Long-term Outcomes and Patterns of Relapse Following High-dose Elective Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Nodes in Prostate Cancer: OLIGOPELVIS (GETUG-P07).

Androgen deprivation therapy (ADT) is a mainstay of treatment for metastatic prostate cancer, while additional salvage radiotherapy may offer prolonged remission for patients with regional node relapses. We report 5-yr outcomes from OLIGOPELVIS (GETUG-P07), an open-label phase 2 trial assessing long-term outcomes and patterns of relapse after 6-mo ADT and elective nodal radiotherapy (ENRT) in men with pelvic nodal oligorecurrence (<6 lesions) of prostate cancer. Progression was defined as two consecutive prostate-specific antigen (PSA) levels above the level at inclusion and/or clinical progression according to Response Evaluation Criteria in Solid Tumors v1.1 and/or death from any cause. Sixty-seven patients were recruited. Median follow-up was 6.1 yr (95% confidence interval 5.9-6.3). Rates of grade 2+ toxicities among patients without progression at 3, 4, and 5 yr were 15%, 9%, and 4% for genitourinary toxicities, and 2%, 3%, and 4% for gastrointestinal toxicities, respectively. The 5-yr progression-free, biochemical relapse-free, and ADT-free survival rates were 39%, 31%, and 64%, respectively. In total, 45 patients experienced progression, which was PSA-only progression in seven cases. Among the other 38 patients, local clinical progression occurred in 18%, progression to N1 stage in 29%, to M1a stage in 50%, to M1b stage in 32%, and to M1c stage in 11%. Finally, combined ENRT and ADT appeared to prolong tumor control with limited toxicity. At 5 yr, one-third of the patients had not experienced biochemical relapse. The major site of relapse was the para-aortic lymph nodes. PATIENT SUMMARY: We evaluated long-term results for high-dose radiotherapy in patients with recurrence of prostate cancer in pelvic lymph nodes. We found that this treatment provided prolonged tumor control without significant toxicity. One-third of the patients were still in complete remission after 5 years.

Post-operative flank irradiation using conformal versus highly conformal radiotherapy techniques for paediatric renal tumours: Results from the French registry PediaRT.

PURPOSE: Three-dimensional conformal RT (3D-RT) techniques are gold standard for post-operative flank radiotherapy (RT) in paediatric renal tumours. Recently, highly conformal RT (HC-RT) techniques have been implemented without comparative clinical data. The main objective of this multicentre study was to compare locoregional control (LRC) in children treated either with HC-RT or 3D-RT techniques. METHODS: Patients treated with post-operative flank RT for renal tumour registered in the national cohort PediaRT between March 2013 and September 2019 were included. Treatment and follow-up data, including toxicities and outcomes, were retrieved from the database. LRC was calculated, and dose reconstruction was performed in case of an event. RESULTS: Seventy-nine patients were included. Forty patients were treated with HC-RT and 39 with 3D-RT. Median follow-up was 4.5 years. Three patients had locoregional failure (LRF; 4%). HC-RT was not associated with a higher risk of LRF. Three-year LRC were 97.4% and 94.7% in the HC-RT and 3D-RT groups, respectively. The proportion of planning target volumes receiving 95% or more of the prescribed dose did not significantly differ between both groups (HC-RT 88%; 3D-RT 69%; p = .05). HC-RT was better achieving dose constraints, and a significant mean dose reduction was observed in the peritoneal cavity and pancreas associated with lower incidence of acute gastrointestinal toxicity. CONCLUSION: LRF after post-operative flank RT for renal tumours was rare and did not increase using HC-RT versus 3D-RT techniques. Dose to the pancreas and the peritoneal cavity, as well as acute toxicity, were reduced with HC-RT compared to 3D-RT.

Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune, inflammatory and fibrotic disease with limited treatment options. Developing new therapies is therefore crucial to address patient needs. To this end, we focused on galectin-3 (Gal-3), a lectin known to be associated with several pathological processes seen in SSc. Using RNA sequencing of whole-blood samples in a cross-sectional cohort of 249 patients with SSc, Gal-3 and its interactants defined a strong transcriptomic fingerprint associated with disease severity, pulmonary and cardiac malfunctions, neutrophilia and lymphopenia. We developed new Gal-3 neutralizing monoclonal antibodies (mAb), which were then evaluated in a mouse model of hypochlorous acid (HOCl)-induced SSc. We show that two of these antibodies, D11 and E07, reduced pathological skin thickening, lung and skin collagen deposition, pulmonary macrophage content, and plasma interleukin-5 and -6 levels. Moreover, E07 changed the transcriptional profiles of HOCl-treated mice, resulting in a gene expression pattern that resembled that of control mice. Similarly, pathological pathways engaged in patients with SSc were counteracted by E07 in mice. Collectively, these findings demonstrate the translational potential of Gal-3 blockade as a therapeutic option for SSc.

Effect of Concomitant Proton Pump Inhibitors with Pazopanib on Cancer Patients: A Retrospective Analysis.

The absorption of pazopanib depends on gastric pH. PPIs are frequently prescribed for cancer patients to modify gastric acidity, decreasing pazopanib absorption. The aim of our study was, retrospectively, to investigate the impact of PPIs on the clinical efficacy and safety of pazopanib in a cohort of patients treated in our health center. Of the 147 patients who were included retrospectively, 79 (54%) did not take PPIs concomitantly with pazopanib (cohort 1), while 68 (46%) patients did take PPIs concomitantly with pazopanib (cohort 2). The efficacy parameters were lower in patients taking pazopanib and PPIs: the i/tumor response was statistically different between the two cohorts (p = 0.008), in particular, with 19% vs. 3% of the objective response and 24% vs. 43% of progression in cohorts 1 and 2, respectively; ii/median overall survival was 17.6 (95% CI: 12.5−32.8) months in cohort 1 and 8.6 months (95% CI: 5.9−18.6) in cohort 2 (HR = 1.7 [95% CI: 1.2−2.5]; p < 0.006); on multivariable analysis, overall survival was associated with performance status, PPI intake, tumor location, hemoglobin, and PMN/lymphocyte ratio. In contrast, the dose reduction for toxicity and severe adverse events were (non-significantly) less frequent in cohort 1. To conclude, our study shows that combining PPIs with pazopanib has an adverse effect on overall survival. The clinical modifications that were observed are in line with a decrease in pazopanib absorption due to PPIs. This co-medication should be avoided.

Structure of the vasopressin hormone-V2 receptor-ß-arrestin1 ternary complex.

Arrestins interact with G protein-coupled receptors (GPCRs) to stop G protein activation and to initiate key signaling pathways. Recent structural studies shed light on the molecular mechanisms involved in GPCR-arrestin coupling, but whether this process is conserved among GPCRs is poorly understood. Here, we report the cryo-electron microscopy active structure of the wild-type arginine-vasopressin V2 receptor (V2R) in complex with ß-arrestin1. It reveals an atypical position of ß-arrestin1 compared to previously described GPCR-arrestin assemblies, associated with an original V2R/ß-arrestin1 interface involving all receptor intracellular loops. Phosphorylated sites of the V2R carboxyl terminus are clearly identified and interact extensively with the ß-arrestin1 N-lobe, in agreement with structural data obtained with chimeric or synthetic systems. Overall, these findings highlight a notable structural variability among GPCR-arrestin signaling complexes.

Discovery and Mechanism of Action of Small Molecule Inhibitors of Ceramidases.

Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes in human physiology. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to produce pro-proliferative sphingosine-1-phosphate. Alkaline ceramidases are transmembrane enzymes that recently attracted attention for drug development in fatty liver diseases. However, due to their hydrophobic nature, no specific small molecule inhibitors have been reported. We present the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3). In particular, we chemically engineered novel fluorescent ceramide substrates enabling screening of large compound libraries and characterized enzyme:inhibitor interactions using mass spectrometry and MD simulations. In addition to revealing a new paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules, our data lay the ground for targeting ACER3 in drug discovery efforts.

Molecular insights into the biased signaling mechanism of the µ-opioid receptor.

GPCR functional selectivity opens new opportunities for the design of safer drugs. Ligands orchestrate GPCR signaling cascades by modulating the receptor conformational landscape. Our study provides insights into the dynamic mechanism enabling opioid ligands to preferentially activate the G protein over the ß-arrestin pathways through the µ-opioid receptor (µOR). We combine functional assays in living cells, solution NMR spectroscopy, and enhanced-sampling molecular dynamic simulations to identify the specific µOR conformations induced by G protein-biased agonists. In particular, we describe the dynamic and allosteric communications between the ligand-binding pocket and the receptor intracellular domains, through conserved motifs in class A GPCRs. Most strikingly, the biased agonists trigger µOR conformational changes in the intracellular loop 1 and helix 8 domains, which may impair ß-arrestin binding or signaling. The findings may apply to other GPCR families and provide key molecular information that could facilitate the design of biased ligands.

Cryo-electron microscopy structure of the antidiuretic hormone arginine-vasopressin V2 receptor signaling complex.

The antidiuretic hormone arginine-vasopressin (AVP) forms a signaling complex with the V2 receptor (V2R) and the Gs protein, promoting kidney water reabsorption. Molecular mechanisms underlying activation of this critical G protein-coupled receptor (GPCR) signaling system are still unknown. To fill this gap of knowledge, we report here the cryo-electron microscopy structure of the AVP-V2R-Gs complex. Single-particle analysis revealed the presence of three different states. The two best maps were combined with computational and nuclear magnetic resonance spectroscopy constraints to reconstruct two structures of the ternary complex. These structures differ in AVP and Gs binding modes. They reveal an original receptor-Gs interface in which the Gαs subunit penetrates deep into the active V2R. The structures help to explain how V2R R137H or R137L/C variants can lead to two severe genetic diseases. Our study provides important structural insights into the function of this clinically relevant GPCR signaling complex.

Challenges in the Triage Care of Low-Risk Laboring Patients: A Comparison of 2 Models of Practice.

Triage and the timing of admission of low-risk pregnant women can affect the use of augmentation, epidural, and cesarean. The purpose of this analysis was to explore these outcomes in a community hospital by the type of provider staffing triage. This was a retrospective cohort study of low-risk nulliparous women with a term, vertex fetus laboring in a community hospital. Bivariate and multivariable statistics evaluated associations between triage provider type and labor and birth outcomes. Patients in this sample (N = 335) were predominantly White (89.5%), with private insurance (77.0%), and married (71.0%) with no significant differences in these characteristics by triage provider type. Patients admitted by midwives had lower odds of oxytocin augmentation (adjusted odds ratio [aOR] = 0.50, 95% confidence interval [CI] = 0.29-0.87), epidural (aOR = 0.29, 95% CI = 0.12-0.69), and cesarean birth (aOR = 0.308, 95% CI = 0.14-0.67), compared with those triaged by physicians after controlling for patient characteristics and triage timing. This study provides additional context to midwives as labor triage providers for healthy, low-risk pregnant individuals; however, challenges persisted with measurement. More research is needed on the specific components of care during labor that support low-risk patients to avoid medical interventions and poor outcomes.

Chlorhexidine plus alcohol versus povidone iodine plus alcohol, combined or not with innovative devices, for prevention of short-term peripheral venous catheter infection and failure (CLEAN 3 study): an investigator-initiated, open-label, single centre, randomised-controlled, two-by-two factorial trial.

BACKGROUND: Two billion peripheral venous catheters are sold globally each year, but the optimal skin disinfection and types of devices are not well established. We aimed to show the superiority of disinfection with 2% chlorhexidine plus alcohol over 5% povidone iodine plus alcohol in preventing infectious complications, and of closed integrated catheters, positive displacement needleless-connectors, disinfecting caps, and single-use prefilled flush syringes used in combination (innovation group) over open catheters and three-way stopcocks for treatment administration (standard group) in preventing catheter failure. METHODS: We did an open-label, randomised-controlled trial with a two-by-two factorial design, for which we enrolled adults (age ≥18 years) visiting the emergency department at the Poitiers University Hospital, France, and requiring one peripheral venous catheter before admission to the medical wards. Before catheter insertion, patients were randomly assigned (1:1:1:1) using a secure web-based random-number generator to one of four treatment groups based on skin preparation and type of devices (innovative devices or standard devices; 2% chlorhexidine plus alcohol or 5% povidone iodine plus alcohol). Primary outcomes were the incidence of infectious complications (local infection, catheter colonisation, or bloodstream infections) and time between catheter insertion and catheter failure (occlusion, dislodgment, infiltration, phlebitis, or infection). This study is registered with ClinicalTrials.gov, NCT03757143. FINDINGS: 1000 patients were recruited between Jan 7, and Sept 6, 2019, of whom 500 were assigned to the chlorhexidine plus alcohol group and 500 to the povidone iodine plus alcohol group (250 with innovative solutions and 250 with standard devices in each antiseptic group). No significant interaction was found between the two study interventions. Local infections occurred less frequently with chlorhexidine plus alcohol than with povidone iodine plus alcohol (0 [0%] of 496 patients vs six [1%] of 493 patients) and the same was observed for catheter colonisation (4/431 [1%] vs 70/415 [17%] catheters among the catheters cultured; adjusted subdistribution hazard ratio 0·08 [95% CI 0·02-0·18]). Median time between catheter insertion and catheter failure was longer in the innovation group compared with the standard group (50·4 [IQR 29·6-69·4] h vs 30·0 [16·6-52·6] h; p=0·0017). Minor skin reactions occurred in nine (2%) patients in the chlorhexidine plus alcohol group and seven (1%) patients in the povidone iodine plus alcohol group. INTERPRETATION: For skin antisepsis, chlorhexidine plus alcohol provides greater protection of peripheral venous catheter-related infectious complications than does povidone iodine plus alcohol. Use of innovative devices extends the catheter complication-free dwell time. FUNDING: Becton Dickinson.

Promoting active labor admission: Early labor lounge implementation barriers and facilitators from the clinician perspective.

BACKGROUND: The cesarean birth rate for low-risk pregnant individuals in the United States exceeds the recommended Healthy People 2020 rate. One recommended strategy to reduce cesarean in this population is delaying hospital admission until active labor commences. A quality improvement program was implemented at a community hospital using the early labor lounge (ELL) to promote admission in active labor. This study focuses on identifying the barriers and facilitators from the clinician perspective to implementing the ELL. METHODS: Interviews were conducted with a purposive sample of clinicians. Interview transcripts were open coded and themes identified inductively. A framework analysis was then conducted using the Consolidated Framework for Implementation Research (CFIR). RESULTS: Twenty-five staff members participated. Barriers and facilitators were identified in four of the CFIR domains. Facilitators included the strength of the evidence and the ELL itself, including the tools it contained for supporting women in latent labor. Barriers to implementation included clinician self-efficacy and perceived low usage of the ELL. CONCLUSION: This analysis using, CFIR identified several barriers and facilitators to the implementation of the ELL. The context of the individual woman presenting in triage and the acceptability and self-efficacy of the individual clinicians represented important factors for implementation.

Clinicians' Perspectives on Admission of Pregnant Women: A Triad.

PURPOSE: Reducing primary cesarean births is a national priority in the United States. Recommendations include delaying admission of low-risk pregnant women to the hospital until they are in active labor, considered to be 6 cm cervical dilatation. How this recommendation affects decision-making during triage requires further exploration. The purpose of this study was to explore the clinician's perspective on the triage process and deferral of hospital admission for low-risk pregnant women who were not yet in active labor. METHODS: A qualitative descriptive approach was used via semistructured interviews with physicians, midwives, and nurses. Data analysis used an inductive approach and identified codes, a theme and subthemes. RESULTS: Twenty-five clinicians participated. A triad of decision-making occurred between three main stakeholders: the low-risk pregnant woman, the triage nurse, and the physician or midwife. One theme and four subthemes related to this triad were identified. The theme Admission of Low-Risk Pregnant Women Depends on Many Factors provides context to the maternity care triage process. There are many factors clinicians consider prior to admitting women, including situational and clinical factors. Subthemes related to the woman are her expectation and knowledge about birth and her ability to cope with labor. Subthemes associated with the provider and triage nurse are care variation and concern for maternal and fetal safety. CLINICAL IMPLICATIONS: From the clinician's perspective, triage is a complex, dynamic process, even for low-risk pregnant women. There is an interplay of different factors affecting clinical decision-making, thus the decision-making triad provides a possible framework for shared decision-making.

Clinicians' Perspectives on Admission of Pregnant Women: A Triad.

PURPOSE: Reducing primary cesarean births is a national priority in the United States. Recommendations include delaying admission of low-risk pregnant women to the hospital until they are in active labor, considered to be 6 cm cervical dilatation. How this recommendation affects decision-making during triage requires further exploration. The purpose of this study was to explore the clinician's perspective on the triage process and deferral of hospital admission for low-risk pregnant women who were not yet in active labor. METHODS: A qualitative descriptive approach was used via semistructured interviews with physicians, midwives, and nurses. Data analysis used an inductive approach and identified codes, a theme and subthemes. RESULTS: Twenty-five clinicians participated. A triad of decision-making occurred between three main stakeholders: the low-risk pregnant woman, the triage nurse, and the physician or midwife. One theme and four subthemes related to this triad were identified. The theme Admission of Low-Risk Pregnant Women Depends on Many Factors provides context to the maternity care triage process. There are many factors clinicians consider prior to admitting women, including situational and clinical factors. Subthemes related to the woman are her expectation and knowledge about birth and her ability to cope with labor. Subthemes associated with the provider and triage nurse are care variation and concern for maternal and fetal safety. CLINICAL IMPLICATIONS: From the clinician's perspective, triage is a complex, dynamic process, even for low-risk pregnant women. There is an interplay of different factors affecting clinical decision-making, thus the decision-making triad provides a possible framework for shared decision-making.

Women's Prenatal and Labor Experiences in a Hospital With an Early-Labor Lounge.

OBJECTIVE: To evaluate the information that women with low-risk pregnancies received during the prenatal period about latent labor and the early-labor lounge (ELL) and their subsequent use of the ELL. DESIGN: Cross-sectional design with survey. SETTING/LOCAL PROBLEM: Community hospital in the northeastern United States with a low-risk cesarean birth rate of 33%, which exceeds the national target rate of 23.9%. PARTICIPANTS: Low-risk, nulliparous, pregnant women with a term singleton vertex fetus at hospital admission (N = 67). INTERVENTION/MEASUREMENTS: An electronic survey was administered before hospital discharge following birth. The survey assessed prenatal education, use of the ELL, admission characteristics, and birth satisfaction. Descriptive analysis was used. RESULTS: Nearly half (43.9%) of the women surveyed used the ELL. ELL users received prenatal care (72.3%), knew signs of active labor (93.1%), and had a cesarean birth rate of 7.1%. Significantly greater proportions of women prenatally cared for by midwives reported knowledge of the signs of early labor (100% vs. 80%; χ2 = 4.4, p = .04) and of the availability of the ELL (18.2% vs. 70.6%; χ2 = 15.2, p < .001). A range of activities were offered in the ELL, and at least 75% of women indicated that all activities were helpful during latent labor. Birth satisfaction scores, measured on a scale of 0 to 40, with 40 indicating greatest satisfaction, ranged from 22 to 35 among ELL participants. CONCLUSION: An ELL is a care innovation that hospitals can consider for providing support to women with low-risk pregnancies during the latent phase of labor. Women who used the ELL reported feeling that it provided guidance and support. An ELL is a woman-centered option for delayed admission.

Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy.

Alkaline ceramidases (ACERs) are a class of poorly understood transmembrane enzymes controlling the homeostasis of ceramides. They are implicated in human pathophysiology, including progressive leukodystrophy, colon cancer as well as acute myeloid leukemia. We report here the crystal structure of the human ACER type 3 (ACER3). Together with computational studies, the structure reveals that ACER3 is an intramembrane enzyme with a seven transmembrane domain architecture and a catalytic Zn2+ binding site in its core, similar to adiponectin receptors. Interestingly, we uncover a Ca2+ binding site physically and functionally connected to the Zn2+ providing a structural explanation for the known regulatory role of Ca2+ on ACER3 enzymatic activity and for the loss of function in E33G-ACER3 mutant found in leukodystrophic patients.

Use of an Early Labor Lounge to Promote Admission in Active Labor.

Professional maternity care organizations within the United States are aligned in the goal to prevent the first cesarean birth in nulliparous women with a term, singleton, vertex fetus. Currently, one in 3 women are at risk for having a cesarean birth. The most common reason for cesarean in the United States is labor dystocia. The evidence supports delaying admission to the birthing unit until active labor is established, thereby minimizing the inadvertent diagnosis of labor dystocia. Providers are familiar with the rationale supporting delayed admission to the birthing unit until active labor is established; however, there is very little evidence on how to effectively promote this delay. Provider apprehension and the lack of early labor support are challenges to sending women home to await the onset of active labor. Maternal anxiety, fear, pain, and unpreparedness also play a part in this reluctance. To address these obstacles, South Shore Hospital created an early labor lounge with stations aimed at instilling confidence in the birth team, promoting teamwork, facilitating relaxation, and reducing anxiety for laboring women. A literature review focusing on women's perceptions of promoting admission in active labor, maternal anxiety, and nonpharmacologic strategies for managing early labor are discussed within the context of the creation, implementation, and evaluation of an early labor lounge.

Improving satisfaction with care and reducing length of stay in an obstetric triage unit using a nurse-midwife-managed model of care.

INTRODUCTION: A quality improvement project was initiated at a tertiary-care center in a suburban area of the northeastern United States to determine whether length of stay and patient satisfaction in an obstetric triage unit could be improved by using a certified nurse-midwife (CNM) to manage and organize care in the triage unit. METHODS: Patient satisfaction was measured using a previously validated instrument that consisted of 6 items using a 6-point Likert-type scale. The items measured patient satisfaction with: wait time for provider, information given, amount of time spent with provider, length of visit, overall care received, and overall triage experience. Patient satisfaction was measured before (n = 37) and after implementing CNM-managed care (n = 66) in an obstetrical triage unit. Length of stay in the triage unit was measured during standard care (n = 121) and after the implementation of CNM-managed care (n = 151) by recording the number of minutes women spent in the triage unit. RESULTS: Participants in the CNM-managed care group reported increased patient satisfaction with care in 5 of the 6 aspects of satisfaction that were measured, including wait time for provider (P = .01), time spent with provider (P = .01), length of visit (P = .04), overall care received (P = .04), and overall triage experience (P = .01). The length of stay was significantly shorter for the women in the CNM-managed group (mean = 94.7 minutes; standard deviation [SD] 50.1) than for the women in the standard care model (mean = 122 minutes; SD = 66.8; P < .01). DISCUSSION: The findings from this project suggest that a CNM-managed obstetric triage unit can improve satisfaction with care during the triage experience and reduce length of stay in the triage unit.

Engineering E. coli for triglyceride accumulation through native and heterologous metabolic reactions.

Triglycerides, traditionally sourced from plant oils, are heavily used in both industrial and healthcare applications. Commercially significant products produced from triglycerides include biodiesel, lubricants, moisturizers, and oils for cooking and dietary supplements. The need to rely upon plant-based production, however, raises concerns of increasing demand and sustainability. The reliance on crop yields and a strong demand for triglycerides provides motivation to engineer production from a robust microbial platform. In this study, Escherichia coli was engineered to synthesize and accumulate triglycerides. Triglycerides were produced from cell wall phospholipid precursors through engineered expression of two enzymes, phosphatidic acid phosphatase (PAP) and diacylglycerol acyltransferase (DGAT). A liquid chromatography-mass spectrometry (LC-MS) method was developed to analyze the production of triglycerides by the engineered E. coli strains. This proof-of-concept study demonstrated a yield of 1.1 mg/L triglycerides (2 g/L dry cell weight) in lysogeny broth medium containing 5 g/L glucose at 8 h following induction of PAP and DGAT expression. LC-MS results also demonstrated that the intracellular triglyceride composition of E. coli was highly conserved. Triglycerides containing the fatty acid distributions 16:0/16:0/16:1, 16:0/16:0/18:1, and 18:1/16:0/16:1 were found in highest concentrations and represent ∼70 % of triglycerides observed.