Abstract Objective There is growing evidence of the importance of psychiatric risk factors for predicting the outcome of heart transplantation (HT) recipients. The aim of our study was to investigate ...the role of major depression and posttraumatic stress disorder (PTSD) in the prediction of the outcome of HT in a consecutive sample of 107 recipients. Method All subjects of the study underwent a structured diagnostic interview for assessing the presence of pretransplant and posttransplant major depression and transplantation-related PTSD 1 to 5 years after HT. The adherence to medical treatment was assessed some months after the structured interview. The medical outcome (acute rejections, cancer, mortality) was followed up for 8 years on average after the interview, using a prospective design. Results Estimated frequency of psychiatric diagnoses after HT was 12% for transplantation-related PTSD and 41% for major depression. The presence of an episode of major depression prior to HT is a significant independent risk factor for posttransplant malignancies. Age, posttransplant malignancies and poor adherence are significant predictors of mortality in the survival analyses. Conclusions The present study highlights the importance of the assessment of psychosocial variables and psychiatric diagnoses before and after transplantation in HT recipients. Our findings have important clinical implications and require replication with larger samples.
Potent and broadly neutralizing antibodies (bnAbs) are the hallmark of HIV-1 protection by vaccination. The membrane-proximal external region (MPER) of the HIV-1 gp41 fusion protein is targeted by ...the most broadly reactive HIV-1 neutralizing antibodies. Here, we examine the structural and molecular mechansims of neutralization by anti-MPER bnAb, LN01, which was isolated from lymph-node-derived germinal center B cells of an elite controller and exhibits broad neutralization breadth. LN01 engages both MPER and the transmembrane (TM) region, which together form a continuous helix in complex with LN01. The tilted TM orientation allows LN01 to interact simultaneously with the peptidic component of the MPER epitope and membrane via two specific lipid binding sites of the antibody paratope. Although LN01 carries a high load of somatic mutations, most key residues interacting with the MPER epitope and lipids are germline encoded, lending support for the LN01 epitope as a candidate for lineage-based vaccine development.
Abstract Objective A careful choice of perioperative care strategies is pivotal in order to improve survival in cardiac surgery. However, there is no general agreement nor particular attention to ...which nonsurgical interventions can reduce mortality in this setting. We sought to address this issue with a consensus-based approach. Design A systematic review of the literature followed by a consensus-based voting process. Setting A web-based international consensus conference. Participants More than 400 physicians from 52 countries participated in this web-based consensus conference Interventions The authors identified all manuscripts published in peer reviewed journals with a statistically significant effect on mortality in the setting of cardiac surgery through a systematic MEDLINE/PubMed and contacts with experts. These studies were discussed during a consensus meeting and those considered eligible were voted by clinicians worldwide. Measurements and main results Eleven interventions were finally selected: ten were shown to reduce mortality (aspiirin, glycemic control, high-volume surgeons, prophylactic intra-aortic balloon pump, levosimendan, leuko-depleted red blood cells transfusion, non-invasive ventilation, tranexamic acid, vacuum-assisted closure, and volatile agents), while one (aprotinin) increased mortality. A significant difference in the percentages of agreement among different countries and a variable gap between agreement and clinical practice were found for most of these interventions. Conclusions This updated consensus process allowed to draw up a list of 11 nonsurgical interventions with possible survival implications for patients undergoing cardiac surgery. This list may help cardiac anesthesiologists and intensivists worldwide in their daily clinical practice and can contribute to direct future research in the field.
The prognostic impact of achieving and in particular maintaining measurable residual disease (MRD) negativity in multiple myeloma is now established; therefore, identifying among MRD-negative ...patients the ones at higher risk of losing MRD negativity is of importance. We analyzed predictors of unsustained MRD negativity in patients enrolled in the FORTE trial (NCT02203643). MRD was performed by multiparameter flow cytometry (sensitivity of 10-5) at premaintenance and every 6 months thereafter. The cumulative incidence (CI) of MRD resurgence and/or progression was analyzed in MRD-negative patients. A total of 306 of 474 (65%) MRD-negative patients were analyzed. After a median follow-up of 50.4 months from MRD negativity, 185 of 306 (60%) patients were still MRD negative and progression free, 118 (39%) lost their MRD-negative status, and 3 patients (1%) died without progression. Amp1q vs normal (4-year CI, 63% vs 34), ≥2 concomitant high-risk cytogenetic abnormalities vs 0 (4-year CI, 59% vs 33%), circulating tumor cells at baseline (high vs low at 4-year CI, 62% vs 32%), and time-to-reach MRD negativity postconsolidation vs preconsolidation (4-year CI, 46% vs 35%) were associated with a higher risk of unsustained MRD negativity in a multivariate Fine-Gray model. During the first 2 years of maintenance, patients receiving carfilzomib-lenalidomide vs lenalidomide alone had a lower risk of unsustained MRD negativity (4-year CI, 20% vs 33%).
First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. ...The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of
(rs683369 c.480C>G) and
(rs1128503 c.1236C>T, rs2032582 c.2677G>T/A, rs1045642 c.3435C>T) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly,
and
polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore,
n contrast to data obtained in patients treated with imatinib,
and
polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.
Experimental data suggest a complex cross-talk between HER-2 and estrogen receptor, and it has been hypothesized that HER-2-positive tumors may be less responsive to certain endocrine treatments. ...Clinical data, however, have been conflicting. We have conducted a meta-analysis on the interaction between the response to endocrine treatment and the overexpression of HER-2 in metastatic breast cancer.
Studies have been identified by searching the Medline, Embase, and American Society of Clinical Oncology abstract databases. Selection criteria were (a) metastatic breast cancer, (b) endocrine therapy (any line of treatment), and (c) evaluation of HER-2 expression (any method). For each study, the relative risk for treatment failure for HER-2-positive over HER-2-negative patients with 95% confidence interval was calculated as an estimate of the predictive effect of HER-2. Pooled estimates of the relative risk were computed by the Mantel-Haenszel method.
Twelve studies (n = 2,379 patients) were included in the meta-analysis. The overall relative risk was 1.42 (95% confidence interval, 1.32-1.52; P < 0.00001; test for heterogeneity = 0.380). For studies involving tamoxifen, the pooled relative risk was 1.33 (95% confidence interval, 1.20-1.48; P < 0.00001; test for heterogeneity = 0.97); for studies involving other hormonal drugs, a pooled relative risk of 1.49 (95% confidence interval, 1.36-1.64; P < 0.00001; test for heterogeneity = 0.08) was estimated. A second meta-analysis limited to tumors that were either estrogen receptor positive, estrogen receptor unknown, or estrogen receptor negative/progesterone receptor positive yielded comparable results.
HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment. This effect holds in the subgroup of patients with positive or unknown steroid receptors.
Prokineticin 2 (Prok2) or prokineticin-receptor2 (Prok-R2) gene mutations are associated with Kallmann syndrome (KS). We describe a new homozygous mutation of Prok-R2 gene in a man displaying KS with ...an apparent reversal of hypogonadism. The proband, offspring of consanguineous parents, presented at age 19 years with absent puberty, no sense of smell, low testosterone and gonadotrophin levels. Magnetic resonance imaging showed olfactory bulb absence. The patient achieved virilization and spermatogenesis with gonadotrophin administration. Two years after discontinuing hormonal therapy, he maintained moderate oligozoospermia and normal testosterone levels. Prok2 and Prok-R2 gene sequence analyses were performed. The proband had a homozygous mutation in Prok-R2 exon 2 that harbours the c.T820>A base substitution, causing the introduction of an aspartic acid in place of valine at position 274 (Val274Asp). His mother had the same mutation in heterozygous state. This report describes a novel homozygous mutation of Prok-R2 gene in a man with variant KS, underlying the role of Prok-R2 gene in the olfactory and reproductive system development in humans. Present findings indicate that markedly delayed activation of gonadotrophin secretion may occur in some KS cases with definite gene defects, and that oligozoospermia might result from a variant form of reversible hypogonadotrophic hypogonadism.
•We analyzed outcome of 2,536 radical cystectomy patients treated with robotic and open radical cystectomy.•The overall surgical margin status was 11%; 10% in the open radical cystectomy group and ...13% in the robotic radical cystectomy group.•After adjusting for the effects of established prognostic factors, no differences were reported regarding surgical margin status between open and robotic radical cystectomy.
The use of robotic-assisted radical cystectomy (RARC) is becoming more widespread. While its safety is accepted, its oncological efficacy as compared to the current standard, open radical cystectomy (ORC), remains debatable.
The aim of this study is to compare the rates of positive soft tissue surgical margins (STSM), between patients treated with RARC or ORC, using a large contemporaneous collaborative database. We included 2,536 patients with urothelial carcinoma of the bladder treated at 26 institutions. A propensity-score matching 1:1 was performed with 3 ORC patients matched to 1 RARC patient. The final cohort included 1,614 patients. Uni- and multivariable logistic regression analyses tested the impact of surgical technique on STSM status, before and after propensity-score matching.
Overall, 870 (34%) patients underwent RARC and 1,666 (66%) ORC. The overall STSM rate was 11%; 10% in the ORC group and 13% in the RARC group. Within the propensity-score-matched cohort, the positive STSM rate were 14% and 13% in the ORC and RARC group, respectively (P = 0.1). In multivariable analysis, after propensity match RARC approach was not associated with the risk of a positive STSM (P = 0.1). These results were confirmed in the subgroup of patients with pathologic non–organ-confined or organ-confined diseases.
While treatment with RARC is associated with a higher absolute rate of STSM, the difference did not remain after adjustment for the effects of other established prognostic factors. Results from ongoing trials are awaited to assess the validity of these findings.
It is widely recognized that airway inflammation and remodeling play a key role not only in the central airway but also small airway pathology during asthma. Nociceptin/Orphanin FQ (N/OFQ), an ...endogenous peptide, and its receptor N/OFQ peptide (NOP) are involved in airway hyperresponsiveness (AHR). We studied a murine model of AHR in order to understand the role of N/OFQ in the inflammation and remodeling of the small airways. Balb/c mice were sensitized to ovalbumin (OVA). At days 0 and 7 (pre‐OVA sensitization) or from day 21 to 23 (post‐OVA sensitization), the mice were treated intraperitoneally with N/OFQ or saline solution. After the last OVA challenge, all OVA‐sensitized mice were aerosol‐challenged with 1% OVA in PBS for 48 h, and then euthanized. Small airway compliance (sCaw) was measured and lung samples were collected for histological and molecular evaluations such as perimeter and diameter of small airway, total wall area, airway smooth muscle (ASM) thickness and number of alveolar attachments. Both pre‐ and post‐OVA sensitization N/OFQ treatments induced: (1) increases in sCaw; (2) reduction of the bronchial wall thickness; (3) attenuation of the hyperplastic phase of airway smooth muscle mass; and (4) protection against loss of alveolar attachments compared with saline solution treatments. These results suggest that N/OFQ protects against inflammation, and mechanical damage and remodeling of small airways caused by OVA sensitization, suggesting a new potential therapeutic target for asthma.
We studied a murine model of AHR in order to understand the role of N/OFQ in the inflammation and remodeling of the small airways. N/OFQ protects against inflammation, and mechanical damage and remodeling of small airways caused by OVA sensitization, suggesting a new potential therapeutic target for asthma.
PDF
