Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial.

BACKGROUND: In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. METHODS: We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697. FINDINGS: Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5-10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. The most common grade 3 and 4 adverse events were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study because of adverse events (64 [3%] were drug-related), as assessed by the investigator, and 171 (7%) people died. The funder assessed causes of death, which were due to disease progression (85 [4%]), an unrelated adverse experience (72 [3%]), and unknown reasons (14 [1%]). Of the 86 deaths not attributable to disease progression, 18 (<1%) were caused by a drug-related adverse event, as assessed by the investigator. Median time to PSA progression was 8·5 months (95% CI 8·3-9·7) and median time to clinical progression was 12·7 months (11·8-13·8). INTERPRETATION: No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy. Future work is needed to ascertain the most effective regimen of abiraterone acetate to optimise patients' outcomes. FUNDING: Janssen Research & Development.

Activity and safety of sunitinib in poor risk metastatic renal cell carcinoma patients.

PURPOSE: To assess the activity, safety and treatment patterns of sunitinib in patients with poor-risk metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: We retrospectively reviewed the charts of poor risk patients treated with sunitinib from October 2006 to July 2013 who met the eligibility criteria. The primary endpoint was overall survival (OS). Tumor radiological response was measured according to RECIST 1.1 and adverse events (AEs) were assessed through standard criteria. RESULTS: Median OS was 8.16 months (95% CI, 5.73-10.59). Of the 53 patients included in this analysis, 9 (17.0%) achieved partial response, 12 (22.6%) had stable disease. Median treatment duration was 3.30 months (95% CI: 1.96-4.63) and 26.4% of patients discontinued treatment due to toxicity. Grade 3 or higher AEs occurred in 39.6% of patients, the most common being fatigue (15.1%), neutropenia (9.5%), nausea, vomiting and diarrhea (7.5% each). DISCUSSION: Sunitinib may benefit some unselected poor-risk patients, although the rates of AEs and drug discontinuation suggest a need for careful patient monitoring.

Risk Assessment of Mercury-Contaminated Fish Consumption in the Brazilian Amazon: An Ecological Study.

Mercury is one of the most dangerous contaminants on the planet. In recent years, evidence of mercury contamination in the Amazon has significantly increased, notably due to gold-mining activities. Although mercury contamination in fish has consistently been documented, little is known about the risk associated with fish consumption by populations in urban areas of the Amazon. We sampled 1010 fish sold in public markets in six state capitals and 11 additional cities. Mercury levels were determined for each specimen, and the evaluation of the health risks associated with consuming mercury-contaminated fish was conducted according to the methodology proposed by the World Health Organization (WHO). Our study reveals that more than one-fifth (21.3%) of the fish sold in urban centers had mercury levels above the safe limits (≥0.5 µg/g) established by the Brazilian Health Surveillance Agency (ANVISA). The prevalence of Hg contamination ≥0.5 µg/g was approximately 14 times higher in carnivorous than in noncarnivorous fish. The analysis of the risk attributable to fish consumption reveals that daily mercury intake exceeded the reference dose recommended by the U.S. EPA in all population groups analyzed, reaching up to 7 and 31 times in women of childbearing age and children from 2 to 4 years old, respectively. However, these risks are diverse depending on the type of fish consumed and must be considered to formulate appropriate nutritional guidelines for safe fish consumption by the local community.

Acquired hemophilia A in a patient with advanced prostate cancer.

Acquired hemophilia A (AHA) is a rare disorder that results from the presence of autoantibodies against the clotting factor VIII (FVIII) causing hemorrhagic disorders. This entity is mostly associated with autoimmune diseases, pregnancy, the postpartum period, drugs and malignancy. Among the solid cancers, prostate neoplasm is the most common cause of AHA. The management of AHA involves the control of active bleeding and the use of specific therapies to eliminate the inhibitor. The authors describe the case of an 87-year-old man with prostate cancer who developed a bleeding disorder 5 years after the cancer diagnosis. Treatment with prednisone did not reach a satisfactory clinical response, which was only achieved with the association of azathioprine. The patient became asymptomatic with no further bleeding episodes, but developed a fatal sepsis after 3 months of treatment with these immunosuppressive agents.

Plasmacytoid urothelial carcinoma: a case of histological variant of urinary bladder cancer with aggressive behavior.

Plasmocytoid variant urothelial carcinoma (PVUC) of the urinary bladder is a rare histological variant of transitional cell carcinoma. Data regarding PVUC shows that this neoplasia presents a distinctive clinical outcome represented by aggressive behavior and poor survival rate. The authors report a case of a 57-year-old male patient with a 3-month history of hematuria and pelvic pain. Radical cystectomy with lymphadenectomy was performed and pathological examination showed a pT3pN0 PVUC of the bladder. The patient remained free of recurrence for 8 months, but the disease recurred involving the abdominal wall and subcutaneous tissue. Chemotherapy provided a positive clinical response and relief of symptoms. The authors call attention to the aggressiveness of this rare variant of bladder cancer and recommend radical surgery and multidisciplinary management of this neoplasm.

Physicochemical characterization of metabolic acidosis induced by normal saline resuscitation of patients with severe sepsis and septic shock. / Caracterização físico-química da acidose metabólica induzida pela expansão volêmica inicial com solução salina a 0,9% em pacientes com sepse grave e choque séptico.

OBJECTIVE: The aim of this study was to characterize and quantify metabolic acidosis that was caused by initial volume expansion during the reanimation of patients with severe sepsis and septic shock. METHODS: A blood sample was drawn for physicochemical characterization of the patient's acid-base equilibrium both before and after volume expansion using 30 mL/kg 0.9% saline solution. The diagnosis and quantification of metabolic acidosis were based on the standard base excess (SBE). RESULTS: Eight patients with a mean age of 58 ± 13 years and mean APACHE II scores of 20 ± 4 were expanded using 2,000 ± 370 mL of 0.9% saline solution. Blood pH dropped from 7.404 ± 0.080 to 7.367 ± 0.086 (p=0.018), and PC O2 increased from 30 ± 5 to 32 ± 2 mmHg (p=0.215); SBE dropped from -4.4 ± 5.6 to -6.0 ± 5.7 mEq/L (p=0.039). The drop in SBE was associated with the acidifying power of two factors, namely, a significant increase in the strong ion gap (SIG) from 6.1 ± 3.4 to 7.7 ± 4.0 mEq/L (p = 0.134) and a non-significant drop in the apparent inorganic strong ion differences (SIDai) from 40 ± 5 to 38 ± 4 mEq/L (p = 0.318). Conversely, the serum albumin levels decreased from 3.1 ± 1.0 to 2.6 ± 0.8 mEq/L (p = 0.003) with an alkalinizing effect on SBE. Increased serum chloride levels from 103 ± 10 to 106 ± 7 mEq/L (p < 0.001) led to a drop in SIDai. CONCLUSION: Initial resuscitation using 30 mL/kg of 0.9% saline solution for patients with severe sepsis and septic shock is associated with worsened metabolic acidosis, as measured by SBE. This worsened SBE can be ascribed to a serum increase in the levels of unmeasurable anions and chloride.

Activity and safety of sunitinib in poor risk metastatic renal cell carcinoma patients

Purpose To assess the activity, safety and treatment patterns of sunitinib in patients with poor-risk metastatic renal cell carcinoma (mRCC). Materials and Methods We retrospectively reviewed the charts of poor risk patients treated with sunitinib from October 2006 to July 2013 who met the eligibility criteria. The primary endpoint was overall survival (OS). Tumor radiological response was measured according to RECIST 1.1 and adverse events (AEs) were assessed through standard criteria. Results Median OS was 8.16 months (95% CI, 5.73-10.59). Of the 53 patients included in this analysis, 9 (17.0%) achieved partial response, 12 (22.6%) had stable disease. Median treatment duration was 3.30 months (95% CI: 1.96-4.63) and 26.4% of patients discontinued treatment due to toxicity. Grade 3 or higher AEs occurred in 39.6% of patients, the most common being fatigue (15.1%), neutropenia (9.5%), nausea, vomiting and diarrhea (7.5% each). Discussion Sunitinib may benefit some unselected poor-risk patients, although the rates of AEs and drug discontinuation suggest a need for careful patient monitoring. .

Caracterização físico-química da acidose metabólica induzida pela expansão volêmica inicial com solução salina a 0,9 por cento em pacientes com sepse grave e choque séptico / Physicochemical characterization of metabolic acidosis induced by normal saline resuscitation of patients with severe sepsis and septic shock

OBJETIVO: O objetivo deste estudo foi caracterizar e quantificar a acidose metabólica causada pela expansão volêmica inicial na reanimação de pacientes com sepse grave e choque séptico. MÉTODOS: Uma coleta de sangue para caracterização físico-química do equilíbrio ácido-básico antes e após a expansão volêmica com 30 mL/kg de solução salina a 0,9 por cento. O diagnóstico e a quantificação da acidose metabólica foram feitas com o uso do "standard base excess" (SBE). RESULTADOS: Oito pacientes com 58 ± 13 anos e APACHE II de 20 ± 4 foram expandidos com 2000 ± 370 mL de solução salina a 0,9 por cento. Houve queda do pH de 7,404 ± 0,080 para 7,367 ± 0,086 (P=0,018) associada a elevação da PCO2 de 30 ± 5 mmHg para 32 ± 2 mmHg (P=0,215) e queda do SBE de -4,4 ± 5,6 para -6,0 ± 5,7 mEq/L (P=0,039). Esta queda do SBE foi associada ao poder acidificante de dois fatores: elevação não significativa do "strong ion gap" (SIG) de 6,1 ± 3,4 para 7,7 ± 4,0 mEq/L (P=0,134) e queda não significativa do "strong ion diference" aparente inorgânico (SIDai) de 40 ± 5 para 38 ± 4 mEq/L (P=0,318). Em contraposição, houve queda da albumina sérica de 3,1 ± 1,0 para 2,6 ± 0,8 mEq/L (P=0,003), que teve um poder alcalinizante sobre o SBE. A elevação do cloro sérico de 103 ± 10 para 106 ± 7 mEq/L (P<0,001) gerou a queda do SIDai. CONCLUSÃO: A reanimação inicial de pacientes com sepse grave e choque séptico com 30 mL/Kg de solução salina a 0,9 por cento é associada a piora da acidose metabólica aferida pelo SBE. Esta piora do SBE pode ser atribuída a uma elevação dos ânions não mensuráveis e do cloro sérico.

OBJECTIVE: The aim of this study was to characterize and quantify metabolic acidosis that was caused by initial volume expansion during the reanimation of patients with severe sepsis and septic shock. METHODS: A blood sample was drawn for physicochemical characterization of the patient's acid-base equilibrium both before and after volume expansion using 30 mL/kg 0.9 percent saline solution. The diagnosis and quantification of metabolic acidosis were based on the standard base excess (SBE). RESULTS: Eight patients with a mean age of 58 ± 13 years and mean APACHE II scores of 20 ± 4 were expanded using 2,000 ± 370 mL of 0.9 percent saline solution. Blood pH dropped from 7.404 ± 0.080 to 7.367 ± 0.086 (p=0.018), and PC O2 increased from 30 ± 5 to 32 ± 2 mmHg (p=0.215); SBE dropped from -4.4 ± 5.6 to -6.0 ± 5.7 mEq/L (p=0.039). The drop in SBE was associated with the acidifying power of two factors, namely, a significant increase in the strong ion gap (SIG) from 6.1 ± 3.4 to 7.7 ± 4.0 mEq/L (p = 0.134) and a non-significant drop in the apparent inorganic strong ion differences (SIDai) from 40 ± 5 to 38 ± 4 mEq/L (p = 0.318). Conversely, the serum albumin levels decreased from 3.1 ± 1.0 to 2.6 ± 0.8 mEq/L (p = 0.003) with an alkalinizing effect on SBE. Increased serum chloride levels from 103 ± 10 to 106 ± 7 mEq/L (p < 0.001) led to a drop in SIDai. CONCLUSION: Initial resuscitation using 30 mL/kg of 0.9 percent saline solution for patients with severe sepsis and septic shock is associated with worsened metabolic acidosis, as measured by SBE. This worsened SBE can be ascribed to a serum increase in the levels of unmeasurable anions and chloride.

Reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome.

RATIONALE: The hypothesis that lung collapse is detrimental during the acute respiratory distress syndrome is still debatable. One of the difficulties is the lack of an efficient maneuver to minimize it. OBJECTIVES: To test if a bedside recruitment strategy, capable of reversing hypoxemia and collapse in > 95% of lung units, is clinically applicable in early acute respiratory distress syndrome. METHODS: Prospective assessment of a stepwise maximum-recruitment strategy using multislice computed tomography and continuous blood-gas hemodynamic monitoring. MEASUREMENTS AND MAIN RESULTS: Twenty-six patients received sequential increments in inspiratory airway pressures, in 5 cm H(2)O steps, until the detection of Pa(O(2)) + Pa(CO(2)) >or= 400 mm Hg. Whenever this primary target was not met, despite inspiratory pressures reaching 60 cm H(2)O, the maneuver was considered incomplete. If there was hemodynamic deterioration or barotrauma, the maneuver was to be interrupted. Late assessment of recruitment efficacy was performed by computed tomography (9 patients) or by online continuous monitoring in the intensive care unit (15 patients) up to 6 h. It was possible to open the lung and to keep the lung open in the majority (24/26) of patients, at the expense of transient hemodynamic effects and hypercapnia but without major clinical consequences. No barotrauma directly associated with the maneuver was detected. There was a strong and inverse relationship between arterial oxygenation and percentage of collapsed lung mass (R = - 0.91; p < 0.0001). CONCLUSIONS: It is often possible to reverse hypoxemia and fully recruit the lung in early acute respiratory distress syndrome. Due to transient side effects, the required maneuver still awaits further evaluation before routine clinical application.