Acute stroke chameleons in a university hospital : Risk factors, circumstances, and outcomes.

OBJECTIVE: To identify risk factors, circumstances, and outcomes for individuals with acute ischemic stroke (AIS) chameleons (AIS-C) arriving in the emergency department of a university hospital. METHODS: We retrospectively reviewed all patients with AIS from the prospectively constructed Acute Stroke Registry and Analysis of Lausanne during 8.25 years. AIS-C were defined as a failure to suspect stroke or as incorrect exclusion of stroke diagnosis. They were compared with patients diagnosed correctly at the time of admission. RESULTS: Forty-seven of 2,200 AIS were missed (2.1%). These AIS-C were either very mild or very severe strokes. Multivariate analysis showed a younger age in patients with AIS-C (odds ratio [OR] per year 0.98, p < 0.01), less prestroke statin treatment (OR 0.29, p = 0.04), and lower diastolic admission blood pressure (OR 0.98 p = 0.04). They showed less eye deviation (OR 0.21, p = 0.04) and more cerebellar strokes (OR 3.78, p < 0.01). AIS-C were misdiagnosed as other neurologic (42.6% of cases) or nonneurologic (17.0%) disease, as unexplained decreased level of consciousness (21.3%), and as concomitantly present disease (19.1%). At 12 months, patients with AIS-C had less favorable outcomes (adjusted OR 0.21, p < 0.01) and higher mortality (adjusted OR 4.37, p < 0.01). CONCLUSIONS: AIS are missed in patients with younger age with a lower cerebrovascular risk profile and may be masked by other acute conditions. Patients with chameleons present more often with milder strokes or coma, fewer focal signs and cerebellar strokes, and have higher disability and mortality rates at 12 months. These findings may be used to raise awareness in emergency departments to recognize and treat such patients appropriately.

Planning and reporting of quality-of-life outcomes in cancer trials.

BACKGROUND: Information about the impact of cancer treatments on patients' quality of life (QoL) is of paramount importance to patients and treating oncologists. Cancer trials that do not specify QoL as an outcome or fail to report collected QoL data, omit crucial information for decision making. To estimate the magnitude of these problems, we investigated how frequently QoL outcomes were specified in protocols of cancer trials and subsequently reported. DESIGN: Retrospective cohort study of RCT protocols approved by six research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We compared protocols to corresponding publications, which were identified through literature searches and investigator surveys. RESULTS: Of the 173 cancer trials, 90 (52%) specified QoL outcomes in their protocol, 2 (1%) as primary and 88 (51%) as secondary outcome. Of the 173 trials, 35 (20%) reported QoL outcomes in a corresponding publication (4 modified from the protocol), 18 (10%) were published but failed to report QoL outcomes in the primary or a secondary publication, and 37 (21%) were not published at all. Of the 83 (48%) trials that did not specify QoL outcomes in their protocol, none subsequently reported QoL outcomes. Failure to report pre-specified QoL outcomes was not associated with industry sponsorship (versus non-industry), sample size, and multicentre (versus single centre) status but possibly with trial discontinuation. CONCLUSIONS: About half of cancer trials specified QoL outcomes in their protocols. However, only 20% reported any QoL data in associated publications. Highly relevant information for decision making is often unavailable to patients, oncologists, and health policymakers.

A Lead-In with Silibinin Prior to Triple-Therapy Translates into Favorable Treatment Outcomes in Difficult-To-Treat HIV/Hepatitis C Coinfected Patients.

BACKGROUND: The efficacy of first-generation protease inhibitor based triple-therapy against hepatitis C virus (HCV) infection is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and non-response to previous peginterferon-ribavirin. These patients have a low chance of achieving a sustained virologic response (SVR) using first generation triple-therapy, with a success rate of only 20%. We investigated the efficacy and safety of lead-in therapy with intravenous silibinin followed by triple-therapy in this difficult-to-treat patient group. METHODOLOGY: Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented previous treatment failure on peginterferon-ribavirin. The intervention was a lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days, followed by triple-therapy (peginterferon-ribavirin and telaprevir) for 12 weeks, and peginterferon-ribavirin alone for 36 weeks. Outcome measurements were HCV-RNA after silibinin lead-in and during triple-therapy, SVR data at week 12, and safety and tolerability of silibinin. RESULTS: We examined sixteen HIV/HCV-coinfected patients with previous peginterferon-ribavirin failure, of whom 14 had a fibrosis grade METAVIR ≥F3. All were on successful antiretroviral therapy. Median (IQR) HCV-RNA decline after silibinin therapy was 2.65 (2.1-2.8) log10 copies/mL. Fifteen of sixteen patients (94%) had undetectable HCV RNA at weeks 4 and 12, eleven patients (69%) showed end-of-treatment response (i.e., undetectable HCV-RNA at week 48), and ten patients (63%) reached SVR at week 12 (SVR 12). Six of the sixteen patients (37%) did not reach SVR 12: One patient had rapid virologic response (RVR) (i.e., undetectable HCV-RNA at week 4) but stopped treatment at week 8 due to major depression. Five patients had RVR, but experienced viral breakthroughs at week 21, 22, 25, or 32, or a relapse at week 52. The HIV RNA remained below the limit of detection in all patients during the complete treatment period. No serious adverse events and no significant drug-drug interactions were associated with silibinin. CONCLUSION: A lead-in with silibinin before triple-therapy was safe and highly effective in difficult-to-treat HIV/HCV coinfected patients, with a pronounced HCV-RNA decline during the lead-in phase, which translates into 63% SVR. An add-on of intravenous silibinin to standard of care HCV treatment is worth further exploration in selected difficult-to-treat patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01816490.

Long-term outcomes following functional endoscopic sinus surgery in Samter's triad.

OBJECTIVE: This study aimed to assess the long-term outcome of functional endoscopic sinus surgery for Samter's triad patients using an objective visual analogue scale and nasal endoscopy. METHOD: Using a retrospective database, 33 Samter's triad patients who underwent functional endoscopic sinus surgery were evaluated pre- and post-operatively between 1987 and 2007 in Hospital of La Chaux-de-Fonds, Switzerland. RESULTS: A total of 33 patients participated in the study, and the mean follow-up period was 11.6 years (range 1.2-20 years). Patients were divided into two groups based on visual analogue scale scores of the five parameters with the greatest difference in intensity of symptoms between the beginning and end of follow up. Group 1 included patients with a mean visual analogue scale score of 6 and below at the end of follow up and group 2 included patients with a mean visual analogue scale score of more than 6. The only statistically significant difference noted between the two groups was the endonasal findings: stage III-IV polyposis was present in 1 out of 24 patients (4 per cent) in group 1 and in 5 out of 9 patients (56 per cent) in group 2. CONCLUSION: The results of our study indicate that functional endoscopic sinus surgery helps stabilise disease progression. Stage III-IV polyposis had a significant adverse effect on long-term outcome.

Successful Surgical Pulmonary Embolectomy for Massive Perinatal Embolism after Emergency Cesarean Section.

Pregnant women are exposed to an increased risk for developing pulmonary embolism (PE), a main cause for maternal mortality. Surgical pulmonary embolectomy is one important therapeutic and potential life-saving armamentarium, considering pregnancy as a relative contraindication for thrombolysis. We present a case of a 36-year-old woman with massive bilateral PE after emergent caesarean delivery, requiring reanimation by external heart massage. The onset of massive intrauterine bleeding contraindicated thrombolysis and emergency surgical pulmonary embolectomy, followed by a hysterectomy, were preformed successfully. Acute surgical pulmonary embolectomy may be an option in critically diseased high-risk patients, requiring a multiteam approach, and should be part of the therapeutic armamentarium of the attending cardiac surgeon.

Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies.

PURPOSE: We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. METHODS: We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. RESULTS: A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. CONCLUSION: This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.

Neuronal death after perinatal cerebral hypoxia-ischemia: Focus on autophagy-mediated cell death.

Neonatal hypoxic-ischemic encephalopathy is a critical cerebral event occurring around birth with high mortality and neurological morbidity associated with long-term invalidating sequelae. In view of the great clinical importance of this condition and the lack of very efficacious neuroprotective strategies, it is urgent to better understand the different cell death mechanisms involved with the ultimate aim of developing new therapeutic approaches. The morphological features of three different cell death types can be observed in models of perinatal cerebral hypoxia-ischemia: necrotic, apoptotic and autophagic cell death. They may be combined in the same dying neuron. In the present review, we discuss the different cell death mechanisms involved in neonatal cerebral hypoxia-ischemia with a special focus on how autophagy may be involved in neuronal death, based: (1) on experimental models of perinatal hypoxia-ischemia and stroke, and (2) on the brains of human neonates who suffered from neonatal hypoxia-ischemia.

Clinical outcomes of lung transplant recipients with telomerase mutations.

BACKGROUND: Successful lung transplantation for patients with pulmonary fibrosis from telomerase mutations may be limited by systemic complications of telomerase dysfunction, including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes in 14 lung transplant recipients with telomerase mutations. METHODS: Subjects underwent lung transplantation between February 2005 and April 2014 at 5 transplant centers. Data were abstracted from medical records, focusing on outcomes reflecting post-transplant treatment effects likely to be complicated by telomerase mutations. RESULTS: The median age of subjects was 60.5 years (interquartile range = 52.0-62.0), 64.3% were male, and the mean post-transplant observation time was 3.2 years (SD ± 2.9). A mutation in telomerase reverse transcriptase was present in 11 subjects, a telomerase RNA component mutation was present in 2 subjects, and an uncharacterized mutation was present in 1 subject. After lung transplantation, 10 subjects were leukopenic and 5 did not tolerate lymphocyte anti-proliferative agents. Six subjects developed recurrent lower respiratory tract infections, 7 developed acute cellular rejection (A1), and 4 developed chronic lung allograft dysfunction. Eight subjects developed at least 1 episode of acute renal failure and 10 developed chronic renal insufficiency. In addition, 3 subjects developed cancer. No subjects had cirrhosis. At data censorship, 13 subjects were alive. CONCLUSIONS: The clinical course for lung transplant recipients with telomerase mutations is complicated by renal disease, leukopenia with intolerance of lymphocyte anti-proliferative agents, and recurrent lower respiratory tract infections. In contrast, cirrhosis was absent, acute cellular rejection was mild, and development of chronic lung allograft dysfunction was comparable to other lung transplant recipients. Although it poses challenges, lung transplantation may be feasible for patients with pulmonary fibrosis from telomerase mutations.

Outcomes After Liver Resection for Hepatic Alveolar Echinococcosis: A Single-Center Cohort Study.

BACKGROUND: Switzerland is a region in which alveolar echinococcosis (AE) is endemic. Studies evaluating outcomes after liver resection (LR) for AE are scarce. The aim of this study was to assess the short- and long-term outcomes of AE patients after LR in a single tertiary referral center. METHODS: We retrospectively analyzed data pertaining to all patients with liver AE who were treated with LR at our institution between January 1992 and December 2013. Patient demographics, intraoperative data, extent of LR procedures (major vs. minor LR), postoperative outcomes, and negative histological margin (R0) resection rate were recorded in a database. Recurrence rates after LR were analyzed. RESULTS: LR was performed in 59 patients diagnosed with hepatic AE (56 complete surgeries, 3 reduction surgeries). Postoperative morbidity and mortality were observed in 34 % (25 % grade I-II, 9 % grade III-IV) and 2 % of the patients, respectively. R0 (complete) resection rate was 71 % (n = 42), and R1/R2 resection rate was 29 % (n = 17). Extra-hepatic recurrence occurred in 1 case (lung) after R0 resection. In cases of R1/R2 resection, 7 intra-hepatic disease progressions occurred with a median time of 10 months (IQR 6-11 months). Long-term (more than 1 year) benzimidazole treatment stabilized the disease in 64 % (9/14) of patients with R1 status. The overall survival rate was 97 %. CONCLUSIONS: Liver AE can be safely and definitively treated with LR, provided that R0 resection is achieved. In cases of R1 resection, benzimidazole therapy seems to be effective in stabilizing the intra-hepatic disease and preventing extra-hepatic recurrence.

Prevalence and clinical outcomes for patients with MET protein expression in patients with non-small cell lung cancer in Europe: Results from the European Thoracic Oncology Platform Lungscape Project.

Aim The reported prevalence of MET overexpression varies from 25-55% in non-small cell lung cancer (NSCLC) and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the Lungscape program, we explore the epidemiology, the natural history of IHC MET positivity and its association to OS, RFS and TTR. Methods Resected stage I-III NSCLC identified based on the quality of clinical data and FFPE tissue availability were assessed for MET expression using immunohistochemistry (IHC) on TMAs (CONFIRM anti total c-MET assay, clone SP44, Ventana BenchMark platform). All cases were analysed at participating pathology laboratories using the same protocol, after passing an external quality assurance program. MET positive status is defined as ≥ 50% of tumor cells staining with 2+ or 3+ intensity. Results A total of 2709 cases are included in the iBiobank and will be analysed. IHC MET expression is currently available for 1552 patients, with positive MET IHC staining in 380 cases [24.5%; IHC 3+ in 157 cases (41.3%) and 2+ in 223 cases (58.7%)]. The cohort of 1552 patients includes 48.2%, 44.7% and 4.4% cases of adenocarcinoma, squamous and large cell histologies, respectively. IHC MET status was independent of stage, age and smoking history. Significant differences in MET positivity were associated with gender (32% vs. 21% for female vs. male, p < 0.001), with performance status (25% vs. 18% for 0 vs. 1-3, p = 0.006), and histology (34%, 14% and 24% for adenocarcinoma, squamous and large cell carcinoma, p < 0.001). IHC MET positivity was independent of the IHC ALK status (p = 0.08). At last FU, 52% of patients were still alive, with a median FU of 4.8 yrs. No association of IHC MET was found with OS, RFS or TTR. Conclusions The preliminary results for this large multicentre European cohort describe a prevalence of MET overexpression that seems lower than previous observations in NSCLC, such as reported for the OAM4971g trial, suggesting potential biological differences between surgically resected and metastatic disease. Analysis for the full cohort is ongoing and results will be presented. Disclosure L. Bubendorf: Disclosures: Stock ownership: Roche Advisory boards: Roche, Pfizer Research support: Roche; K. Schulze: Full time employee of Roche; A. Das-Gupta: I am a full time employee of Roche. All other authors have declared no conflicts of interest.

Standard care practices and psychosocial interventions aimed at reducing parental distress following stillbirth: A systematic narrative review

Objective: To summarise and critically evaluate the evidence informing the provision of standard care practices and psychosocial interventions following stillbirth. Background: Stillbirth is increasingly recognised as a significant bereavement experience with the potential to cause substantial psychological distress for parents. Standard care practices and psychosocial interventions to support parents have undergone dramatic changes, with limited basis in evidence. Methods: A systematic narrative review was conducted of quantitative studies examining interventions designed to reduce psychological distress in parents following the loss of a stillborn baby. Results: Twenty-five studies met the inclusion criteria for the review. Substantial methodological weaknesses were identified among reviewed studies, including small and heterogeneous loss samples, weak study designs and lack of clarity in reported methods and outcomes. Inadequate replication of many findings substantially limits the generalisability of the evidence. Conclusion: Tentative evidence was found for the provision of mementoes of the baby and information regarding the cause of the loss, support group attendance, and cognitive behavioural interventions for parents identified with clinical levels of distress. Contradictory findings for the impact of contact with the baby prevent the formation of clear conclusions for this practice. Due to the methodological weaknesses prevalent in the research identified, the current evidence base is not considered sufficiently able to reliably inform care practices and intervention approaches. High-quality research evidence in this field is urgently required.

Procedural Results and Clinical Outcomes of Transcatheter Aortic Valve Implantation in Switzerland: An Observational Cohort Study of Sapien 3 Versus Sapien XT Transcatheter Heart Valves.

BACKGROUND: New generation transcatheter heart valves (THV) may improve clinical outcomes of transcatheter aortic valve implantation. METHODS AND RESULTS: In a nationwide, prospective, multicenter cohort study (Swiss Transcatheter Aortic Valve Implantation Registry, NCT01368250), outcomes of consecutive transfemoral transcatheter aortic valve implantation patients treated with the Sapien 3 THV (S3) versus the Sapien XT THV (XT) were investigated. An overall of 153 consecutive S3 patients were compared with 445 consecutive XT patients. Postprocedural mean transprosthetic gradient (6.5±3.0 versus 7.8±6.3 mm Hg, P=0.17) did not differ between S3 and XT patients, respectively. The rate of more than mild paravalvular regurgitation (1.3% versus 5.3%, P=0.04) and of vascular (5.3% versus 16.9%, P<0.01) complications were significantly lower in S3 patients. A higher rate of new permanent pacemaker implantations was observed in patients receiving the S3 valve (17.0% versus 11.0%, P=0.01). There were no significant differences for disabling stroke (S3 1.3% versus XT 3.1%, P=0.29) and all-cause mortality (S3 3.3% versus XT 4.5%, P=0.27). CONCLUSIONS: The use of the new generation S3 balloon-expandable THV reduced the risk of more than mild paravalvular regurgitation and vascular complications but was associated with an increased permanent pacemaker rate compared with the XT. Transcatheter aortic valve implantation using the newest generation balloon-expandable THV is associated with a low risk of stroke and favorable clinical outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01368250.