Hemorragia alveolar pulmonar como presentación poco frecuente de infección por Leptospira spp: una enfermedad ocupacional del personal militar en zonas tropicales / Pulmonary alveolar hemorrhage as an unusual presentation of Leptospira spp: an occupational-disease of military personnel in tropical zones

Resumen La leptospirosis es una de las zoonosis endémicas más importantes en el mundo con un aumento de la incidencia en los últimos años. En el personal militar podría ser catalogada como una enfermedad ocupacional dado sus actividades específicas en áreas rurales. Su presentación clínica es variable siendo en la mayoría de los casos una enfermedad febril autolimitada. De acuerdo con diversos factores dependientes del patógeno y del hospedero pueden presentarse manifestaciones severas de la enfermedad dentro de la cual destaca el compromiso pulmonar con una alta tasa de mortalidad. Existe evidencia del uso de esteroide sistémico como parte del tratamiento de esta complicación. Presentamos el caso de un paciente joven, militar, que debuta con síndrome de hemorragia alveolar difusa secundario a leptospirosis y presenta una excelente respuesta al tratamiento con altas dosis de metilprednisolona, con una discusión del proceso diagnóstico y aspectos fisiopatológicos de esta condición.

Leptospirosis is one of the most important endemic zoonoses in the world with an increase in incidence in recent years. In military personnel it could be classified as an occupational disease given their specific activities in rural areas. Its clinical presentation is variable being in most cases a self-limited febrile disease. According to various factors dependent on the pathogen and the host, severe manifestations of the disease may occur within which the pulmonary involvement with a high mortality rate stands out. There is evidence of systemic steroid use as part of the treatment of this complication. We present a case of a young, military patient who debuts with diffuse alveolar hemorrhage syndrome secondary to leptospirosis and presents an excellent response to treatment with high doses of methylprednisolone, with a discussion of the diagnostic process and pathophysiological aspects of this condition.

[Phenotypic and genotypic detection of the production of carbapenemases type NDM-1 and KPC in isolated Enterobacteriaceae in a clinical laboratory in Maracay, Venezuela]. / Detección fenotípica y genotípica de la producción de carbapenemasas tipo NDM-1 y KPC en enterobacterias aisladas en un laboratorio clínico en Maracay, Venezuela.

BACKGROUND: The production of carbapenem-hydrolyzing ß-lactamases is one of the most concerning resistance mechanisms since it eliminates the last therapeutic option against multidrug resistant microorganisms. AIM: To determine the production of KPC and NDM-1 type carbapenemases, using phenotypic and genotypic methods, in isolated enterobacteria in a clinical laboratory in the city of Maracay, Venezuela. METHODS: The production of carbapenemases was determined by phenotypic (according to the Malbrán algorithm) and genotypic methods (amplification of the blaNDM-1 and blaKPC genes by PCR) in clinical isolates of Enterobacteriaceae during the period March-August 2018. RESULTS: 605 Enterobacteriaceae of different species were identified, being Escherichia coli the strain with the highest percentage of isolation (61.3%), followed by Klebsiella pneumoniae (14.9%). Sixteen strains (2.64%) were positive for carbapenemases production: 13 strains of K. pneumoniae and three of the Enterobacter cloacae complex. PCR showed that 14 strains (87.5%) carry the blaNDM-1 gene and two strains (12.5%) the blaKPC gene; 100% agreement was observed between phenotypic determination and PCR for both groups of enzymes. CONCLUSIONS: The results of this study showed a higher incidence of metallo-ß-lactamase type NDM-1, which rapid dissemination and consequently difficult control has been cause of epidemiological alert. The identification of the type of enzyme would allow establishing more accurate management and control strategies in order to eradicate these pathogens.

Detección fenotípica y genotípica de la producción de carbapenemasas tipo NDM-1 y KPC en enterobacterias aisladas en un laboratorio clínico en Maracay, Venezuela / Phenotypic and genotypic detection of the production of carbapenemases type NDM-1 and KPC in isolated Enterobacteriaceae in a clinical laboratory in Maracay, Venezuela

INTRODUCCIÓN: La producción de beta-lactamasas capaces de hidrolizar a los carbapenémicos es uno de los mecanismos de resistencia más preocupantes porque eliminan la última opción terapéutica frente a los microorganismos multi-resistentes. OBJETIVO: Determinar la producción de carbapenemasas tipo KPC y NDM-1, empleando métodos fenotípicos y genotípicos, en enterobacterias aisladas en un laboratorio clínico de la ciudad de Maracay, Venezuela. MÉTODOS: Se determinó la producción de carbapenemasas mediante métodos fenotípicos (según algoritmo de Malbrán) y genotípicos (amplificación de los genes blaNDM-1 y blaKPC por RPC) en enterobacterias aisladas en un laboratorio clínico durante el período marzo-agosto 2018. RESULTADOS: Se identificaron 605 enterobacterias de diferentes especies, siendo Escherichia coli la cepa con mayor porcentaje de aislamiento (61,3%), seguida por Klebsiella pneumoniae (14,9%). Diez y seis enterobacterias (2,64%) fueron positivas para la producción de carbapenemasas: 13 cepas de K. pneumoniae y tres del complejo Enterobacter cloacae. La RPC demostró que 14 cepas (87,5%) contienen el gen blaNDM-1 y dos (12,5%) el gen blaKPC; se observó 100% de concordancia entre la determinación fenotípica y la RPC para ambos grupos de enzimas. CONCLUSIONES: Los resultados mostraron mayor incidencia de la metalo-beta-lactamasa tipo NDM-1, reconocida como una alarma epidemiológica debido a que su rápida diseminación dificulta su control, por lo que la identificación del tipo de enzima permitiría establecer estrategias de manejo y control más certeras con la finalidad de erradicar a dichos patógenos.

BACKGROUND: The production of carbapenem-hydrolyzing beta-lactamases is one of the most concerning resistance mechanisms since it eliminates the last therapeutic option against multidrug resistant microorganisms. AIM: To determine the production of KPC and NDM-1 type carbapenemases, using phenotypic and genotypic methods, in isolated enterobacteria in a clinical laboratory in the city of Maracay, Venezuela. METHODS: The production of carbapenemases was determined by phenotypic (according to the Malbrán algorithm) and genotypic methods (amplification of the blaNDM-1 and blaKPC genes by PCR) in clinical isolates of Enterobacteriaceae during the period March-August 2018. RESULTS: 605 Enterobacteriaceae of different species were identified, being Escherichia coli the strain with the highest percentage of isolation (61.3%), followed by Klebsiella pneumoniae (14.9%). Sixteen strains (2.64%) were positive for carbapenemases production: 13 strains of K. pneumoniae and three of the Enterobacter cloacae complex. PCR showed that 14 strains (87.5%) carry the blaNDM-1 gene and two strains (12.5%) the blaKPC gene; 100% agreement was observed between phenotypic determination and PCR for both groups of enzymes. CONCLUSIONS: The results of this study showed a higher incidence of metallo-beta-lactamase type NDM-1, which rapid dissemination and consequently difficult control has been cause of epidemiological alert. The identification of the type of enzyme would allow establishing more accurate management and control strategies in order to eradicate these pathogens.

68Ga-PSMA PET/CT-based metastasis-directed radiotherapy for oligometastatic prostate cancer recurrence after radical prostatectomy.

PURPOSE: The aim of this communication was to assess the efficacy of directed oligometastatic radiotherapy (RT) based on 68Ga-PSMA PET/CT in patients with prostate cancer (PCa) biochemical relapse (BCR) after primary treatment with curative intent. METHODS: This is a retrospective analysis of a monocentric cohort of PCa patients diagnosed with oligometastatic disease on 68Ga-PSMA PET/CT and treated with metastasis-directed RT. Inclusion criteria were: histologically proven PCa, BCR after primary treatment with curative intent, oligometastatic disease defined as ≤ 3 metastatic lesions. To evaluate the efficacy of the therapy, biochemical response defined as a decrease of > 50% of PSA (PSA50) was measured at 1 and 4 months. Patients were followed up until progression and start of androgen deprivation therapy (ADT). BCR-free survival and ADT-free survival were calculated. RESULTS: 20 patients met the inclusion criteria. Median PSA value: 1.4 ng/ml (IQR, 0.3-2.3 ng/ml). A total of 30 PSMA-positive lesions were treated: 18 lymph nodes (60%), nine bone (30%) and three visceral lesions (10%). Median follow-up was 15 months (range 4-33 months). Biochemical response at 1 and 4 months was found in 3/20 patients (15%) and 14/20 (70%), respectively. BCR-free survival rate at 1 year was 79% and 53% at 2 years. ADT-free survival at 2 years was 74%. CONCLUSION: This retrospective study suggests that metastasis-directed RT based on 68Ga-PSMA PET/CT may be a valuable treatment in patients with PCa oligometastatic disease, providing promising BCR-free survival rates and potentially postponing ADT for at least 2 years in 74% of the patients. Response assessment should not be measured before 4 months after treatment.

European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Experience with Advanced/Metastatic Epithelioid Sarcoma Patients Treated in Prospective Trials: Clinical Profile and Response to Systemic Therapy.

AIMS: Epithelioid sarcoma is a soft tissue sarcoma associated with a high rate of local recurrence after wide resection and high incidence of distant metastasis. Little is known about the clinical course and response to systemic treatments in epithelioid sarcoma patients. We carried out a retrospective analysis of clinical data from epithelioid sarcoma patients to provide a reference for the design of future epithelioid sarcoma-specific studies. PATIENTS AND METHODS: Data from patients with epithelioid sarcoma entered in prospective multi-sarcoma phase II/III trials were pooled: EORTC trial 62012 (doxorubicin versus doxorubicin/ifosfamide), 62043 (pazopanib), 62072 (pazopanib versus placebo) and 62091 (doxorubicin versus trabectedin). Patients had either a local or a centrally confirmed diagnosis of epithelioid sarcoma, had inoperable/metastatic disease at study entry and were eligible for the according trial. Response was assessed according to RECIST 1.1. Progression-free survival (PFS) and overall survival were calculated from date of entry. RESULTS: Among 976 patients with advanced sarcomas, 27 epithelioid sarcoma patients (2.8%) were eligible for the analysis (17 men, median age at diagnosis 50 years, range 19-72). Eighteen (66.7%) received chemotherapy as first-line treatment (five doxorubicin, eight doxorubicin/ifosfamide, two pazopanib, three trabectedin) and nine (33.3%) received pazopanib as second line or later. The primary tumour was located in the lower extremity (n = 8; 29.6%), upper extremity (n = 5; 18.5%), retro/intra-abdominal (n = 4; 14.8%) and in other locations (n = 10; 37.0%). At entry, metastases were mainly found in lung (n = 17; 63%), lymph nodes (n = 9; 33.3%), bone (n = 8; 29.6%) and soft tissue (n = 7; 25.9%). The best response for first-line patients was four partial responses (22.2%), 10 stable disease (55.6%) and four progressive disease (22.2%). In subsequent lines, pazopanib achieved one partial response (11.1%), four stable disease (44.4%) and four progressive disease (44.4%). All patients but one progressed on treatment. The median PFS and overall survival were 3.8 (95% confidence interval 2.2-4.8) and 10.8 months (95% confidence interval 8.1-21.3), respectively. Five patients were still alive at the time of the according trial analysis. CONCLUSION: With all limitations of such a rare disease and small data set, objective response and survival outcomes are similar in epithelioid sarcoma to non-selected sarcoma populations. The clinical testing of novel systemic treatments for epithelioid sarcoma remains an unmet medical need and a high priority.

International study on nurses' views and experiences of compassion.

BACKGROUND: Compassion is considered the cornerstone of nursing practice. However, the recent failures in delivering high-quality compassionate nursing care in the UK's National Health Service have brought the topic of compassion to the attention of the public, service providers, policy makers and academics. AIM: The aim of this study was to explore the nurses' views and experiences of a number of compassion-related issues in nursing and describe similarities and differences at an international level as well as from the different nursing roles of the participating nurses. METHODS: An exploratory, cross-sectional descriptive study, using the International Online Compassion Questionnaire. A total of 1323 nurses from 15 countries completed the questionnaire. RESULTS: The majority of participants (59.5%) defined compassion as "Deep awareness of the suffering of others and wish to alleviate it" but definitions of compassion varied by country. Of participants, 69.6% thought compassion was very important in nursing and more than half (59.6%) of them argued that compassion could be taught. However, only 26.8% reported that the correct amount and level of teaching is provided. The majority of the participants (82.6%) stated that their patients prefer knowledgeable nurses with good interpersonal skills. Only 4.3% noted that they are receiving compassion from their managers. A significant relationship was found between nurses' experiences of compassion and their views about teaching of compassion. CONCLUSION: Our study is unique in identifying the views and experiences of nurses from 15 different countries worldwide. The findings reveal that compassion is neither addressed adequately in nursing education nor supported in the practice environment by managers. LIMITATIONS: Self-report bias was inherent to our survey study design. Furthermore, the individual cultural differences and similarities in the findings are difficult to extrapolate owing to the fact that our analysis was at country level, as well as at the level of the participating nurses. IMPLICATIONS FOR NURSING POLICY: Understanding the influence of culture on nurses' views about compassion is critical in the current multicultural healthcare environment and merits further research. This will potentially drive changes in nursing education (ensuring that compassion is taught to nurses) and in the way healthcare leaders and managers foster a compassionate culture within their organizations (e.g. by leading by example and compassionate to their staff).

Outcome of uterine sarcoma patients treated with pazopanib: A retrospective analysis based on two European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) clinical trials 62043 and 62072.

BACKGROUND: Uterine sarcomas are a group of mesenchymal tumours comprising several histologies. They have a high recurrence rate following surgery, modest outcome to systemic therapy, and poor overall survival. Pazopanib is a multi-targeted tyrosine kinase inhibitor approved for non-adipocytic advanced soft tissue sarcomas (STS). Here we investigated whether response to pazopanib in patients with uterine sarcomas differs from that of patients with non-uterine sarcomas. PATIENTS AND METHODS: Uterine sarcoma patients were retrieved from all soft tissue sarcoma patients treated with pazopanib in EORTC Phase II (n=10) and Phase III (PALETTE) (n=34) studies. Patient and tumour characteristics, response, progression free and overall survival data were compared. RESULTS: Forty-four patients with uterine sarcoma were treated with pazopanib. The majority of patients had uterine leiomyosarcoma (LMS) (n=39, 88.6%) with high grade tumours (n=37, 84.1%) compared to 54.8% (n=164) in the non-uterine population. The median age was 55years (range 33-79) and median follow up was 2.3years. Uterine patients were heavily pre-treated, 61.3% having ≥2 lines of chemotherapy prior to pazopanib compared to 40.8% in the non-uterine population. Five patients (11%), all LMS, had a partial response (95% CI 3.8-24.6). Median progression free survival (PFS) 3.0months (95% CI 2.5-4.7) in uterine versus 4.5 (95% CI 3.7-5.1) in non-uterine STS. Median overall survival (OS) was 17.5months (95% CI 11.1-19.6), longer than the non-uterine population, 11.1months (95% CI 10.2-12.0) (p=0.352). CONCLUSIONS: Despite heavy pre-treatment, pazopanib shows signs of activity in patients with uterine sarcoma with the similar outcomes to patients with non-uterine STS.

Role of corticosteroids in prostate cancer progression: implications for treatment strategy in metastatic castration-resistant patients.

Corticosteroid agents (CA) are widely used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) either as concomitant treatment with active agents such as docetaxel, cabazitaxel and abiraterone or in a palliative setting, predominantly due to their anti-inflammatory activity. However, the chronic use of CA has numerous side effects, especially in case of steroid-induced adrenal insufficiency. Furthermore, the latest clinical and preclinical data demonstrate that CA themselves are likely to promote tumour progression in certain populations of patients with mCRPC. Therefore, the role of CA in advanced disease should be carefully weighed for each patient and their withdrawal should be considered in some patients. This is necessary, especially in clinical trials that need good performance status patients to evaluate the activity and the safety of emerging drugs in mCRPC that do not require the concurrent use of CA. In oncology, there is no consensus on an algorithm of gradual steroid tapering and frequently the approach to this procedure is empirical. An algorithm is presented in this article based on clinical observations. Prospective studies are necessary to evaluate the efficacy and safety of the above-proposed algorithm in metastatic castration-resistant prostate cancer.

A prospective case-control study of non-healing wounds of the lower limbs - the value of biopsies for ulcerating carcinoma.

BACKGROUND: In some leg ulcer patients there is cancer that is responsible for lack of healing of such a wound. AIM: This study was aimed at prospective analysis of histopathology of non-healing wounds (NHWs) in the patient presenting with high and low suspicion for ulcerating carcinoma. MATERIAL AND METHODS: Forty patients with NHWs were enrolled and had been prospectively divided into two groups: 25 patients with high suspicion for ulcerating carcinoma according to their medical history and physical examination, and the second group of 15 patients without suspicion for malignancy (control group). All NHWs were photographed and underwent biopsies. RESULTS: In the control group biopsies did not reveal cancers. On the contrary, in 10 patients (40%) from high suspicion group biopsies revealed cancers: seven basal cell carcinomas (BCCs), one - malignant melanoma, one - Bowen's disease and one - squamous cell carcinomas. Histopathology of six of seven BCCs suggested that non-healing benign wound might have preceded malignancy. We found that leg ulcers which were small (wound area less than 3 cm(2) ), longstanding (duration 24 ≤ weeks), presenting with granulation tissue covering ≥75% of the wound area, with a dull pink appearance of the granulation tissue, or an atypical clinical presentation, can actually be an ulcerating carcinoma. Dull pink granulation tissue or an atypical clinical presentation of ulceration, as a single clinical finding, suggested an underlying malignancy with a statistical significance (71.5% vs. 0%; P = 0.001 and 27.8% vs. 0%; P = 0.0049 respectively). CONCLUSIONS: Prevalence of malignancy, primarily: BCCs in NHWs, may be higher than expected and clinical features suggestive of such a nature of ulcer are an indication for diagnostic biopsy.

Prospective non-interventional multicentre observational trial of first-line anti-cancer treatment in patients with metastatic renal cell cancer in Belgium.

OBJECTIVES: Renal cell carcinoma (RCC) accounts for 2·4% of all new cancers in Belgium. Over the past decade, the armamentarium for systemic therapy of metastatic RCC (mRCC) has undergone important changes with implementation of targeted therapies directed against pathways involved in the pathogenesis of RCC. We describe first-line treatment choice of a group of patients in 9 Belgian oncology centres between October 2009 and November 2012. METHODS: A clinical report form was established to assess patient characteristics, Karnofsky performance score, Memorial Sloan-Kettering Cancer Center risk criteria (MSKCC) and first-line therapy of mRCC patients. Choice of therapy and starting dose was analyzed before and after reimbursement of pazopanib in Belgium. RESULTS: Ninety-six patients were eligible for the study. Non-smokers accounted for 53% of the patients. Seventy-three per cent of the patients had 0 or 1 MSKCC criteria in the group of patients that started treatment more than 1 year after initial diagnosis. In the group of patients that started therapy less than 1 year after diagnosis, 85% had 2 or more MSKCC criteria. This difference was statistically significant (P<0·0001). Overall distribution of the first-line therapies consisted of 43% sunitinib, 33% pazopanib, 14% temsirolimus, 7% everolimus and 3% sorafenib. Seventeen (18%) out of 96 patients started at a reduced dose level. CONCLUSION: This report shows that the guidelines for the start of first-line treatment in mRCC in 9 centres in Belgium were applied most of the time: a tyrosine kinase inhibitor was the first treatment choice for most patients while temsirolimus was an option for poor prognosis patients. In the majority of patients standard dose levels were initiated, although in some patients adaptation of dosage/treatment schedule was recorded.

Phase I trial combining temozolomide plus lapatinib for the treatment of brain metastases in patients with HER2-positive metastatic breast cancer: the LAPTEM trial.

BACKGROUND: Brain metastases (BMs) pose a clinical challenge in breast cancer (BC). Lapatinib or temozolomide showed activity in BM. Our study assessed the combination of both drugs as treatment for patients with HER2-positive BC and BM. METHODS: Eighteen patients were enrolled, with sixteen of them having recurrent or progressive BM. Any type of previous therapy was allowed, and disease was assessed by gadolinium (Gd)-enhanced magnetic resonance imaging (MRI). The primary end points were the evaluation of the dose-limiting toxicities (DLTs) and the determination of the maximum-tolerated dose (MTD). The secondary end points included objective response rate, clinical benefit and duration of response. RESULTS: The lapatinib-temozolomide regimen showed a favorable toxicity profile because the MTD could not be reached. The most common adverse events (AEs) were fatigue, diarrhea and constipation. Disease stabilization was achieved in 10 out of 15 assessable patients. The estimated median survival time for the 16 patients with BM reached 10.94 months (95% CI: 1.09-20.79), whereas the median progression-free survival time was 2.60 months [95% confidence interval (CI): 1.82-3.37]. CONCLUSIONS: The lapatinib-temozolomide combination is well tolerated. Preliminary evidence of clinical activity was observed in a heavily pretreated population, as indicated by the volumetric reductions occurring in brain lesions.

Autoimmune haemolytic anaemia in a patient treated with capecitabine.

A 61-year-old female, followed-up for a metastatic breast cancer, was admitted in our institution with conjunctival icterus, asthenia and abdominal crampoid pain. The patient was included in a clinical trial comparing the efficiency of capecitabine monotherapy versus capecitabine conjugated with a new biological agent in a randomised and double blind trial. The patient was in the capecitabine alone arm. Biological tests performed upon admission suggested the diagnosis of haemolytic anaemia. Moreover, the direct Coombs test result was twice positive indicating autoimmune haemolytic anaemia. Capecitabine has been reported to cause haemolysis either alone or combined with lapatinib, each time with a mechanism other than immunological. In this clinical case, capecitabine is the most likely factor causing an autoimmune haemolytic anaemia.

An open-label, phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours.

BACKGROUND: Cixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours. METHODS: In this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10mg/kg) for 1h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12 weeks. In each tier of disease histology, Simon's optimum 2-stage design was applied (PFR at 12 weeks P0=20%, P1=40%, α=0.10, ß=0.10). Stage 1 enrolled 17 patients in each disease group/tier, with at least four patients with stable disease or better required at 12 weeks to proceed to stage 2. RESULTS: A total of 113 patients were enrolled; all tiers except adipocytic sarcoma were closed after stage 1 due to futility. The 12-week PFR was 12% for rhabdomyosarcoma (n=17), 14% for leiomyosarcoma (n=22), 32% for adipocytic sarcoma (n=37), 18% for synovial sarcoma (n=17) and 11% for Ewing family of tumours (n=18). Median progression-free survival (weeks) was 6.1 for rhabdomyosarcoma, 6.0 for leiomyosarcoma, 12.1 for adipocytic sarcoma, 6.4 for synovial sarcoma and 6.4 for Ewing family of tumours. Among all patients, the most frequent treatment-emergent adverse events (AEs) were nausea (26%), fatigue (23%), diarrhoea (23%) and hyperglycaemia (20%). CONCLUSIONS: Patients with adipocytic sarcoma may benefit from treatment with cixutumumab. Cixutumumab treatment was well tolerated, with limited gastrointestinal AEs, fatigue and hyperglycaemia.