Cetuximab in combination with chemoradiotherapy prior to surgery in patients with resectable, locally advanced esophageal carcinoma : a prospective, multicenter phase lb-ll trial of the Swiss Group for Clinical Cancer Research (SAKK 75/06) : 4570

Background: Cetuximab significantly enhances efficacy of radiotherapy and chemotherapy in head and neck cancer. We investigated the safety and feasibility of adding cetuximab to neoadjuvant chemoradiation of locally advanced esophageal cancer. Methods: Pts with resectable, locally advanced squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus or gastroesophageal junction (staged by EUS, CT and PET scan) were treated with 2 cycles of induction chemotherapy (docetaxel 75mg/m2, cisplatin 75mg/m2 q3w and weekly cetuximab 250mg/m2), followed by concomitant chemo- immuno-radiation therapy (CIRT: docetaxel 20mg/m2, cisplatin 25mg/m2 and cetuximab 250mg/m2 weekly five times concomitant with 45 Gy radiotherapy in 25 fractions); followed by surgery 4-8 weeks later. The phase I part consisted of 2 cohorts of 7 patients each, without and with docetaxel during CIRT, respectively. Interpatient dose-escalation (adding docetaxel during CIRT) was possible if < 2 out of 7 pts of the 1st cohort experienced limiting toxicity. Having finished the phase 1 part, 13 additional patients were treated with docetaxel-containing CIRT in a phase II part. Pathological response was evaluated according to the Mandard classification. Results: 27 pts from 12 institutions were included. As of today, results from 20 pts are available (cohort 1: 7, cohort 2: 7, phase ll : 6). Median age was 64yrs (range 47-71). 11 AC; 9 SCC. 19 pts (95%) completed CIRT (1 pt stopped treatment during induction therapy due to sepsis). 17 pts underwent resection (no surgery: 1pt for PD, 1pt for cardiac reasons). Grade 3 toxicities during CIRT included anorexia 15%, dysphagia/esophagitis 15%, fatigue 10%, nausea 10%, pruritus 5%, dehydration 5%, nail changes 5% and rash 5% .1 pt suffered from pulmonary embolism. 13 pts (65%, intention-to-treat) showed a complete or near complete pathological remission (cohort 1: 5, cohort 2: 4, phase II: 4). Conclusions: Adding cetuximab to preoperative chemoradiation for esophageal cancer is safe and feasible in a community-based multicenter setting. Antineoplastic activity is encouraging with 65% pathological responders.

Performance of panel-based criteria to evaluate the appropriateness of colonoscopy: a prospective study.

BACKGROUND: Prospective data describing the appropriateness of use of colonoscopy based on detailed panel-based clinical criteria are not available. METHODS: In a cohort of 553 consecutive patients referred for colonoscopy to two university-based Swiss outpatient clinics, the percentage of patients who underwent colonoscopy for appropriate, equivocal, and inappropriate indications and the relationship between appropriateness of use and the presence of relevant endoscopic lesions was prospectively assessed. This assessment was based on criteria of the American Society for Gastrointestinal Endoscopy and explicit American and Swiss criteria developed in 1994 by a formal panel process using the RAND/UCLA appropriateness method. RESULTS: The procedures were rated appropriate or equivocal in 72.2% by criteria of the American Society for Gastrointestinal Endoscopy, in 68.5% by explicit American criteria, and in 74.4% by explicit Swiss criteria (not statistically significant, NS). Inappropriate use (overuse) of colonoscopy was found in 27.8%, 31.5%, and 25.6%, respectively (NS). The proportion of appropriate procedures was higher with increasing age. Almost all reasons for using colonoscopy could be assessed by the two explicit criteria sets, whereas 28.4% of reasons for using colonoscopy could not be evaluated by the criteria of the American Society for Gastrointestinal Endoscopy (p < 0.0001). The probability of finding a relevant endoscopic lesion was distinctly higher in the procedures rated appropriate or equivocal than in procedures judged inappropriate. CONCLUSIONS: The rate of inappropriate use of colonoscopy is substantial in Switzerland. Explicit criteria allow assessment of almost all indications encountered in clinical practice. In this study, all sets of appropriateness criteria significantly enhanced the probability of finding a relevant endoscopic lesion during colonoscopy.

Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study.

BACKGROUND: Bullous pemphigoid (BP), pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune bullous diseases characterized by the presence of tissue-bound and circulating autoantibodies directed against disease-specific target antigens of the skin. Although rare, these diseases run a chronic course and are associated with significant morbidity and mortality. There are few prospective data on gender- and age-specific incidence of these disorders. OBJECTIVES: Our aims were: (i) to evaluate the incidence of BP and PV/PF in Swiss patients, as the primary endpoint; and (ii) to assess the profile of the patients, particularly for comorbidities and medications, as the secondary endpoint. METHODS: The protocol of the study was distributed to all dermatology clinics, immunopathology laboratories and practising dermatologists in Switzerland. All newly diagnosed cases of BP and pemphigus occurring between 1 January 2001 and 31 December 2002 were collected. In total, 168 patients (73 men and 95 women) with these autoimmune bullous diseases, with a diagnosis based on clinical, histological and immunopathological criteria, were finally included. RESULTS: BP showed a mean incidence of 12.1 new cases per million people per year. Its incidence increased significantly after the age of 70 years, with a maximal value after the age of 90 years. The female/male ratio was 1.3. The age-standardized incidence of BP using the European population as reference was, however, lower, with 6.8 new cases per million people per year, reflecting the ageing of the Swiss population. In contrast, both PV and PF were less frequent. Their combined mean incidence was 0.6 new cases per million people per year. CONCLUSIONS; This is the first comprehensive prospective study analysing the incidence of autoimmune bullous diseases in an entire country. Our patient cohort is large enough to establish BP as the most frequent autoimmune bullous disease. Its incidence rate appears higher compared with other previous studies, most likely because of the demographic characteristics of the Swiss population. Nevertheless, based on its potentially misleading presentations, it is possible that the real incidence rate of BP is still underestimated. Based on its significant incidence in the elderly population, BP should deserve more public health concern.

Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies.

Background Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. Methods We conducted a pooled analysis of eight cohort studies comprising more than 80% of the world's published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All P values are two-sided. Results Statistically significant inverse associations with breast cancer were observed for α-carotene (top vs bottom quintile RR = 0.87, 95% CI = 0.71 to 1.05, Ptrend = .04), β-carotene (RR = 0.83, 95% CI = 0.70 to 0.98, Ptrend = .02), lutein+zeaxanthin (RR = 0.84, 95% CI = 0.70 to 1.01, Ptrend = .05), lycopene (RR = 0.78, 95% CI = 0.62 to 0.99, Ptrend = .02), and total carotenoids (RR = 0.81, 95% CI = 0.68 to 0.96, Ptrend = .01). β-Cryptoxanthin was not statistically significantly associated with risk. Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER(-)) than for ER(+) tumors (eg, β-carotene: ER(-): top vs bottom quintile RR = 0.52, 95% CI = 0.36 to 0.77, Ptrend = .001; ER(+): RR = 0.83, 95% CI = 0.66 to 1.04, Ptrend = .06; Pheterogeneity = .01). Conclusions This comprehensive prospective analysis suggests women with higher circulating levels of α-carotene, β-carotene, lutein+zeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer.

Treatment patterns and health care resource utilization in a 1-year observational cohort study of outpatients with schizophrenia at risk of nonadherence treated with long-acting injectable antipsychotics

Purpose: To describe (1) the clinical profiles and the patterns of use of long-acting injectable (LAI) antipsychotics in patients with schizophrenia at risk of nonadherence with oral antipsychotics, and in those who started treatment with LAI antipsychotics, (2) health care resource utilization and associated costs. Patients and methods: A total of 597 outpatients with schizophrenia at risk of nonadherence, according to the psychiatrist's clinical judgment, were recruited at 59 centers in a noninterventional prospective observational study of 1-year follow-up when their treatment was modified. In a post hoc analysis, the profiles of patients starting LAI or continuing with oral antipsychotics were described, and descriptive analyses of treatments, health resource utilization, and direct costs were performed in those who started an LAI antipsychotic. Results: Therapy modifications involved the antipsychotic medications in 84.8% of patients, mostly because of insufficient efficacy of prior regimen. Ninety-two (15.4%) patients started an LAI antipsychotic at recruitment. Of these, only 13 (14.1%) were prescribed with first-generation antipsychotics. During 1 year, 16.3% of patients who started and 14.9% of patients who did not start an LAI antipsychotic at recruitment relapsed, contrasting with the 20.9% who had been hospitalized only within the prior 6 months. After 1 year, 74.3% of patients who started an LAI antipsychotic continued concomitant treatment with oral antipsychotics. The mean (median) total direct health care cost per patient per month during the study year among the patients starting any LAI antipsychotic at baseline was 1,407 ( 897.7). Medication costs (including oral and LAI antipsychotics and concomitant medication) represented almost 44%, whereas nonmedication costs accounted for more than 55% of the mean total direct health care costs. Conclusion: LAI antipsychotics were infrequently prescribed in spite of a psychiatrist-perceived risk of nonadherence to oral antipsychotics. Mean medication costs were lower than nonmedication costs.

Progression of human carotid and femoral atherosclerosis: a prospective follow-up study by magnetic resonance vessel wall imaging.

AIMS: The time course of atherosclerosis burden in distinct vascular territories remains poorly understood. We longitudinally evaluated the natural history of atherosclerotic progression in two different arterial territories using high spatial resolution magnetic resonance imaging (HR-MRI), a powerful, safe, and non-invasive tool. METHODS AND RESULTS: We prospectively studied a cohort of 30 patients (mean age 68.3, n = 9 females) with high Framingham general cardiovascular disease 10-year risk score (29.5%) and standard medical therapy with mild-to-moderate atherosclerosis intra-individually at the level of both carotid and femoral arteries. A total of 178 HR-MRI studies of carotid and femoral arteries performed at baseline and at 1- and 2-year follow-up were evaluated in consensus reading by two experienced readers for lumen area (LA), total vessel area (TVA), vessel wall area (VWA = TVA - LA), and normalized wall area index (NWI = VWA/TVA). At the carotid level, LA decreased (-3.19%/year, P = 0.018), VWA increased (+3.83%/year, P = 0.019), and TVA remained unchanged. At the femoral level, LA remained unchanged, VWA and TVA increased (+5.23%/year and +3.11%/year, both P < 0.01), and NWI increased for both carotid and femoral arteries (+2.28%/year, P = 0.01, and +1.8%/year, P = 0.033). CONCLUSION: The atherosclerotic burden increased significantly in both carotid and femoral arteries. However, carotid plaque progression was associated with negative remodelling, whereas the increase in femoral plaque burden was compensated by positive remodelling. This finding could be related to anatomic and flow differences and/or to the distinct degree of obstruction in the two arterial territories.

Patterns of cannabis use and prospective associations with health issues among young males.

BACKGROUND AND AIMS: To test prospective associations between cannabis disorder symptoms/frequency of cannabis use and health issues and to investigate stability versus transience in cannabis use trajectories. DESIGN: Two waves of data collection from the longitudinal Cohort Study on Substance Use Risk Factors (C-SURF). SETTING: A representative sample of young Swiss men in their early 20s from the general population. PARTICIPANTS: A total of 5084 young men (mean age 19.98 ± 1.19 years at time 1). MEASUREMENTS: Cannabis use (life-time use, frequency of use, cannabis disorder symptoms) and self-reported measures of health issues (depression, mental/physical health, health consequences) were assessed. Significant changes in cannabis use were tested using t-test/Wilcoxon's rank test for paired data. Cross-lagged panel models provided evidence regarding longitudinal associations between cannabis use and health issues. FINDINGS: Most of the participants (84.5%) remained in the same use category and cannabis use kept to similar levels at times 1 and 2 (P = 0.114 and P = 0.755; average of 15 ± 2.8 months between times 1 and 2). Cross-lagged panel models showed that cannabis disorder symptoms predicted later health issues (e.g. depression, β = 0.087, P < 0.001; health consequences, β = 0.045, P < 0.05). The reverse paths from health issues to cannabis disorder symptoms and the cross-lagged panel model between frequency of cannabis use and health issues were non-significant. CONCLUSIONS: Patterns of cannabis use showed substantial continuity among young Swiss men in their early 20s. The number of symptoms of cannabis use disorder, rather than the frequency of cannabis use, is a clinically important measure of cannabis use among young Swiss men.

Infectious Disease Burden after Solid Organ Transplantation (SOT) in the Swiss Transplant Cohort Study (STCS).

Infectious diseases (ID) are a major cause of morbidity and mortality after SOT. Since May 2008, the STCS has registered 95% of all SOT recipients in Switzerland. The extensive data set includes pre- and post-transplant variables that are prospectively collected at transplantation, 6 months post-transplant, and yearly thereafter. All ID events are recorded using internationally validated defi nitions. We obtained data from 1101 patients (79 heart, 685 kidney, 29 kidney-pancreas, 212 liver, and 96 lung transplants). So far the median observation times were 0.8 (IQR 0.3-1.4; heart); 1.1 (0.6-1.8, kidney); 1.1 (0.6-1.9, kidney-pancreas); 1.0 (0.5-1.7, liver); and 0.9 years (0.5-1.5, lung). The highest rates of proven or probable ID events were seen in lung (76%), followed by liver (64%), heart (62%), kidney-pancreas (62%), kidney (58%). During the observation period, ID was the cause of death in 19 patients (1.7%). Rates of infections per person-years according to pathogen and type of transplantation are shown in Figure 1. The data indicate that virus infections are only second after bacteria whereas fungi occur at relatively low rates. This prospective and standardized long-term collection of all ID events will allow a comprehensive assessment of the burden of ID across all SOT types in Switzerland. Regular analysis will identify new trends, serve as a quality control and help design anti-infectious interventions aiming at increasing safety and improving overall transplantation outcome.

Optimal and continuous anaemia control in a cohort of dialysis patients in Switzerland.

BACKGROUND: Guidelines for the management of anaemia in patients with chronic kidney disease (CKD) recommend a minimal haemoglobin (Hb) target of 11 g/dL. Recent surveys indicate that this requirement is not met in many patients in Europe. In most studies, Hb is only assessed over a short-term period. The aim of this study was to examine the control of anaemia over a continuous long-term period in Switzerland. METHODS: A prospective multi-centre observational study was conducted in dialysed patients treated with recombinant human epoetin (EPO) beta, over a one-year follow-up period, with monthly assessments of anaemia parameters. RESULTS: Three hundred and fifty patients from 27 centres, representing 14% of the dialysis population in Switzerland, were included. Mean Hb was 11.9 +/- 1.0 g/dL, and remained stable over time. Eighty-five % of the patients achieved mean Hb &gt;or= 11 g/dL. Mean EPO dose was 155 +/- 118 IU/kg/week, being delivered mostly by subcutaneous route (64-71%). Mean serum ferritin and transferrin saturation were 435 +/- 253 microg/L and 30 +/- 11%, respectively. At month 12, adequate iron stores were found in 72.5% of patients, whereas absolute and functional iron deficiencies were observed in only 5.1% and 17.8%, respectively. Multivariate analysis showed that diabetes unexpectedly influenced Hb towards higher levels (12.1 +/- 0.9 g/dL; p = 0.02). One year survival was significantly higher in patients with Hb &gt;or= 11 g/dL than in those with Hb &lt;11 g/dL (19.7% vs 7.3%, p = 0.006). CONCLUSION: In comparison to European studies of reference, this survey shows a remarkable and continuous control of anaemia in Swiss dialysis centres. These results were reached through moderately high EPO doses, mostly given subcutaneously, and careful iron therapy management.

Efficacy, tolerability and risk factors for virological failure of darunavir-based therapy for treatment-experienced HIV-infected patients: the Swiss HIV Cohort Study.

OBJECTIVES: Darunavir was designed for activity against HIV resistant to other protease inhibitors (PIs). We assessed the efficacy, tolerability and risk factors for virological failure of darunavir for treatment-experienced patients seen in clinical practice. METHODS: We included all patients in the Swiss HIV Cohort Study starting darunavir after recording a viral load above 1000 HIV-1 RNA copies/mL given prior exposure to both PIs and nonnucleoside reverse transcriptase inhibitors. We followed these patients for up to 72 weeks, assessed virological failure using different loss of virological response algorithms and evaluated risk factors for virological failure using a Bayesian method to fit discrete Cox proportional hazard models. RESULTS: Among 130 treatment-experienced patients starting darunavir, the median age was 47 years, the median duration of HIV infection was 16 years, and 82% received mono or dual antiretroviral therapy before starting highly active antiretroviral therapy. During a median patient follow-up period of 45 weeks, 17% of patients stopped taking darunavir after a median exposure of 20 weeks. In patients followed beyond 48 weeks, the rate of virological failure at 48 weeks was at most 20%. Virological failure was more likely where patients had previously failed on both amprenavir and saquinavir and as the number of previously failed PI regimens increased. CONCLUSIONS: As a component of therapy for treatment-experienced patients, darunavir can achieve a similar efficacy and tolerability in clinical practice to that seen in clinical trials. Clinicians should consider whether a patient has failed on both amprenavir and saquinavir and the number of failed PI regimens before prescribing darunavir.

Assessment of early-stage optic nerve invasion in retinoblastoma using high-resolution 1.5 Tesla MRI with surface coils: a multicentre, prospective accuracy study with histopathological correlation.

OBJECTIVES: To assess the accuracy of high-resolution (HR) magnetic resonance imaging (MRI) in diagnosing early-stage optic nerve (ON) invasion in a retinoblastoma cohort. METHODS: This IRB-approved, prospective multicenter study included 95 patients (55 boys, 40 girls; mean age, 29 months). 1.5-T MRI was performed using surface coils before enucleation, including spin-echo unenhanced and contrast-enhanced (CE) T1-weighted sequences (slice thickness, 2 mm; pixel size <0.3 × 0.3 mm(2)). Images were read by five neuroradiologists blinded to histopathologic findings. ROC curves were constructed with AUC assessment using a bootstrap method. RESULTS: Histopathology identified 41 eyes without ON invasion and 25 with prelaminar, 18 with intralaminar and 12 with postlaminar invasion. All but one were postoperatively classified as stage I by the International Retinoblastoma Staging System. The accuracy of CE-T1 sequences in identifying ON invasion was limited (AUC = 0.64; 95 % CI, 0.55 - 0.72) and not confirmed for postlaminar invasion diagnosis (AUC = 0.64; 95 % CI, 0.47 - 0.82); high specificities (range, 0.64 - 1) and negative predictive values (range, 0.81 - 0.97) were confirmed. CONCLUSION: HR-MRI with surface coils is recommended to appropriately select retinoblastoma patients eligible for primary enucleation without the risk of IRSS stage II but cannot substitute for pathology in differentiating the first degrees of ON invasion. KEY POINTS: • HR-MRI excludes advanced optic nerve invasion with high negative predictive value. • HR-MRI accurately selects patients eligible for primary enucleation. • Diagnosis of early stages of optic nerve invasion still relies on pathology. • Several physiological MR patterns may mimic optic nerve invasion.

Exposure to bioaerosols, respiratory health and lung-specific proteins: a prospective study in garbage and wastewater workers.

Objectives To prospectively assess respiratory health in wastewater workers and garbage collectors over 5 years. Methods Exposure, respiratory symptoms and conditions, spirometry and lung-specific proteins were assessed yearly in a cohort of 304 controls, 247 wastewater workers and 52 garbage collectors. Results were analysed with random coefficient models and linear regression taking into account several potential confounders. Results Symptoms, spirometry and lung-specific proteins were not affected by occupational exposure. Conclusions In this population no effects of occupational exposure to bioaerosols were found, probably because of good working conditions.

Patterns of Adherence to Raltegravir-Based Regimens and the Risk of Virological Failure Among HIV-Infected Patients: The RALTECAPS Cohort Study.

ABSTRACT:: Adherence patterns and their influence on virologic outcome are well characterized for protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We aimed to determine how patterns of adherence to raltegravir influence the risk of virological failure. We conducted a prospective multicenter cohort following 81 HIV-infected antiretroviral-naive or experienced subjects receiving or starting twice-a-day raltegravir-based antiretroviral therapy. Their adherence patterns were monitored using the Medication Events Monitoring System. During follow-up (188 days, ±77), 12 (15%) of 81 subjects experienced virological failure. Longer treatment interruption [adjusted odds ratio per 24-hour increase: 2.4; 95% confidence interval: 1.2 to 6.9; P < 0.02] and average adherence (odds ratio per 5% increase: 0.68; 95% confidence interval: 0.46 to 1.00, P < 0.05) were both independently associated with virological failure controlling for prior duration of viral suppression. Timely interdose intervals and high levels of adherence to raltegravir are both necessary to control HIV replication.

Cohort profile: the Swiss HIV Cohort study.

The substantial recurrence rate of colorectal cancer following potentially curative resection has fuelled the search for effective adjuvant therapy. Previous trials using 5-fluorouracil (5-FU) as a single agent or in combination chemotherapy regimens have not demonstrated meaningful benefits, an impression reflected in the results of a meta-analysis encompassing large patient numbers. Newer developments utilizing intraportal chemotherapy and the combination of 5-FU and levamisole have resulted in lower recurrence rates and improved survival in patients with colon cancer. In advanced disease, the biochemical modulation of 5-FU by Leucovorin has been shown to prolong survival in some studies. Combined chemotherapy and radiotherapy or chemotherapy alone have showed promising results in rectal cancer. These developments have now been incorporated into ongoing trials.

Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration.

BACKGROUND: Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients. METHODS: We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely to be affected by antiretroviral therapy, cohort, calendar year, and use of other antiretrovirals. FINDINGS: Over 157,912 person-years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent-but not cumulative-use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47-2.45 [p=0.0001] with abacavir and 1.49, 1.14-1.95 [p=0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14-1.95 [p=0.004] with didanosine; 1.89, 1.47-2.45 [p=0.0001] with abacavir). INTERPRETATION: There exists an increased risk of myocardial infarction in patients exposed to abacavir and didanosine within the preceding 6 months. The excess risk does not seem to be explained by underlying established cardiovascular risk factors and was not present beyond 6 months after drug cessation.