tissue damage, suggesting that modulation of chemokine expression may be an important target for the patient's well being thus the identification of innovative anti-inflammatory drugs is considered a longterm goal to prevent progressive tissue deterioration. Phloridzin, isolated from Malus domestica by a selective molecular imprinting extraction, and its structural analogues, Phloridzin heptapropionate (F1) and Phloridzin tetrapropionate (F2), were initially investigated because of their ability to reduce IL-6 and IL-8 expression in human CF bronchial epithelial cells (IB3-1) stimulated with TNF-α. Release of these cytokines by CF cells was shown to be controlled by the Transcription Factor (TF) NF-kB. The results of the present investigation show that of all the derivatives tested, Phloridzin tetrapropionate (F2) is the most interesting and has greatest potential as it demonstrates inhibitory effects on the expression and production of different cytokines involved in CF inflammation processes, including RANTES, VEGF, GM-CSF, IL-12, G-CSF, MIP-1b, IL-17, IL-10 and IP-10, without any correlated anti-proliferative and pro-apoptotic effects.

Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing: a retrospective study.

BACKGROUND: The majority of patients with stage III-IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S). PATIENTS AND METHODS: Matched biopsies (33) taken at Ft-S and Sd-S were selected from the 'Pandora' tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated. RESULTS: A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction. CONCLUSIONS: There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.

Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes.

The World Health Organization classification of myelodysplastic syndromes (MDS) is based on morphological evaluation of marrow dysplasia. We performed a systematic review of cytological and histological data from 1150 patients with peripheral blood cytopenia. We analyzed the frequency and discriminant power of single morphological abnormalities. A score to define minimal morphological criteria associated to the presence of marrow dysplasia was developed. This score showed high sensitivity/specificity (>90%), acceptable reproducibility and was independently validated. The severity of granulocytic and megakaryocytic dysplasia significantly affected survival. A close association was found between ring sideroblasts and SF3B1 mutations, and between severe granulocytic dysplasia and mutation of ASXL1, RUNX1, TP53 and SRSF2 genes. In myeloid neoplasms with fibrosis, multilineage dysplasia, hypolobulated/multinucleated megakaryocytes and increased CD34+ progenitors in the absence of JAK2, MPL and CALR gene mutations were significantly associated with a myelodysplastic phenotype. In myeloid disorders with marrow hypoplasia, granulocytic and/or megakaryocytic dysplasia, increased CD34+ progenitors and chromosomal abnormalities are consistent with a diagnosis of MDS. The proposed morphological score may be useful to evaluate the presence of dysplasia in cases without a clearly objective myelodysplastic phenotype. The integration of cytological and histological parameters improves the identification of MDS cases among myeloid disorders with fibrosis and hypocellularity.

DNA-damage response gene polymorphisms and therapeutic outcomes in ovarian cancer.

Epithelial ovarian cancer has a poor prognosis owing to late diagnosis and frequent relapse after first-line therapy. Analysis of individual genetic variability could aid in the identification of markers, which could help in stratifying patients with the aim of optimizing individual therapy. In this study we assessed polymorphisms in three genes important in drugs' response in 97 early and 235 late-stage ovarian cancer patients. The Asp1104His polymorphism in xpg, a gene important for removal of platinum adducts, was associated with progression-free survival in early- and late-stage ovarian cancer. Our data indicate that a simple diagnostic analysis such as xpg genotyping can help in predicting response, and extension to other possibly relevant genotypes could be useful in selecting patients with epithelial ovarian cancer for optimal therapy and hence increase the chance of response.

Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series.

BACKGROUND: To assess the long-term oncological outcome and the fertility of young women with early-stage epithelial ovarian cancer (ES/EOC) treated with fertility-sparing surgery (FSS). PATIENTS AND METHODS: All patients treated with FSS for ES/EOC in two Italian centers were considered for this analysis. Univariate and multivariate analyses were used to test demographic characteristics and clinical features for the association with overall survival (OS), recurrence-free survival (RFS) and fertility. RESULTS: From 1982 to 2010, 240 patients with malignant ES/EOC were treated with FSS in two tertiary centers in Italy. At a median follow-up of 9 years, 27 patients had relapsed (11%) and 11 (5%) had died of progressive disease. Multivariate analysis found only grade 3 negatively affected the prognosis of patients [hazard ratio (HR) for recurrence: 4.2, 95% confidence interval (CI): 1.5-11.7, P=0.0067; HR for death: 7.6, 95% CI: 2.0-29.3, P=0.0032]. Grade 3 was also significantly associated with extra-ovarian relapse (P=0.006). Of the 105 patients (45%) who tried to become pregnant, 84 (80%) were successful. CONCLUSIONS: Conservative treatment can be proposed to all young patients when tumor is limited to the ovaries, as ovarian recurrences can always be managed successfully. Patients with G3 tumors are more likely to have distant recurrences and should be closely monitored.

Systematic lymphadenectomy in ovarian cancer at second-look surgery: a randomised clinical trial.

BACKGROUND: The role of systematic aortic and pelvic lymphadenectomy (SAPL) at second-look surgery in early stage or optimally debulked advanced ovarian cancer is unclear and never addressed by randomised studies. METHODS: From January 1991 through May 2001, 308 patients with the International Federation of Gynaecology and Obstetrics stage IA-IV epithelial ovarian carcinoma were randomly assigned to undergo SAPL (n=158) or resection of bulky nodes only (n=150). Primary end point was overall survival (OS). RESULTS: The median operating time, blood loss, percentage of patients requiring blood transfusions and hospital stay were higher in the SAPL than in the control arm (P<0.001). The median number of resected nodes and the percentage of women with nodal metastases were higher in the SAPL arm as well (44% vs 8%, P<0.001 and 24.2% vs 13.3%, P:0.02). After a median follow-up of 111 months, 171 events (i.e., recurrences or deaths) were observed, and 124 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for progression and death were not statistically different (hazard ratio (HR) for progression=1.18, 95% confidence interval (CI)=0.87-1.59; P=0.29; 5-year progression-free survival (PFS)=40.9% and 53.8%; HR for death=1.04, 95% CI=0.733-1.49; P=0.81; 5-year OS=63.5% and 67.4%, in the SAPL and in the control arm, respectively). CONCLUSION: SAPL in second-look surgery for advanced ovarian cancer did not improve PFS and OS.

Obesity and the "obesity paradox" in cardiovascular diseases.

Obesity adversely affects most cardiovascular (CV) risk factors and is strongly associated, probably as an independent risk factor, with most CV diseases. However, substantial evidence points to the existence of an "obesity paradox," in that overweight and obese patients with established CV diseases typically have a better prognosis than leaner patients with the same CV disease. Despite this paradox, we believe that the "weight" of evidence still supports efforts at purposeful weight loss in both primary and secondary CV prevention.

Total laparoscopic radical hysterectomy and pelvic lymphadenectomy in locally advanced stage IB2-IIB cervical cancer patients after neoadjuvant chemotherapy.

OBJECTIVE: To evaluate the feasibility and morbidity of total laparoscopic class C2 radical hysterectomy (TLRH) with pelvic lymphadenectomy in patients with locally advanced cervical cancer stage IB2 to IIB after neoadjuvant chemotherapy (NACT). METHODS: A prospective study was conducted from October 2004 to September 2009. Cervical cancer patients, stage IB2-IIB with complete clinical response after 3 courses of NACT with paclitaxel 175 mg/m(2), ifosfamide 5 g/m(2) and cisplatin 75 mg/m(2) (TIP) underwent TLRH. RESULTS: Forty patients were included, with a median age of 46 years (range, 25-65), BMI of 24 kg/m(2) (range, 15-49). FIGO staging was IB2 in 23, IIA > 4 cm in 6 and IIB in 11 patients. Four patients required conversion to laparotomy. Pathological evaluation showed 9 complete response (pCR), 9 partial response (pPR1) with microscopic tumour, and 15 partial response (pPR2) with macroscopic tumour. Three patients had no response. The median operative time was 305 min (range, 215-430); the median estimated blood loss was 250 ml (range, 100-400), with four postoperative blood transfusion; the median number of removed pelvic lymph nodes was 25 (range, 11-64). The median length of hospital stay was 6 days (range, 3-12). The median follow-up time was 37 months (range, 10-69), with three patients having a recurrence. One patient died of disease (DOD) after 12 months. CONCLUSIONS: TLRH can be safely performed in patients with stage IB2-IIB carcinoma of cervix after NACT, with advantages of minimal blood loss and morbidity.

Effect of different gonadotrophin priming on IVM of oocytes from women with normal ovaries: a prospective randomized study.

This study was designed to determine if the efficiency of in-vitro maturation (IVM) in women with normal ovaries can be improved by gonadotrophin administration. 400 women were randomly allocated in four groups: group A, non-primed cycles; group B, human chorionic gonadotrophin (HCG)-primed cycles; group C, FSH-primed cycles; and group D, FSH- plus HCG-primed cycles. There were significant differences in the IVM rate among the groups. In groups where HCG was used, the overall maturation rate was higher (57.9% in group B and 77.4% in group D; 48.4% in group A and 50.8% in group C) and the percentage of total available metaphase II-stage oocytes was higher (60.4% in group B and 82.1% in group D; 48.4% in group A and 50.8% in group C). The overall clinical pregnancy rate per transfer (CPR) was 18.3% and the implantation rate (IR) was 10.6%. There was a difference in CPR among the groups: group D (29.9%) versus group A (15.3%), P = 0.023; group D versus group B (7.6%), P < 0.0001; group D versus group C (17.3%), P = 0.046. The results of this study are clearly in favour of FSH plus HCG priming. FSH priming and HCG priming alone showed no significant effects on clinical outcome.

Intractable neurostenalgia of the ulnar nerve abolished by neurolysis 18 years after injury.

A 39 year-old farmer sustained a closed rupture of the left brachial artery, which was successfully managed by emergency vein graft repair of the artery. Adjacent nerve trunks were seen to be intact, but stretched. Burning pain in the distribution of the ulnar nerve started at day seven postoperatively, and worsened over the ensuing years. There was no response to membrane stabilising drugs, amitryptiline, nor to regional sympatholytic or local anaesthetic blocks. Neurolysis of the ulnar nerve, which was densely adherent to the dilated vein graft, abolished his pain.

Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome.

The safety and efficacy of reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (SCT) for relapsed lymphomas remains unresolved. We conducted a prospective, multicentered, phase II trial. A total of 170 relapsed/refractory lymphomas received a RIC regimen followed by SCT from sibling donors. The primary study end point was non-relapse mortality (NRM). Histologies were non-Hodgkin's lymphomas (NHL) (indolent (LG-NHL), n=63; aggressive (HG-NHL), n=61; mantle cell lymphoma (MCL), n=14) and Hodgkin's disease (HD, n=32). Median follow-up was 33 months (range, 12-82). The results show that frequencies were as follows: cumulative NRM at 3 years, 14%; acute and chronic graft-versus-host disease (GVHD) 35 and 52%, respectively; 3-year overall survival (OS), 69% for LG-NHL, 69% for HG-NHL, 45% for MCL and 32% for HD (P=0.058); and 3-year relapse incidence, 29, 31, 35 and 81%, respectively (P<0.001). Relapse risk differed significantly at 3 years between follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) (14 versus 46%, P=0.04). Molecular remission occurred in 94 and 40% (P=0.002) of patients with FL and CLL, respectively. On multivariate analysis, OS was influenced by chemorefractory disease (hazard ratio (HR)=3.6), diagnosis of HD (HR=3.5), and acute GVHD (HR=5.9). RIC allogeneic SCT is a feasible and effective salvage strategy in both indolent and aggressive NHL.

Cannabis and Ecstasy/MDMA (3,4-methylenedioxymethamphetamine): an analysis of their neuropsychobiological interactions in recreational users.

The majority of recreational Ecstasy/MDMA users (90-98%) also take cannabis. This co-drug usage is often viewed as a methodological confound, which needs to be removed statistically. Here we take a rather different approach, and debate the potential complexities of their psychobiological interactions. The ring-substituted amphetamine derivate MDMA (3,4-methylendioxymethamphetmaine, or 'Ecstasy') is a powerful CNS stimulant, whereas cannabis is a relaxant. Their co-usage may reflect opposing effects in three psychobiological areas: arousal, body temperature, and oxidative stress. Firstly MDMA is alerting whereas cannabis is sedating. Secondly MDMA is hyperthermic whereas cannabis is hypothermic. Thirdly MDMA increases oxidative stress whereas cannabinoids are antioxidant. Hence cannabis may modulate the acute and sub-acute reactions to MDMA, reduce the acute hyperthermia induced by MDMA, and ameliorate the oxidative stress caused by MDMA. The limited empirical evidence on each topic will be critically examined. In terms of chronic effects each drug is functionally damaging, so that polydrug users generally display cumulative neurobiological impairments. However in certain aspects their neuropsychobiological effects may interactive rather than additive. In particular, the combined use of cannabis and MDMA may have rather different neuropsychobiological implications, than their separate usage. In order to investigate these potential complexities, future research will need better empirical data on the exact patterns of co-drug usage.

Pattern of cannabis use in ecstasy polydrug users: moderate cannabis use may compensate for self-rated aggression and somatic symptoms.

Cannabis is one of the most common 'co-drugs' for ecstasy users. The aim of the present study was to explore self-reported psychobiological problems in ecstasy polydrug users in relation to their pattern of cannabis use. Two hundred and eighty ecstasy polydrug users were allocated into five cannabis groups according to the frequency of their cannabis use. The control group comprised 121 alcohol-tobacco users. There were no significant group differences with regard to age, diagnosed family psychiatric history and level of self-rated stress experienced during 6 months prior to the study. The present study produced three main findings: (a) Ecstasy users with no concomitant use of cannabis displayed more self-rated aggression and somatic symptoms compared with ecstasy users who were smoking cannabis on a monthly or weekly basis. (b) Ecstasy users who reported heavy cannabis use in the past displayed higher paranoid symptoms compared with ecstasy weekly and daily cannabis users. (c) Former heavy cannabis users were the most likely to complain of a variety of ecstasy related long-term problems. In conclusion, moderate cannabis use may help to ameliorate or mask MDMA-induced aggressivity and somatic symptoms. However, this study confirms that heavy cannabis and ecstasy use is associated with several psychobiological problems, which may emerge after a period of abstinence from both drugs.