[The early use of sepsis scores to predict respiratory failure and mortality in non-ICU patients with COVID-19]. / Utilidad de las escalas de sepsis para predecir el fallo respiratorio y la muerte en pacientes con COVID-19 fuera de las Unidades de Cuidados Intensivos.

This observational retrospective study aimed to investigate the usefulness of Sequential Organ Failure Assessment (SOFA), Quick SOFA (qSOFA), National Early Warning Score (NEWS), and quick NEWS in predicting respiratory failure and death among patients with COVID-19 hospitalized outside of intensive care units (ICU). We included 237 adults hospitalized with COVID-19 who were followed-up on for one month or until death. Respiratory failure was defined as a PaO2/FiO2 ratio ≤ 200 mmHg or the need for mechanical ventilation. Respiratory failure occurred in 77 patients (32.5%), 29 patients (12%) were admitted to the ICU, and 49 patients (20.7%) died. Discrimination of respiratory failure was slightly higher in NEWS, followed by SOFA. Regarding mortality, SOFA was more accurate than the other scores. In conclusion, sepsis scores are useful for predicting respiratory failure and mortality in COVID-19 patients. A NEWS score ≥ 4 was found to be the best cutoff point for predicting respiratory failure.

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

The early use of sepsis scores to predict respiratory failure and mortality in non-ICU patients with COVID-19.

This observational retrospective study aimed to investigate the usefulness of Sequential Organ Failure Assessment (SOFA), Quick SOFA (qSOFA), National Early Warning Score (NEWS), and quick NEWS in predicting respiratory failure and death among patients with COVID-19 hospitalized outside of intensive care units (ICU). We included 237 adults hospitalized with COVID-19 who were followed-up on for one month or until death. Respiratory failure was defined as a PaO2/FiO2 ratio ≤200mmHg or the need for mechanical ventilation. Respiratory failure occurred in 77 patients (32.5%), 29 patients (12%) were admitted to the ICU, and 49 patients (20.7%) died. Discrimination of respiratory failure was slightly higher in NEWS, followed by SOFA. Regarding mortality, SOFA was more accurate than the other scores. In conclusion, sepsis scores are useful for predicting respiratory failure and mortality in COVID-19 patients. A NEWS score ≥4 was found to be the best cutoff point for predicting respiratory failure.

Screening in patients with increased risk of breast cancer (part 1): pros and cons of MRI screening. / Cribado en pacientes con riesgo incrementado de cáncer de mama (parte 1). Pros y contras del cribado con resonancia magnética.

Screening plays an important role in women with a high risk of breast cancer. Given this population's high incidence of breast cancer and younger age of onset compared to the general population, it is recommended that screening starts earlier. There is ample evidence that magnetic resonance imaging (MRI) is the most sensitive diagnostic tool, and American and the European guidelines both recommend annual MRI screening (with supplementary annual mammography) as the optimum screening modality. Nevertheless, the current guidelines do not totally agree about the recommendations for MRI screening in some subgroups of patients. The first part of this article on screening in women with increased risk of breast cancer reviews the literature to explain and evaluate the advantages of MRI screening compared to screening with mammography alone: increased detection of smaller cancers with less associated lymph node involvement and a reduction in the rate of interval cancers, which can have an impact on survival and mortality (with comparable effects to other preventative measures). At the same time, however, we would like to reflect on the drawbacks of MRI screening that affect its applicability.

Screening in patients with increased risk of breast cancer (part 2). Where are we now? Actual MRI screening controversies. / Cribado en pacientes con riesgo incrementado de cáncer de mama (parte 2). ¿Dónde estamos? Controversias actuales del cribado con resonancia magnética.

For women with a high risk of breast cancer, early detection plays an important role. Due to the high incidence of breast cancer, and at a younger age than in the general population, screening begins earlier, and there is considerable evidence that magnetic resonance is the most sensitive diagnostic tool, and the principal American and European guidelines agree on the recommendation to perform annual magnetic resonance (with supplemental annual mammography) as an optimal mode of screening. In addition to the absence of current consensus on which patients should be included in the recommendation for magnetic resonance screening (widely discussed in the introduction of part 1 of this work), there are other aspects that are different between guidelines, that are not specified, or that are susceptible to change based on the evidence of several years of experience, that we have called «controversies¼, such as the age to begin screening, the possible advisability of using a different strategy in different subgroups, performing alternate versus synchronous magnetic resonance and mammography, the age at which to terminate the two techniques, or how to follow up after risk reduction surgery.The aim of the second part of the paper is, by reviewing the literature, to provide an update in relation to some of the main «controversies¼ in high risk screening with magnetic resonance. And finally, based on all this, to propose a possible model of optimal and updated screening protocol.

Metacarpophalangeal portal safety. An anatomical study. / Seguridad de los portales metacarpofalángicos. Estudio anatómico.

AIM: To quantify the risk of dorsal innervation injury when performing direct metacarpophalangeal joint portals of the second to fifth fingers. MATERIAL AND METHOD: An anatomical study of 11 upper limbs of fresh corpses was carried out. After placing them in a traction tower, the metacarpophalangeal portals were developed on both sides of the extensor tendon. The dorsal sensory branches were dissected and the distances between the portal and the nearest nerve were measured by a digital caliper. The portals of all the fingers were compared globally to assess the safest finger and two to two radial and ulnar portals were compared in each of the fingers to assess the safest portal within each finger. RESULTS: The overall comparison of all portals and fingers showed that the third finger is the safest in any of its portals, while the ulnar side of the second and radial of the fourth are the portals with the highest risk of nerve injury (P=8.96·10-5). Comparing two to two of the radial and ulnar portals in each of the fingers showed that the ulnar portal is safer than the radial on the fourth finger (P=.042), while the radial is safer than the ulnar on the fifth finger (P=.003). CONCLUSIONS: The third finger was the safest to perform metacarpophalangeal portals, while the ulnar side of the second finger and radial side of the fourth had the highest risk of nerve injury.

Utilidad de las escalas de sepsis para predecir el fallo respiratorio y la muerte en pacientes con COVID-19 fuera de las Unidades de Cuidados Intensivos / The early use of sepsis scores to predict respiratory failure and mortality in non-ICU patients with COVID-19

El presente estudio retrospectivo observacional tiene como objetivo analizar la utilidad de las escalas SOFA (Sequential Organ Failure Assessment), qSOFA (Quick SOFA), NEWS (National Early Warning Score ) y Quick NEWS para predecir el fallo respiratorio y la muerte en pacientes con COVID-19 atendidos fuera de la Unidad de Cuidados Intensivos (UCI). Se incluyeron 237 adultos con COVID-19 hospitalizados seguidos durante un mes o hasta su fallecimiento. El fallo respiratorio se definió como un cociente PaO2/FiO2 ≤ 200 mmHg o la necesidad de ventilación mecánica. Setenta y siete pacientes (32,5%) desarrollaron fallo ventilatorio; 29 (12%) precisaron ingreso en UCI, y 49 fallecieron (20,7%). La discriminación del fallo ventilatorio fue algo mayor con la puntuación NEWS, seguida de la SOFA. En cuanto a la mortalidad, la puntuación SOFA fue más exacta que las otras escalas. En conclusión, las escalas de sepsis son útiles para predecir el fallo respiratorio y la muerte en COVID-19. Una puntuación ≥ 4 en la escala NEWS sería el mejor punto de corte para predecir fallo respiratorio (AU)

This observational retrospective study aimed to investigate the usefulness of Sequential Organ Failure Assessment (SOFA), Quick SOFA (qSOFA), National Early Warning Score (NEWS), and quick NEWS in predicting respiratory failure and death among patients with COVID-19 hospitalized outside of intensive care units (ICU). We included 237 adults hospitalized with COVID-19 who were followed-up on for one month or until death. Respiratory failure was defined as a PaO2/FiO2 ratio ≤ 200 mmHg or the need for mechanical ventilation. Respiratory failure occurred in 77 patients (32.5%), 29 patients (12%) were admitted to the ICU, and 49 patients (20.7%) died. Discrimination of respiratory failure was slightly higher in NEWS, followed by SOFA. Regarding mortality, SOFA was more accurate than the other scores. In conclusion, sepsis scores are useful for predicting respiratory failure and mortality in COVID-19 patients. A NEWS score ≥ 4 was found to be the best cutoff point for predicting respiratory failure (AU)

Protease-activated receptors (PARs) are partly pro-inflammatory and partly anti-inflammatory: will PAR agonists or antagonists participate in future drug therapies?

Protease-activated receptors (PARs) are characterised by a unique mechanism of activation, which enables them to act as cellular sensors for protease activity. PARs are expressed throughout the cardiovascular, gastrointestinal and pulmonary systems, where they are potential drug targets for the treatment of disease. However, there are currently very few selective PAR antagonists or potent PAR agonists available as effective research tools, and moreover, there is considerable evidence to suggest that PARs can promote both pro-inflammatory and anti-inflammatory responses in a wide range of disease models. These confounding issues have, to date, prevented us from developing a clear understanding of the role of PARs in disease. Nevertheless, this review provides an overview of the distribution and function of PARs in the cardiovascular, gastrointestinal and pulmonary systems, and attempts to evaluate whether PAR agonists or antagonists have a place in future drug therapy.

Histopathological findings after radiofrequency (RITA) treatment for prostate cancer.

Radiofrequency interstitial tumor ablation (RITA) is a thermal ablation method that uses needles and low radiofrequency (RF) energy. The aim of our study was to evaluate the histopathology of thermal lesions induced by RF energy delivered interstitially in prostate cancer patients who subsequently underwent prostatectomy, and to determine the feasibility, effectiveness and safety of this new method in a pilot study.

Biological markers in transurethral biopsies from bladder-cancer - preliminary-results.

A biologic profile including proliferative.activity, evaluated as H-3-thymidine labeling index (H-3-dT LI), DNA ploidy, p53 tumor-suppressor gene and P-glycoprotein (P-170), as an expression of the multidrug resistance gene, was defined for 50 primary transitional cell carcinomas of the bladder. H-3-dT LI was evaluated by autoradiography on histologic sections after incubation of fresh tumor biopsies with H-3-thymidine. Ploidy was defined by flow cytometric analysis of DNA content on nuclei suspensions obtained from frozen material. Expression of p53 protein and P-170 glycoprotein was detected by immunohistochemistry using the PAb1801 and C219 monoclonal antibody respectively, on sections from paraffin-embedded tumor biopsies. Invasive tumors showed a higher median H-3-dT LI (12.7% vs 4.2%) and a higher frequency of aneuploidy (73% vs 43%) and more frequently expressed p53 (82% vs 36%) than superficial tumors. Further analysis showed that proliferative activity was higher in invasive than in superficial cancers only in p53-positive or aneuploid tumors and not in p53-negative or diploid tumors. Moreover, proliferative activity and p53 overexpression, but not ploidy, were directly related to histologic grading and tumor stage. Generally, P-170 was not significantly related to any biologic or clinico-pathologic factor. Kinetic and phenotypic biologic markers are differently related to clinico-pathologic factors. A panel of biologic features can be easily evaluated on small transurethral biopsies at diagnosis, during endocavitary treatment or follow-up in bladder cancer patients.

Macrocryosectioning of the prostate: a simple technique.

Whole mount sections of the prostate are widely used in many laboratories. Macrocryosections of the gland; that is, whole mount frozen sections of the prostate from radical prostatectomies represent a useful new research protocol. The technique is very simple and does not require expensive equipment.

Transurethral needle ablation (TUNA) of the prostate: a clinical and urodynamic evaluation.

OBJECTIVES: This prospective study evaluated the clinical and urodynamic changes in patients with obstruction due to benign prostatic hyperplasia (BPH) treated with transurethral needle ablation (TUNA). METHODS: One hundred twenty patients with obstructive uropathy due to BPH were treated with the TUNA procedure between January 1994 and December 1995. All patients were selected according to the criteria established by the guidelines proposed by the International Consensus Committee (World Health Organization, Paris, 1993). The TUNA procedure was performed in an outpatient setting using topical intraurethral anesthesia (2% lidocaine gel). RESULTS: Patients showed a decrease in irritative symptoms as measured by the international Prostate Symptom Score (IPSS) and postprocedure urodynamic parameters. The mean (+/- SD) pretreatment IPSS was 20.8 +/- 4.5. At 3 months, the IPSS decreased to 9.7 +/- 3.0 (108 patients) (P < 0.001). At 6 months it decreased to 6.8 +/- 3.1 (86 patients) and remained at 6.2 +/- 2.9 (72 patients) and 6.7 +/- 3.8 (42 patients) at 12 and 18 months, respectively (P < 0.001). At 1 year after treatment, the peak flow rate (Qmax) increased from 8.2 +/- 3.4 mL/s to 15.9 +/- 2.1 mL/s and was 14.1 +/- 2.5 mL/s at 18 months of follow-up (P < 0.01). Urodynamic re-evaluation performed in 72 patients 12 months after TUNA demonstrated the absence of obstruction in 30 (41.7%). An additional 30 patients (41.7%) had equivocal results, whereas the remaining 12 (16.6%) still had obstruction, according to the Abrams-Griffith nomogram. Mean detrusor pressure at Qmax decreased from 85.3 +/- 18.5 cm H2O to 63.7 +/- 24.9 cm H2O at 12 months of follow-up. CONCLUSIONS: Our results confirm that the TUNA procedure is safe and effective when performed as an outpatient procedure. In addition, TUNA produced better results in patients presenting with moderate to severe irritative symptoms and minimal obstruction as determined by pressure/flow studies.

Intravesical electromotive administration of drugs for treatment of superficial bladder cancer: a comparative Phase II study.

OBJECTIVES: To evaluate the efficacy of electromotive administration (EMDA) of intravesical mitomycin-C (MMC) in patients with superficial bladder tumors and to evaluate the toxicity of the treatment. METHODS: Thirteen patients with multifocal Stages Ta-T1 and G1-G2 transitional cell carcinoma (TCC) of the bladder, primary or recurrent (group A), received MMC 40 mg (retained in the bladder for 2 hours) once a week for 8 weeks. Fifteen patients with the same characteristics (group B) were treated with EMDA/MMC at a current of 15 mA for 20 minutes once a week for 8 weeks. All lesions in the bladder except one (marker) were resected in each patient. RESULTS: In group A, 5 of 12 patients (41.6%) demonstrated complete macroscopic and histologic disappearance of the marker lesion (complete response [CR]). In group B, 6 of 15 patients (40%) had a similar CR. Recurrence rate in responders was 60% in group A versus 33% in group B after 7.6 and 6 months, respectively. Disease-free interval was 14.5 months in the EMDA/MMC group compared to 10.5 months in the MMC group. Side effects were few. CONCLUSIONS: In intermediate risk patients with TCC of the bladder, EMDA/MMC was not superior to MMC alone with a CR rate of 41% versus 41.6%. In responders, a lower recurrence rate and a longer disease-free interval were observed in the EMDA/MMC group.

Elevated E-cadherin and alpha/beta-catenin expression after androgen deprivation therapy in prostate adenocarcinoma.

The histological patterns of anti-androgen-treated prostate adenocarcinoma mimic high grade tumors classified according to the widely used Gleason scoring system. However, the biological characteristics of anti-androgen treated carcinoma are largely unknown. E-cadherin, alpha-catenin, and beta-catenin adhesion molecules are down-regulated in pharmacologically untreated high grade prostate carcinoma. In this study, we used immunohistochemical techniques to investigate their expression in twenty acinar adenocarcinomas after anti-androgen therapy in prostatectomy specimens. After adrogen ablation therapy, expression of all these adhesion molecules was higher than that of pretreatment biopsies of the same patient group and high grade matched untreated controls. These results emphasize the inaccuracy of the Gleason score for anti-androgen-treated prostate adenocarcinoma and the more differentiated phenotype of prostate adenocarcinoma after anti-hormonal therapy.

Bladder urethral dysfunction after abdominoperineal resection of the rectum for ano-rectal cancer.

We prospectively studied bladder and urethral function in 44 patients before and after abdominoperineal resection of the rectum for ano-rectal cancer. The patients were investigated with the following examinations: combined cystometry and electromyography, urethral pressure profile measurement, urecholine denervation test, urine culture, urethrogram and residual urine measurement after voiding. Urodynamic results after surgery demonstrated the partial or total denervation of the detrusor muscle with bladder areflexia in the 54% of the cases, the decrease in the urethral pressure profile in the 48% of the cases, and the absence of detrusor sphincter dyssynergia in all cases. Urethrogram results showed a high incidence of bladder dislocation into the presacral space (36%). Urine cultures were frequently positive in 52% of the patients. Most patients (52%) had difficulty in voiding with high residual urine and/or stress incontinence (4.5%). All the patients received an early rehabilitative treatment with kinesitherapy and/or pharmacologic therapy after bladder catheter removal and after urodynamic results. The patients with neurogenic bladder with residual urine volume had satisfactory functional recovery of the activity.

The role of partial cystectomy in the management of transitional bladder cancer.

A study on 81 patients who underwent partial cystectomy for bladder cancer is presented. The low postoperative mortality (2.46%) and the high 5-year survival (72%) show that this type of surgery is effective and without major complications. Thirty-eight patients were treated with endovesical thiotepa (OTT); the remaining 41 patients were untreated after surgery. Results showed that survival and number of relapses were similar in the two groups. This fact seems to prove that chemotherapy with OTT is not essential after segmental cystectomy. To explain this assertion, several hypotheses are presented.

Sacral chordoma and rehabilitative treatment of urinary disorders.

Sacral chordoma is one of the rarest tumors of the central nervous system (less than 1% of the entire group). Mictional disorders are among the most frequent symptoms and are caused by the extrinsic compression brought to bear on the cauda equina and by surgical demolition of the sacrum. Seven patients who had undergone sacral resection for chordoma, starting from S2, were followed for at least one year. It was observed that mictional disorders were often early symptoms signalling the presence of chordoma. Several patients were affected by a complete bladder denervation (infrasacral lesion) after surgery. Early rehabilitative treatment given after surgery for one year restored normal bladder functions in all the patients whose bladder denervation seemed to be not total (negative Lapides' test). Even when a complete infrasacral lesion of the bladder has been ascertained, early rehabilitative treatment may well prevent serious renal damage.

Renal cell carcinoma and transitional cell carcinomas of the pelvis and bladder in a patient affected by chronic renal failure due to abuse of phenacetin.

This is a report on a case of 2 concurrent neoplasms of different histology within the same kidney: a renal cell carcinoma and a transitional cell carcinoma of the renal pelvis in a patient affected by chronic renal failure due to abuse of phenacetin. There was also a transitional cell carcinoma of the urinary bladder.

Neoadjuvant CMV chemotherapy plus radical cystectomy in locally advanced bladder cancer: the impact of pathologic response on long-term results.

AIMS AND BACKGROUND: Neoadjuvant systemic chemotherapy in infiltrating transitional cell carcinoma of the bladder has proved to be effective and to provide a pathologic complete response in about 30% of patients. No survival benefit has yet been proved. METHODS: We analyzed the outcome of 75 patients with advanced bladder cancer (stages T2-T4 N+/N0 M0) treated from 1985 to 1993 at two institutions in the same geographic area with 2 or 3 cycles of neoadjuvant CMV (cisplatin, methotrexate and vinblastine) chemotherapy plus cystectomy. Transurethral resection of the tumor was expressly avoided in order to keep the tumor intact as a marker lesion to evaluate response to chemotherapy. RESULTS: At the time of analysis, the median follow-up of 67 assessable patients was 51.5 +/- 3.9 (SE) months. Forty-six patients (69%) had clinical evidence of extravesical spread of the bladder tumor and 6 of lymph node metastases at presentation. After cystectomy, a pathologic complete response (pT0, pN0) was achieved in only 6 cases (9%) and a pathologic partial response in 32 patients (48%). The overall 5-year survival rate of all patients was 61 +/- 6%. Those patients who had a major response to chemotherapy (pCR +pPR) had a 5-year disease-free survival rate of 74%, which was statistically higher (P = 0.0021) than the 44% for the remaining nonresponding patients (pNR). Overall, 43% of the patients with stage T2-T3a disease achieved tumor downstaging (CR, 5%; PR, 38%) compared with 63% of the patients with T3b-T4 (CR, 11%; PR, 52%), although there was no significant difference in 5-year survival curves between the two groups. CONCLUSIONS: A pathologic complete response was achieved in less than 10% of the cases without a preoperative tumor resection. Unfortunately, most of the responses were only partial. Even though the study appears to suggest a survival advantage for those patients who achieved a downstaging, CMV chemotherapy had a limited curative potential in most of the patients. It seems unlikely that determinant proof will be obtained that neoadjuvant chemotherapy may improve survival over a nontreatment control arm. The intrinsic chemoresistance or the suboptimal response to chemotherapy of bladder cancer remains the most adverse prognostic factor.