Complications and Functional Results of Surgery for Locally Advanced Prostate Cancer

The role of surgery in clinical stage T3 prostate cancer (cT3 PCa) is still subject to debate. We reviewed the records of 139 consecutive patients who underwent a radical prostatectomy (RP) for cT3 PCa with a mean follow-up of 8 years. All data related to surgical and perioperative complications were collected. Continence and erectile function were assessed at 12 months postoperatively and long-term oncologic outcomes were analyzed. Rectal injury and injury of the obturator nerve occurred both in 0.7% of cases. No serious in-hospital complications were noted and no reintervention was needed. Lymphatic leakage was noted in 2.2% of patients and 1.4% experienced prolonged drainage of urine. In 7.2%, wound-related problems occurred. Anastomotic stricture occurred in 2.9%. These complication rates were not different compared to surgical series of RP in localized PCa. At 12 months, complete continence was 87.8% and erectile function had fully recovered in 6% and 10% of patients who underwent a non-nerve sparing or unilateral nerve-sparing procedure, respectively. 10-year estimated biochemical PFS, clinical PFS, CSS and OS were 51.8%, 85.6%, 94.6% and 85.9%, respectively. In cT3 PCa, RP is technically feasible with morbidity comparable to RP in clinically localized PCa. Long-term oncologic control was excellent

Blood pressure changes after renal denervation at 10 European expert centers

We did a subject-level meta-analysis of the changes (Δ) in blood pressure (BP) observed 3 and 6 months after renal denervation (RDN) at 10 European centers. Recruited patients (n=109; 46.8% women; mean age 58.2 years) had essential hypertension confirmed by ambulatory BP. From baseline to 6 months, treatment score declined slightly from 4.7 to 4.4 drugs per day. Systolic/diastolic BP fell by 17.6/7.1 mm Hg for office BP, and by 5.9/3.5, 6.2/3.4, and 4.4/2.5 mm Hg for 24-h, daytime and nighttime BP (P0.03 for all). In 47 patients with 3- and 6-month ambulatory measurements, systolic BP did not change between these two time points (P0.08). Normalization was a systolic BP of <140 mm Hg on office measurement or <130 mm Hg on 24-h monitoring and improvement was a fall of 10 mm Hg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9, 59.6 and 22.9% of patients, respectively; for 24-h BP, these proportions were 14.7, 31.2 and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow-up; higher baseline serum creatinine was associated with lower probability of improvement of 24-h BP (odds ratio for 20-μmol l(-1) increase, 0.60; P=0.05) and higher probability of experiencing no BP decrease (OR, 1.66; P=0.01). In conclusion, BP responses to RDN include regression-to-the-mean and remain to be consolidated in randomized trials based on ambulatory BP monitoring. For now, RDN should remain the last resort in patients in whom all other ways to control BP failed, and it must be cautiously used in patients with renal impairment

Comparison of phenotypic and genotypic tropism determination in triple-class-experienced HIV patients eligible for maraviroc treatment

BACKGROUND: Determination of HIV-1 tropism is a pre-requisite to the use of CCR5 antagonists. This study evaluated the potential of population genotypic tropism tests (GTTs) in clinical practice, and the correlation with phenotypic tropism tests (PTTs) in patients accessing routine HIV care. METHODS: Forty-nine consecutive plasma samples for which an original Trofile(TM) assay was performed were obtained from triple-class-experienced patients in need of a therapy change. Viral tropism was defined as the consensus of three or more tropism calls obtained from the combination of two independent population PTT assays (Trofile Biosciences, San Francisco, CA, USA, and Virco, Beerse, Belgium), population GTTs and GTTs based on ultra-deep sequencing. If no consensus was reached, a clonal PTT was performed in order to finalize the tropism call. This two-step approach allowed the definition of a reference tropism call. RESULTS: According to the reference tropism result, 35/49 samples were CCR5 tropic (R5) (patients eligible for maraviroc treatment) and 14/49 were assigned as non-R5 tropic. The non-R5 samples [patients not eligible for maraviroc treatment according to the FDA/European Medicines Agency (EMEA) label] group included both the CXCR4 (X4) samples and the dual and mixed CCR5/CXCR4 (R5/X4) samples. Compared with Trofile(TM) population PTTs, population GTTs showed a higher sensitivity (97%) and a higher negative predictive value (91%), but almost equal specificity and an equal positive predictive value. CONCLUSIONS: In line with recent reports from clinical trial data, our data support the use of population genotypic tropism testing as a tool for tropism determination before the start of maraviroc

Tropospheric Products from High-Level GNSS Processing in Latin America

ARTÍCULO PUBLICADO EN REVISTA EXTERNA. The present geodetic reference frame in Latin America and the Caribbean is given by a network of about 400 continuously operating GNSS stations. These stations are routinely processed by ten Analysis Centres following the guidelines and standards set up by the International Earth Rotation and Reference Systems Service (IERS) and International GNSS Service (IGS). The Analysis Centres estimate daily and weekly station positions and station zenith tropospheric path delays (ZTD) with an hourly sampling rate. This contribution presents some attempts aiming at combining the individual ZTD estimations to generate consistent troposphere solutions over the entire region and to provide reliable time series of troposphere parameters, to be used as a reference. The study covers ZTD and IWV series for a time-span of 5 years (2014–2018). In addition to the combination of the individual solutions, some advances based on the precise point positioning technique using BNC software (BKG NTRIP Client) and Bernese GNSS Software V.5.2 are presented. Results are validated using the IGS ZTD products and radiosonde IWV data. The agreement was evaluated in terms of mean bias and rms of the ZTD differences w.r.t IGS products (mean bias 1.5 mm and mean rms 6.8 mm) and w.r.t ZTD from radiosonde data (mean bias 2 mm and mean rms 7.5 mm). IWV differences w.r.t radiosonde IWV data (mean bias 0.41 kg/m2 and mean rms 3.5 kg/m2).Sitio de la revista: https://link.springer.com/chapter/10.1007/1345_2020_12

Challenges in physician supply planning: the case of Belgium

<p>Abstract</p> <p>Introduction</p> <p>Planning human resources for health (HRH) is a complex process for policy-makers and, as a result, many countries worldwide swing from surplus to shortage. In-depth case studies can help appraising the challenges encountered and the solutions implemented. This paper has two objectives: to identify the key challenges in HRH planning in Belgium and to formulate recommendations for an effective HRH planning, on the basis of the Belgian case study and lessons drawn from an international benchmarking.</p> <p>Case description</p> <p>In Belgium, a numerus clausus set up in 1997 and effective in 2004, aims to limit the total number of physicians working in the curative sector. The assumption of a positive relationship between physician densities and health care utilization was a major argument in favor of medical supply restrictions. This new regulation did not improve recurrent challenges such as specialty imbalances, with uncovered needs particularly among general practitioners, and geographical maldistribution. New difficulties also emerged. In particular, limiting national training of HRH turned out to be ineffective within the open European workforce market. The lack of integration of policies affecting HRH was noteworthy. We described in the paper what strategies were developed to address those challenges in Belgium and in neighboring countries.</p> <p>Discussion and evaluation</p> <p>Planning the medical workforce involves determining the numbers, mix, and distribution of health providers that will be required at some identified future point in time. To succeed in their task, health policy planners have to take a broader perspective on the healthcare system. Focusing on numbers is too restrictive and adopting innovative policies learned from benchmarking without integration and coordination is unfruitful. Evolving towards a strategic planning is essential to control the effects of the complex factors impacting on human resources. This evolution requires an effective monitoring of all key factors affecting supply and demand, a dynamic approach, and a system-level perspective, considering all healthcare professionals, and integrating manpower planning with workforce development.</p> <p>Conclusion</p> <p>To engage in an evidence-based action, policy-makers need a global manpower picture, from their own country and abroad, as well as reliable and comparable manpower databases allowing proper analysis and planning of the workforce.</p

Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer.

BACKGROUND: Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers. DESIGN: Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials. RESULTS: At the imaging level, magnetic resonance imaging-based and novel positron emission tomography/computed tomography-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-human epidermal growth factor receptor 2 (HER2) therapies in the adjuvant setting and cyclin-dependent kinases 4 and 6 inhibitors in the metastatic setting. The clinical utility of the commercially available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than in NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC. CONCLUSION: ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST

Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1maturation inhibitor bevirimat

Background: The maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage. Recent clinical trials demonstrated that a significant proportion of HIV-1-infected patients do not respond to BVM. A patient’s failure to respond correlated with baseline polymorphisms at SP1 residues 6-8. Results: In this study, we demonstrate that varying levels of BVM resistance are associated with point mutations at these residues. BVM susceptibility was maintained by SP1-Q6A, -Q6H and -T8A mutations. However, an SP1-V7A mutation conferred high-level BVM resistance and SP1-V7M and T8Δ mutations conferred intermediate levels of BVM resistance. Conclusions: Future exploitation of the CA-SP1 cleavage site as an antiretroviral drug target will need to overcome the baseline variability in the SP1 region of Gag.Publisher PDFPeer reviewe

Predicting Bevirimat resistance of HIV-1 from genotype

<p>Abstract</p> <p>Background</p> <p>Maturation inhibitors are a new class of antiretroviral drugs. Bevirimat (BVM) was the first substance in this class of inhibitors entering clinical trials. While the inhibitory function of BVM is well established, the molecular mechanisms of action and resistance are not well understood. It is known that mutations in the regions CS p24/p2 and p2 can cause phenotypic resistance to BVM. We have investigated a set of p24/p2 sequences of HIV-1 of known phenotypic resistance to BVM to test whether BVM resistance can be predicted from sequence, and to identify possible molecular mechanisms of BVM resistance in HIV-1.</p> <p>Results</p> <p>We used artificial neural networks and random forests with different descriptors for the prediction of BVM resistance. Random forests with hydrophobicity as descriptor performed best and classified the sequences with an area under the Receiver Operating Characteristics (ROC) curve of 0.93 ± 0.001. For the collected data we find that p2 sequence positions 369 to 376 have the highest impact on resistance, with positions 370 and 372 being particularly important. These findings are in partial agreement with other recent studies. Apart from the complex machine learning models we derived a number of simple rules that predict BVM resistance from sequence with surprising accuracy. According to computational predictions based on the data set used, cleavage sites are usually not shifted by resistance mutations. However, we found that resistance mutations could shorten and weaken the <it>α</it>-helix in p2, which hints at a possible resistance mechanism.</p> <p>Conclusions</p> <p>We found that BVM resistance of HIV-1 can be predicted well from the sequence of the p2 peptide, which may prove useful for personalized therapy if maturation inhibitors reach clinical practice. Results of secondary structure analysis are compatible with a possible route to BVM resistance in which mutations weaken a six-helix bundle discovered in recent experiments, and thus ease Gag cleavage by the retroviral protease.</p

Improved Bevirimat resistance prediction by combination of structural and sequence-based classifiers

<p>Abstract</p> <p>Background</p> <p>Maturation inhibitors such as Bevirimat are a new class of antiretroviral drugs that hamper the cleavage of HIV-1 proteins into their functional active forms. They bind to these preproteins and inhibit their cleavage by the HIV-1 protease, resulting in non-functional virus particles. Nevertheless, there exist mutations in this region leading to resistance against Bevirimat. Highly specific and accurate tools to predict resistance to maturation inhibitors can help to identify patients, who might benefit from the usage of these new drugs.</p> <p>Results</p> <p>We tested several methods to improve Bevirimat resistance prediction in HIV-1. It turned out that combining structural and sequence-based information in classifier ensembles led to accurate and reliable predictions. Moreover, we were able to identify the most crucial regions for Bevirimat resistance computationally, which are in line with experimental results from other studies.</p> <p>Conclusions</p> <p>Our analysis demonstrated the use of machine learning techniques to predict HIV-1 resistance against maturation inhibitors such as Bevirimat. New maturation inhibitors are already under development and might enlarge the arsenal of antiretroviral drugs in the future. Thus, accurate prediction tools are very useful to enable a personalized therapy.</p