Risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients.

BACKGROUND: Abiraterone and enzalutamide use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude and clinical relevance of this association in real-world prostate cancer (PC) population remain unknown. MATERIALS AND METHODS: We retrospectively reviewed the MarketScan claims databases (1 January 2013 to 30 September 2018) to identify adults with diagnosis of metastatic PC who received treatment with androgen deprivation therapy (ADT) and novel antiandrogen agents (abiraterone or enzalutamide). The primary CV outcome measure was composite outcome of acute myocardial infarction (MI) or stroke. Secondary outcomes were individual risks of MI or stroke. We used an intention-to-treat approach to analyze the CV outcomes associated with drug exposure among patients with metastatic PC. Cox regression model was used to estimate the independent association of two drugs with CV risk after adjustment for age, baseline atrial fibrillation, and Charlson Comorbidity Index. RESULTS: A total of 6294 patients with metastatic PC who were treated with ADT and either abiraterone or enzalutamide were included in the final analysis. Of these, 4017 (63.8%) patients used abiraterone and 2217 (32.2%) patients used enzalutamide. During the study period, 255 (6.3%) primary endpoint events occurred, resulting in an incidence rate of 4.3 per 100 patient-years. In multivariable analysis, abiraterone use was associated with a 31% increased risk of MI or stroke compared to enzalutamide (hazard ratio 1.31; 95% confidence interval 1.05-1.63; P = 0.01). The incidence rate was similar in patients who switched initial therapy from abiraterone to enzalutamide or vice versa (5.0 versus 5.6 per 100 patient-years, respectively). CONCLUSIONS: To our knowledge, this is the first real-world assessment of MI and stroke among metastatic PC patients receiving novel anti-androgens. Our findings of increased MI and stroke risk with abiraterone compared with enzalutamide are consistent with data from clinical trials and suggest that enzalutamide may be preferable for prostate cancer patients at high CV risk.

Screening for second malignancies in mycosis fungoides: non-Hodgkin lymphoma, Hodgkin lymphoma, lung cancer, bladder cancer and melanoma.

BACKGROUND: Patients with mycosis fungoides (MF) are at increased risk of developing non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), lung cancer, bladder cancer and melanoma. The characteristics of patients developing these malignancies have not been specifically delineated. In addition, there are no established guidelines for screening MF patients for second malignancies. MATERIALS/METHODS: We identified 742 patients with MF who developed second malignancies in the Surveillance Epidemiology and End Result-18 database. RESULTS: The majority of second malignancy patients were white and male, mean age 55-67 years at diagnosis of MF, and mean age 61-72 years at diagnosis of second malignancy. The majority of patients diagnosed with second malignancies had early stage MF. MF patients with NHL, lung cancer, and bladder cancer tended to be diagnosed at earlier stages of the second malignancy than patients without MF and demonstrated better 5-year overall survival. There was no improvement in stage at diagnosis or survival for MF patients who were diagnosed with melanoma compared to patients without MF. CONCLUSIONS: Improvements in survival in MF/NHL, MF/lung cancer and MF/bladder cancer patients may reflect differences in disease biology secondary to having MF or the importance of increased contact with the healthcare system. MF/melanoma data suggest that patients require regular pigmented-lesion-focused skin examinations. Tools for screening include regular lymph node examinations, pigmented-lesion-focused examinations and detailed review of systems questions. Smoking cessation counseling is key intervention in this population, as is ensuring that all age- and sex-specific cancer screenings are up-to-date (e.g. lung cancer screening, mammography, and colonoscopy). The utility of regular imaging for second malignancy screening and lab testing such as routine urinalysis requires additional study and expert consensus.

Demonstrating a Continuous Set of Two-Qubit Gates for Near-Term Quantum Algorithms.

Quantum algorithms offer a dramatic speedup for computational problems in material science and chemistry. However, any near-term realizations of these algorithms will need to be optimized to fit within the finite resources offered by existing noisy hardware. Here, taking advantage of the adjustable coupling of gmon qubits, we demonstrate a continuous two-qubit gate set that can provide a threefold reduction in circuit depth as compared to a standard decomposition. We implement two gate families: an imaginary swap-like (iSWAP-like) gate to attain an arbitrary swap angle, θ, and a controlled-phase gate that generates an arbitrary conditional phase, ϕ. Using one of each of these gates, we can perform an arbitrary two-qubit gate within the excitation-preserving subspace allowing for a complete implementation of the so-called Fermionic simulation (fSim) gate set. We benchmark the fidelity of the iSWAP-like and controlled-phase gate families as well as 525 other fSim gates spread evenly across the entire fSim(θ,ϕ) parameter space, achieving a purity-limited average two-qubit Pauli error of 3.8×10^{-3} per fSim gate.

Mycosis fungoides: developments in incidence, treatment and survival.

BACKGROUND: Prior studies have demonstrated improved disease-specific survival of mycosis fungoides (MF) patients over the last 50 years. OBJECTIVE: To analyse patterns of survival and incidence from 1973 to 2016 and determine whether apparent improvements in MF-specific survival are due to lead-time bias rather than improvements in treatment. METHODS: We performed an analysis of 10 155 patients diagnosed with MF from 1973 to 2016 in the United States cancer registries of SEER-18. We also performed a literature review of papers including stage data for unselected populations of MF patients prior to 2000. RESULTS: Incidence of MF increased from 3.0 per million person-years in the 1970s to 5.9 in the 2010s. For all cohorts, non-Hodgkin lymphoma (including MF) was the leading cause of death. Survival analysis demonstrated marked improvement in disease-specific and overall survival from the 1970s to 2010s. Based on systematic review of the literature, 32%-73% of patients diagnosed prior to 2000 were diagnosed with early-stage disease, as opposed to 81% of patients in the SEER 2000-2016 cohort (P < 0.035 for all cohorts). CONCLUSIONS: Although there have been improvements in MF-related survival over the last 50 years, these may reflect improvements in our ability to diagnose early-stage disease rather than improved treatment.

Predicting post-transarterial chemoembolization outcomes: A comparison of direct and total bilirubin serums levels.

PURPOSE: To retrospectively review the ability of direct bilirubin serum level to predict mortality and complications in patients undergoing transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) and compare it to the predictive value of the currently utilized total bilirubin serum level. MATERIALS AND METHODS: A total of 219 patients who underwent TACE for 353 hepatocelluar carcinomas (HCC) at a single institution were included. There were 165 men and 54 women, with a mean age of 61.4±7.6 (SD) [range: 27-86 years]. The patients' electronic medical records were evaluated and they were divided into cohorts based on total bilirubin (<2, 2-3, and >3mg/dL) as well as direct bilirubin (<1 and 1-2mg/dL). RESULTS: Direct bilirubin serum level was significantly greater in the cohort of patients who did not survive as compared to those who survived 6 months ([0.58±0.46 (SD) mg/dL; range: <0.1-1.8mg/dL] vs. [0.40±0.31 (SD) mg/dL; range: <0.1-1.6mg/dL], respectively) (P=0.04) and 12 months ([0.49±0.38 (SD) mg/dL; range: <0.1-1.8mg/dL] vs. [0.38±0.32 (SD) mg/dL; range: <0.1-1.6mg/dL], respectively) (P=0.03). While total bilirubin serum level was not significantly different in those who did not and did survive 6 months ([1.54±0.99 (SD) mg/dL; range: 0.3-3.9mg/dL] vs. [1.27±0.70 (SD) mg/dL; range: 0.3-3.75mg/dL], respectively) (P=0.16), it was significantly different when evaluating 12 months survival ([1.46±0.87 (SD)mg/dL; range: 0.3-3.9mg/dL] vs. [1.22±0.65 (SD) mg/dL; range: 0.3-3.9mg/dL]) (P=0.03). Akaike information criterion (AIC) analysis revealed that direct bilirubin level more accurately predicted overall survival (AIC=941.19 vs. 1000.51) and complications (AIC=352.22 vs. 357.42) than total bilirubin serum levels. CONCLUSION: Direct bilirubin serum level appears to outperform total bilirubin concentration for predicting complications and overall survival in patients undergoing TACE. Patients with relatively maintained direct bilirubin levels should be considered for TACE, particularly in the setting of bridging to transplant.

Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression.

Regulatory T cells (Tregs) act as indispensable unit for maintaining peripheral immune tolerance mainly by regulating effector T cells. T cells resistant to suppression by Tregs pose therapeutic challenges in the treatment of autoimmune diseases, while augmenting susceptibility to suppression may be desirable for cancer therapy. To understand the cell intrinsic signals in T cells during suppression by Tregs, we have previously performed a global phosphoproteomic characterization. We revealed altered phosphorylation of protein phosphatase 1 regulatory subunit 11 (PPP1R11; Inhibitor-3) in conventional T cells upon suppression by Tregs. Here, we show that silencing of PPP1R11 renders T cells resistant toward Treg-mediated suppression of TCR-induced cytokine expression. Furthermore, whole-transcriptome sequencing revealed that PPP1R11 differentially regulates not only the expression of specific T cell stimulation-induced cytokines but also other molecules and pathways in T cells. We further confirmed the target of PPP1R11, PP1, to augment TCR-induced cytokine expression. In conclusion, we present PPP1R11 as a novel negative regulator of T cell activation-induced cytokine expression. Targeting PPP1R11 may have therapeutic potential to regulate the T cell activation status including modulating the susceptibility of T cells toward Treg-mediated suppression, specifically altering the stimulation-induced T cell cytokine milieu.

Phosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cells.

Regulatory T cells (Tregs) control key events of immune tolerance, primarily by suppression of effector T cells. We previously revealed that Tregs rapidly suppress T cell receptor (TCR)-induced calcium store depletion in conventional CD4+CD25- T cells (Tcons) independently of IP3 levels, consequently inhibiting NFAT signaling and effector cytokine expression. Here, we study Treg suppression mechanisms through unbiased phosphoproteomics of primary human Tcons upon TCR stimulation and Treg-mediated suppression, respectively. Tregs induced a state of overall decreased phosphorylation as opposed to TCR stimulation. We discovered novel phosphosites (T595_S597) in the DEF6 (SLAT) protein that were phosphorylated upon TCR stimulation and conversely dephosphorylated upon coculture with Tregs. Mutation of these DEF6 phosphosites abrogated interaction of DEF6 with the IP3 receptor and affected NFAT activation and cytokine transcription in primary Tcons. This novel mechanism and phosphoproteomics data resource may aid in modifying sensitivity of Tcons to Treg-mediated suppression in autoimmune disease or cancer.

Validation of an emergency triage scale for obstetrics and gynaecology: a prospective study.

OBJECTIVE: To evaluate the reliability of a four-level triage scale for obstetrics and gynaecology emergencies and to explore the factors associated with an optimal triage. DESIGN: Thirty clinical vignettes presenting the most frequent indications for obstetrics and gynaecology emergency consultations were evaluated twice using a computerised simulator. SETTING: The study was performed at the emergency unit of obstetrics and gynaecology at the Geneva University Hospitals. SAMPLE: The vignettes were submitted to nurses and midwives. METHODS: We assessed inter- and intra-rater reliability and agreement using a two-way mixed-effects intra-class correlation (ICC). We also performed a generalised linear mixed model to evaluate factors associated triage correctness. MAIN OUTCOME MEASURES: Triage acuity. RESULTS: We obtained a total of 1191 evaluations. Inter-rater reliability was good (ICC 0.748; 95% CI 0.633-0.858) and intra-rater reliability was almost perfect (ICC 0.812; 95% CI 0.726-0.889). We observed a wide variability: the mean number of questions varied from 6.9 to 18.9 across individuals and from 8.4 to 16.9 across vignettes. Triage acuity was underestimated in 12.4% of cases and overestimated in 9.3%. Undertriage occurred less frequently for gynaecology compared with obstetric vignettes [odds ratio (OR) 0.45; 95% CI 0.23-0.91; P = 0.035] and decreased with the number of questions asked (OR 0.94; 95% CI 0.88-0.99; P = 0.047). Certification in obstetrics and gynaecology emergencies was an independent factor for the avoidance of undertriage (OR 0.35; 95% CI 0.17-0.70; P = 0.003). CONCLUSION: The four-level triage scale is a valid and reliable tool for the integrated emergency management of obstetrics and gynaecology patients. TWEETABLE ABSTRACT: The Swiss Emergency Triage Scale is a valid and reliable tool for obstetrics and gynaecology emergency triage.

[Laparoscopic lateral suspension, another way to treat genital prolapse]. / La suspension latérale cœlioscopique, une autre façon de traiter les prolapsus génitaux.

The laparoscopic sacrocolpopexy is the treatment of choice of pelvic organ prolapses since more than twenty years. The laparoscopic lateral suspension with mesh is an alternative technique. Its originality is the subperitoneal passing of the lateral arm of the mesh in the lateral abdominal wall, leaving the skin above the iliac crest, in a place without risks of vascular, nerve, bowel injuries. We report in this article the results of the three main publications on the subject. The indications are cystocele and apical descent. It can be envisaged when the access of the promontory is difficult; for instance in the presence of obesity, adhesions, sigmoid megacolon, or low position of the left common iliac vein, partially covering the promontory. It is also a practical technique for surgeons having a moderate experience of the promontory access.

Human macrophages induce CD4(+)Foxp3(+) regulatory T cells via binding and re-release of TGF-ß.

While pro-inflammatory immune responses are a requirement to combat microbes, uncontrolled self-directed inflammatory immune responses are the hallmark of autoimmune diseases. Restoration of immunological tolerance involves both suppression of ongoing tissue-destructive immune responses and re-education of the host immune system. Both functionally immunosuppressive macrophages (M2) and regulatory T cells (Tregs) are implicated in these processes. Their mutual interaction is synergistic in this context and adoptive transfer of each cell type has been functioning as immunotherapy in experimental models, being particularly effective when using M2 macrophages generated with an optimized interleukin-4 (IL-4)/interleukin-10 (IL-10)/transforming growth factor-ß (TGF-ß) combination. As a prerequisite for eventual translation of M2 therapy into clinical settings we herein studied the induction, stability and mechanism of generation of human induced Tregs (iTregs) by M2 macrophages generated with IL-4/IL-10/TGF-ß. The supernatants of monocyte-derived human M2 macrophages robustly induced FOXP3 and other Treg signature molecules such as CTLA-4 and IKZF4 in human naïve CD4 T cells. M2-induced iTregs displayed enhanced FOXP3 stability and low expression of pro-inflammatory cytokines interferon-γ and IL-17, as well as functional immunosuppressive activity compared with control T cells. The FOXP3-inducing activity was dependent on TGF-ß, which was both expressed and captured with re-release by M2 macrophages into the soluble supernatant fraction, in which the TGF-ß was not confined to extracellular vesicles such as exosomes. We propose that adoptive transfer of human M2 macrophages may be exploited in the future to induce Tregs in situ by delivering TGF-ß, which could be developed as a therapeutic strategy to target autoimmune and other inflammatory diseases.

[Uterine volume and vaginal hysterectomy: Interest and limits of uterine morcellation]. / Volume utérin et hystérectomie vaginale : intérêt et limites de l'hystérectomie vaginale.

Abdominal hysterectomy remains the preferred approach for large uteri or in case of narrow vaginal access. However, the traditional morcellation techniques allow safe and efficient extraction when choosing the vaginal route. Uterine volume reductive techniques do not increase perioperative morbidity thus complications do not seem to be linked to uterine size. There are numerous advantages of the vaginal route in comparison with laparotomy, such as aesthetic benefits, decreased postoperative pain, reduced hospital stay and recovery as well as decreased perioperative morbidity. Compared to laparoscopy, surgical outcomes and blood loss of the vaginal approach of a large uterus seem to be similar. Nevertheless, laparoscopic hysterectomy is associated with longer operative time and significant increase in hospital cost. Hence, a thorough knowledge and mastery of uterine morcellation techniques are essential when performing vaginal hysterectomy for large uteri or when the vagina is narrow. They must therefore continue to be taught, spread and regularly used in order to stretch the indications for vaginal hysterectomy in favour of an abdominal approach.

In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-ß-containing Protocol.

Regulatory T cells (Tregs) are an integral part of peripheral tolerance, suppressing immune reactions against self-structures and thus preventing autoimmune diseases. Clinical approaches to adoptively transfer Tregs, or to deplete Tregs in cancer, are underway with promising first outcomes. Because the number of naturally occurring Tregs (nTregs) is very limited, studying certain Treg features using in vitro induced Tregs (iTregs) can be advantageous. To date, the best although not absolutely specific protein marker to delineate Tregs is the transcription factor FOXP3. Despite the importance of Tregs including non-redundant roles of peripherally induced Tregs, the protocols to generate iTregs are currently controversial, particularly for human cells. This protocol therefore describes the in vitro differentiation of human CD4+FOXP3+ iTregs from human naïve T cells using a range of Treg-inducing factors (TGF-ß plus IL-2 only, or their combination with retinoic acid, rapamycin or butyrate) in parallel. It also describes the phenotyping of these cells by flow cytometry and qRT-PCR. These protocols result in reproducible expression of FOXP3 and other Treg signature genes and enable the study of general FOXP3-regulatory mechanisms as well as protocol-specific effects to delineate the impact of certain factors. iTregs can be utilized to study various phenotypic aspects as well as molecular mechanisms of Treg induction. Detailed molecular studies are facilitated by relatively large cell numbers that can be obtained. A limitation for the application of iTregs is the relative instability of FOXP3 expression in these cells compared to nTregs. iTregs generated by these protocols can also be used for functional assays such as studying their suppressive function, in which iTregs induced by TGF-ß plus retinoic acid and rapamycin display superior suppressive activity. However, the suppressive capacity of iTregs can differ from nTregs and the use of appropriate controls is crucial.

[Overactive bladder syndrome--a public health challenge]. / Syndrome de la vessie hyperactive chez la femme: un défi de santé publique.

Overactive bladder is a highly prevalent clinical syndrome affecting up to 17% of women. It is often associated with urodynamic detrusor overactivity, leads to embarrassment and is frequently under-diagnosed and insufficiently treated. Its pathophysiology is complex and the numerous treatment modalities, some of them of poor evidence, aim to improve quality of life. When physiotherapy fails, anticholinergics are recommended as first-line medical treatment. They can be combined with or replaced by beta3-adrenergic agonists whereas sacral neuromodulation or posterior tibia nerve stimulation are considered an efficient alternative. Addidtionally, cystoscopic injection of botulinum toxine in the bladder has recently been validated in Switzerland as a treatment option for idiopathic overactive bladder.

Longitudinal studies of a B cell-derived signature of tolerance in renal transplant recipients.

Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients, we confirmed our previous finding that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years, although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and that it is a useful monitoring tool in prospective trials.

Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression.

We report here the long-term results of HLA-mismatched kidney transplantation without maintenance immunosuppression (IS) in 10 subjects following combined kidney and bone marrow transplantation. All subjects were treated with nonmyeloablative conditioning and an 8- to 14-month course of calcineurin inhibitor with or without rituximab. All 10 subjects developed transient chimerism, and in seven of these, IS was successfully discontinued for 4 or more years. Currently, four subjects remain IS free for periods of 4.5-11.4 years, while three required reinstitution of IS after 5-8 years due to recurrence of original disease or chronic antibody-mediated rejection. Of the 10 renal allografts, three failed due to thrombotic microangiopathy or rejection. When compared with 21 immunologically similar living donor kidney recipients treated with conventional IS, the long-term IS-free survivors developed significantly fewer posttransplant complications. Although most recipients treated with none or two doses of rituximab developed donor-specific antibody (DSA), no DSA was detected in recipients treated with four doses of rituximab. Although further revisions of the current conditioning regimen are planned in order to improve consistency of the results, this study shows that long-term stable kidney allograft survival without maintenance IS can be achieved following transient mixed chimerism induction.

Native portal vein embolization for persistent hyperoxaluria following kidney and auxiliary partial liver transplantation.

Type 1 primary hyperoxaluria (PH1) causes renal failure, for which isolated kidney transplantation (KT) is usually unsuccessful treatment due to early oxalate stone recurrence. Although hepatectomy and liver transplantation (LT) corrects PH1 enzymatic defect, simultaneous auxiliary partial liver transplantation (APLT) and KT have been suggested as an alternative approach. APLT advantages include preservation of the donor pool and retention of native liver function in the event of liver graft loss. However, APLT relative mass may be inadequate to correct the defect. We here report the first case of native portal vein embolization (PVE) to increase APLT to native liver mass ratio (APLT/NLM-R). Following initial combined APLT-KT, both allografts functioned well, but oxalate plasma levels did not normalize. We postulated the inadequate APLT/NLM-R could be corrected by trans-hepatic native PVE. The resulting increased APLT/NLM-R decreased serum oxalate to normal levels within 1 month following PVE. We conclude that persistently elevated oxalate levels after combined APLT-KT for PH1 treatment, results from inadequate relative functional capacity. This can be reversed by partial native PVE to decrease portal flow to the native liver. This approach might be applicable to other scenarios where partial grafts have been transplanted to replace native liver function.

Human plasmacytoid dendritic cells are equipped with antigen-presenting and tumoricidal capacities.

Human plasmacytoid dendritic cells (pDCs) represent a highly specialized naturally occurring dendritic-cell subset and are the main producers of type I interferons (IFNs) in response to viral infections. We show that human pDCs activated by the preventive vaccine FSME specifically up-regulate CD56 on their surface, a marker that was thought to be specific for NK cells and associated with cytolytic effector functions. We observed that FSME-activated pDCs specifically lysed NK target cells and expressed cytotoxic molecules, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and granzyme B. Elevated levels of these molecules coincided with the expression of CD56, indicative for skewing human pDCs toward an interferon-producing killer DC subset. Detailed phenotypical and functional analysis revealed that pDCs attained a mature phenotype, secreted proinflammatory cytokines, and had the capacity to present antigens and stimulate T cells. Here, we report on the generation of CD56(+) human interferon producing killer pDCs with the capacity to present antigens. These findings aid in deciphering the role for pDCs in antitumor immunity and present a promising prospect of developing antitumor therapy using pDCs.