Multi-Disciplinary Expert Perspective on the Management of Type 2 Inflammation-Driven Severe CRSwNP: A Brief Overview of Pathophysiology and Recent Clinical Insights.

Severe chronic rhinosinusitis with nasal polyposis (CRSwNP) is a disabling airway disease that significantly impacts patients' lives through the severity of symptoms, the need for long-term medical treatment and the high risk of recurrence post-surgery. Biological agents targeting type 2 immune responses underlying the pathogenesis of CRSwNP have shown effectiveness in reducing polyp size and eosinophilic infiltrate, and in decreasing the need for additional sinus surgeries. However, despite recent progress in understanding and treating the disease, type 2 inflammation-driven severe CRSwNP continues to pose challenges to clinical management due to several factors such as persistent inflammation, polyp recurrence, heterogeneity of disease, and comorbidities. This article presents the findings of a scientific discussion involving a panel of ear, nose and throat (ENT) specialists and pulmonologists across Sweden and Finland. The discussion aimed to explore current management practices for type 2 inflammation-driven severe CRSwNP in the Nordic region. The main topics examined encompassed screening and referral, measurements of disease control, treatment goals, and future perspectives. The experts emphasized the importance of a collaborative approach in the management of this challenging patient population. The discussion also revealed a need to broaden treatment options for patients with type 2 inflammation-driven CRSwNP and comorbid conditions with shared type 2 pathophysiology. In light of the supporting evidence, a shift in the disease model from the presence of polyps to that of type 2 inflammation may be warranted. Overall, this discussion provides valuable insights for the scientific community and can potentially guide the future management of CRSwNP.

Advances in fixation strength of reorienting rectangular triple pelvic innominate osteotomies - A biomechanical investigation of two screw fixation techniques.

BACKGROUND: Reorientating pelvic osteotomies are performed to prevent femoral-acetabular impingement or degenerative arthritis. A Toennis-Kalchschmidt triple pelvis innominate osteotomy is used in symptomatic patients. This study aimed to investigate the biomechanical behaviour of two different acetabular screw configurations for triple pelvis innominate osteotomy osteosynthesis. METHODS: Two screw-orientation techniques in rectangular os ilium osteotomy were compared by osteotomising 12 artificial hemipelvises with triple pelvis innominate osteotomy protocol (fragment reorientation: 10.5° inclination and 10.0° anteversion) and randomising them in 2 groups (n = 6) for implantation with three 4.5 mm screws. Bidirectional group had a bidirectional screw orientation and Monoaxial group had a monoaxial direction of all three screws through iliac crest. All specimens were tested under progressively increasing cyclic loading until failure. Group-wise comparisons of acetabular cup medialisation, anteversion and inclination were evaluated via motion tracking at cycles 250, 500, 750, 1000, 1250, 1500, 1750, 2000, 2250, and 2500. Failure was defined as reaching 5° inclination or 5° anteversion. FINDINGS: Acetabular cup medialisation (p ≤ 0.026), anteversion (p ≤ 0.021) and inclination (p ≤ 0.039) all increased significantly during testing in both groups. There were no significant differences for the group-wise comparisons at the cycle points defined in the methods (p ≥ 0.182). No significant differences were detected between groups for cycles to failure and failure load (p = 0.873). INTERPRETATION: Bidirectional screw alignment does not lead to significant advantages compared to pure monoaxial if all three axial screws are evenly distributed over the osteotomy geometry. The triple pelvis innominate osteotomy is susceptible to changes in anteversion, inclination and medialisation under partial weight-bearing. Cautious rehabilitation protocols are recommended.

Integrated Analysis of the RASH Study with the Use of the "Burden of Therapy" (BOTh®TM) Methodology-A Novel Tool for Assessing Adverse Events in Metastatic Pancreatic Cancer.

This analysis of the RASH trial (NCT01729481) aimed at gaining a better understanding of the "Burden of Therapy" (BOTh®TM) in pancreatic ductal adenocarcinoma (PDAC). In the RASH study, 150 patients with newly diagnosed metastatic PDAC were treated with gemcitabine plus erlotinib (gem/erlotinib) for four weeks. Patients who developed a skin rash during this four-week run-in phase continued with the gem/erlotinib treatment, while rash-negative patients were switched to FOLFIRINOX. The study demonstrated a 1-year survival rate of rash-positive patients who received gem/erlotinib as first-line treatment that was comparable to previous reports of patients receiving FOLFIRINOX. To understand whether these comparable survival rates may be accompanied by better tolerability of the gem/erlotinib treatment compared to FOLFIRINOX, the BOTh®TM methodology was used to continuously quantify and depict the burden of therapy generated by treatment emergent events (TEAEs). Sensory neuropathy was significantly more common in the FOLFIRINOX arm, and prevalence as well as severity increased over time. In both arms, the BOTh®TM associated with diarrhea decreased over the course of treatment. The BOTh®TM caused by neutropenia was comparable in both arms but decreased in the FOLFIRINOX arm over time, possibly due to chemotherapy dose reductions. Overall, gem/erlotinib was associated with a slightly higher overall BOTh®TM, but the difference was not statistically significant (p = 0.6735). In summary, the BOTh®TM analysis facilitates the evaluation of TEAEs. In patients fit for intense chemotherapeutic regimens, FOLFIRINOX is associated with a lower BOTh®TM than gem/erlotinib.

Serum prolactin level as a predictive factor for abiraterone response in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. METHODS: This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression-free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI). RESULTS: The study included 61 patients with a median follow-up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate-specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037). CONCLUSIONS: Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.

Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy-Analysis of the Phase 3 XELAVIRI Trial.

INTRODUCTION: Early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial. METHODS: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex. RESULTS: In 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in RAS/BRAF wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: p < 0.001, HR 0.532; OS: p < 0.001, HR 0.574 vs. PFS: p = 0.107; OS: p = 0.965). CONCLUSIONS: Initial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

Gender-dependent survival benefit from first-line irinotecan in metastatic colorectal cancer. Subgroup analysis of a phase III trial (XELAVIRI-study, AIO-KRK-0110).

BACKGROUND: XELAVIRI compared sequential (Arm A) versus initial (Arm B) irinotecan in combination with fluoropyrimidine plus bevacizumab in patients with metastatic colorectal cancer, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown. The present analysis was performed to evaluate the effect of gender on treatment outcome and tolerability. METHODS: The study end-points overall response rate (ORR), progression-free survival (PFS), TFS and overall survival (OS) were evaluated in female versus male patients and in molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests. RESULTS: In total, 281 male and 140 female patients (n = 421) were evaluated. Among the male patients, the ORR was 33.6% without and 58.3% with initial irinotecan (P < 0.001). PFS (hazard ratio [HR] 0.54; 95% confidence interval [CI] 0.42-0.69; P < 0.001) and OS (HR 0.63; 95% CI 0.47-0.85; P = 0.002) were also significantly better with initial irinotecan. Among the female patients, the ORR was 42.7% in Arm A and 43.1% in Arm B, PFS was similar (HR 1.09; 95% CI 0.76-1.55; P = 0.649) without and with initial irinotecan. A strong trend for inferior outcome with regard to OS with initial irinotecan was observed (HR 1.46; 95% CI 0.95-2.24; P = 0.081) and the trend reached significance in the multivariate analysis (HR 1.78; 95% CI 1.08-2.95; P = 0.02). Formal interaction of treatment and gender was observed for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). Treatment-related adverse events were not significantly different between male and female patients. CONCLUSIONS: The present analysis suggests that gender interacts with efficacy of initial irinotecan when used in combination with fluoropyrimidines and bevacizumab. Although male patients derived a significant and clinically meaningful benefit from initial combination chemotherapy, this was not observed in female patients.

Impact of age on efficacy and early mortality of initial sequential treatment versus upfront combination chemotherapy in patients with metastatic colorectal cancer: a subgroup analysis of a phase III trial (AIO KRK0110, XELAVIRI study).

INTRODUCTION: The XELAVIRI study compared application of fluoropyrimidine (FP) and bevacizumab (Bev) followed by sequential escalation to irinotecan (Iri), FP and Bev (arm A) to upfront combination therapy with FP, Iri and Bev (arm B) in patients with metastatic colorectal cancer (mCRC). To elucidate the impact of age on survival, we evaluated efficacy and early mortality in the underlying trial. METHODS: Patients were stratified for age in three cohorts (<65 years, 65-74 years and ≥75 years). Survival end-points were expressed by the Kaplan-Meier method and compared by log-rank testing and Cox regression. Objective response and 60-day mortality were evaluated by chi-square testing. RESULTS: The efficacy analyses suggest more substantial benefit from upfront combination chemotherapy in younger patients with mCRC. Elderly patients (≥75 years) derived limited benefit from upfront combination chemotherapy, particularly in terms of overall survival. Of 421 randomised patients, 13 patients (3.1%) died within 60 days after treatment initiation with the highest prevalence in elderly patients (1.6% < 65 years, 2.8% 65-74 years and 5.2% ≥ 75 years, p = 0.26). The frequency of 60-day mortality was significantly associated with age (with a maximum of 8.7% in patients aged ≥75 years) in patients undergoing upfront combination therapy (p = 0.027) but not in patients receiving sequential treatment (p = 0.63). CONCLUSION: Combination therapy with FP, Iri and Bev does not substantially improve the outcome of patients aged ≥75 years as compared with sequential treatment algorithm. These patients appear to be at a relevant risk for 60-day mortality under Iri-based combination chemotherapy plus Bev.

Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110).

PURPOSE: The XELAVIRI trial investigated the optimal treatment strategy for patients with untreated metastatic colorectal cancer. We tested the noninferiority of initial treatment with a fluoropyrimidine plus bevacizumab, followed by the addition of irinotecan at first progression (arm A) versus upfront use of fluoropyrimidine plus irinotecan plus bevacizumab (arm B) in a 1:1 randomized, controlled phase III trial. METHODS: The primary efficacy end point was time to failure of the strategy (TFS). Given a 90% CI, a power of 70%, and a one-sided α of .05, the margin for noninferiority was set at 0.8. In the case of demonstrated noninferiority of TFS, an analysis of symptomatic toxicities during TFS would define the superior strategy. Secondary end points included the effect of molecular subgroups on efficacy parameters. RESULTS: A total of 421 randomly assigned patients (arm A: n = 212; arm B: n = 209) formed the full analysis set. Median age was 71 and 69 years, respectively. Noninferiority of TFS was not shown (hazard ratio [HR], 0.86; 90% CI, 0.73 to 1.02). In detail, patients with RAS/BRAF wild-type tumors benefitted from combination chemotherapy (HR, 0.61; 90% CI, 0.46 to 0.82; P = .005), whereas patients with RAS mutant tumors (HR, 1.09; 90% CI, 0.81 to 1.46; P = .58) did not (Cox model for interaction of study arm and RAS status: P = .03). Comparable results were obtained for overall survival. CONCLUSION: Noninferiority of sequential escalation therapy compared with initial combination chemotherapy could not be demonstrated for TFS. RAS status may be important to guide therapy as treatment of patients with upfront combination therapy was clearly superior in RAS/BRAF wild-type tumors, whereas sequential escalation chemotherapy seems to provide comparable results in patients with RAS mutant tumors.

High burden of atopy in immigrant families in substandard apartments in Sweden - on the contribution of bad housing to poor health in vulnerable populations.

BACKGROUND: Atopic disorders are a global concern. Studies in migrant populations can illuminate the interplay of genetic and environmental factors. Exposures related to bad housing (indoor dampness, mould growth, crowding etc.) are likely to play a role in how socioeconomic inequalities can turn into health disparities for disadvantaged populations. The sizable immigrant population living in very poor-quality housing in Malmö, Sweden, became the focus of a cross-sectional study. OBJECTIVE: To describe atopic disorders and sensitizations in a population living in substandard housing in Malmö, Sweden, with an emphasis on their relation to harmful exposures from the built environment. METHODS: Families were recruited via identification of any children with symptomatic airway afflictions from health care records, and also asymptomatic children from school lists. Interviewer-led health questionnaire data and data from self-reports about living conditions were obtained together with data from home inspections carried out by health communicators. Families underwent skin prick tests (SPT) against common aeroallergens. RESULTS: As could be expected from background demographic information, it turned out that we effectively studied an immigrant population inhabiting very precarious housing outside the center of Malmö. A total of 359 children from 130 families (total 650 participants) were included. Overall the prevalence of potentially harmful environmental exposures was high (signs of moisture or mould in more than 50% of apartments, indoor smoking in 37% of households). Atopic disorders were common among both adults and children. SPTs showed a spectrum of sensitizations consistent with unselected populations in Sweden. Paternal sensitization in the SPT was associated with higher risk of sensitization for offspring than maternal sensitization. Few statistically significant associations of atopic sensitization with studied environmental exposures were detected (for example objective signs of dampness /mould in bathrooms). There were marked discrepancies between asthma diagnoses obtained from the health records and parental reports of such diagnoses and treatment for their children. CONCLUSIONS: The atopic burden in this selected immigrant population was high, and results point to unmet medical needs. Health care systems caring for such populations need to be aware of their specific health needs; comprehensive asthma and allergy care should include consideration of harmful environmental exposures, adhering to the precautionary principle.

Poor housing conditions in association with child health in a disadvantaged immigrant population: a cross-sectional study in Rosengård, Malmö, Sweden.

OBJECTIVES: To describe the home environment in terms of housing conditions and their association with child health in a disadvantaged immigrant population. DESIGN: A cross-sectional observational study. SETTING: Enrolment took place during 2010-2011 in Rosengård, Malmö, Sweden. PARTICIPANTS: Children aged 0-13 years in 2 study neighbourhoods were recruited from local health records and from schools. 359 children participated, with a participation rate of 40%. Data on health, lifestyle and apartment characteristics from questionnaire-led interviews with the mothers of the children were obtained together with data from home inspections carried out by trained health communicators. OUTCOME MEASURES: Logistic regression analysis was used to estimate ORs for various health outcomes, adjusted for demographic information and lifestyle factors. RESULTS: The housing conditions were very poor, especially in one of the study neighbourhoods where 67% of the apartments had been sanitised of cockroaches, 27% were infested with cockroaches and 40% had a visible mould. The association between housing conditions and health was mostly inconclusive, but there were statistically significant associations between current asthma and dampness (OR=4.1, 95% CI 1.7 to 9.9), between asthma medication and dampness (OR=2.8, 95% CI 1.2 to 6.4), and between mould and headache (OR=4.2, 95% CI 1.2 to 14.8). The presence of cockroaches was associated with emergency care visits, with colds, with headache and with difficulty falling asleep, and worse general health was associated with mould and presence of cockroaches. CONCLUSIONS: The associations between dampness and asthma, and the association between mould and headache, are in line with current knowledge. The presence of cockroaches seemed to be associated with various outcomes, including those related to mental well-being, which is less described in the literature. The results of the present study are hypothesis generating and provide strong incentives for future studies in this study population.

Evaluation of a revised version of computer-assisted diagnosis system, BONENAVI version 2.1.7, for bone scintigraphy in cancer patients.

OBJECTIVE: BONENAVI is a computer-assisted diagnosis system that analyzes bone scintigraphy automatically. We experienced more than a few segmentation errors with the previous BONENAVI version (2.0.5). We have since obtained a revised version (2.1.7) and evaluate it. METHODS: Bone scans of patients were analyzed by BONENAVI version 2.0.5 and a revised version 2.1.7 with regard to segmentation errors, sensitivity, and specificity. Patients with skeletal metastases from prostate cancer, lung cancer, breast cancer, and other cancers were included in the study as true-positive cases. Patients with no skeletal metastasis (regardless of hot spots), and patients with abnormal bone scans but no skeletal metastasis were included as negative cases. Bone-scan patients were subjected to artificial neural network (ANN) evaluation. Values equal to or above 0.5 were regarded as positive, and those below 0.5 as negative. The patients whose clinical status did not correspond to their ANN scores were assessed for any similarities. RESULTS: The frequency of segmentation errors was statistically significantly reduced when using BONENAVI version 2.1.7. The differences in sensitivity and specificity for the results of version 2.0.5 versus version 2.1.7 were not different, giving a high Cohen's kappa coefficient. In the patients who showed an increased ANN value with version 2.1.7, a few false-positive thoracic lesions were identified. Patients whose ANN value was significantly high with version 2.0.5 showed no tendencies. CONCLUSION: Revised BONENAVI version 2.1.7 for bone scintigraphy was superior with regard to segmentation errors. However, its sensitivity and specificity were similar to those of version 2.0.5. The false-positive identification of thoracic lesions in revised version 2.1.7 might be subject to remedy.

Exposure to harmful housing conditions is common in children admitted to Wellington Hospital.

AIM: To measure the prevalence of exposure to potentially modifiable risk factors in the homes of children hospitalised in Wellington. METHODS: Parents/caregivers of all children admitted to Wellington Public Hospital during a two-week period in July 2012 completed a standardised questionnaire in a face-to-face interview. The questionnaire collected sociodemographic, health and housing condition data. RESULTS: We interviewed parents/caregivers of 106 children, of whom 72% were aged 0-4 years. Respiratory conditions were the most common cause of admission. One third of parents noticed dampness and mould in their house, 50% stated that their house was colder than they preferred during the past month, 20% lived in uninsulated houses, 20% lived in overcrowded houses, and 38% were exposed to second hand smoke (SHS). Compared to New Zealand European (NZE) children, the odds ratios (OR) for Pacific children living in cold and overcrowded houses and being exposed to SHS were 14.0 (95%CI 3.0-66.0), 10.8 (95%CI 2.6-44.1) and 16.0 (95%CI 4.8-55.5) respectively. OR for Maori children living in cold and overcrowded houses and being exposed to SHS were 3.0 (95%CI 1.0-9.0), 6.8 (95%CI 1.6-30.1) and 8.0 (95%CI 2.5-28.6) respectively, compared to NZE children. The OR for children from deprived neighbourhoods (NZDep2006 areas 7-10) living in cold and overcrowded houses and being exposed to SHS were 4.1 (95%CI 1.8-9.6), 5.7 (95%CI 1.9-17.0) and 4.1 (95%CI 1.6-9.6) respectively. CONCLUSIONS: Among children admitted to Wellington Hospital there is a high prevalence of exposure to cold, damp and overcrowded houses and many children are exposed to SHS. Maori and Pacific children and children living in socioeconomically deprived areas are more likely than others to be exposed to these potential risk factors for childhood hospitalisation. This audit of child admissions could be repeated to provide surveillance of modifiable risk factors. A shortened version of the questionnaire could be used to screen children to identify those with harmful exposures in their home environment, provided suitable intervention programmes can be established.

A novel automated platform for quantifying the extent of skeletal tumour involvement in prostate cancer patients using the Bone Scan Index.

BACKGROUND: There is little consensus on a standard approach to analysing bone scan images. The Bone Scan Index (BSI) is predictive of survival in patients with progressive prostate cancer (PCa), but the popularity of this metric is hampered by the tedium of the manual calculation. OBJECTIVE: Develop a fully automated method of quantifying the BSI and determining the clinical value of automated BSI measurements beyond conventional clinical and pathologic features. DESIGN, SETTING, AND PARTICIPANTS: We conditioned a computer-assisted diagnosis system identifying metastatic lesions on a bone scan to automatically compute BSI measurements. A training group of 795 bone scans was used in the conditioning process. Independent validation of the method used bone scans obtained ≤3 mo from diagnosis of 384 PCa cases in two large population-based cohorts. An experienced analyser (blinded to case identity, prior BSI, and outcome) scored the BSI measurements twice. We measured prediction of outcome using pretreatment Gleason score, clinical stage, and prostate-specific antigen with models that also incorporated either manual or automated BSI measurements. MEASUREMENTS: The agreement between methods was evaluated using Pearson's correlation coefficient. Discrimination between prognostic models was assessed using the concordance index (C-index). RESULTS AND LIMITATIONS: Manual and automated BSI measurements were strongly correlated (ρ=0.80), correlated more closely (ρ=0.93) when excluding cases with BSI scores≥10 (1.8%), and were independently associated with PCa death (p<0.0001 for each) when added to the prediction model. Predictive accuracy of the base model (C-index: 0.768; 95% confidence interval [CI], 0.702-0.837) increased to 0.794 (95% CI, 0.727-0.860) by adding manual BSI scoring, and increased to 0.825 (95% CI, 0.754-0.881) by adding automated BSI scoring to the base model. CONCLUSIONS: Automated BSI scoring, with its 100% reproducibility, reduces turnaround time, eliminates operator-dependent subjectivity, and provides important clinical information comparable to that of manual BSI scoring.

A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: the AIO KRK 0110 trial/ML22011 trial.

BACKGROUND: Several randomized trials have indicated that combination chemotherapy applied in metastatic colorectal cancer (mCRC) does not significantly improve overall survival when compared to the sequential use of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present study investigates the question whether this statement holds true also for bevacizumab-based first-line treatment including escalation- and de-escalation strategies. METHODS/DESIGN: The AIO KRK 0110/ML22011 trial is a two-arm, multicenter, open-label randomized phase III trial comparing the efficacy and safety of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in the first-line treatment of metastatic colorectal cancer. Patients with unresectable metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, will be assigned in a 1:1 ratio to receive either capecitabine 1250 mg/m(2) bid for 14d (d1-14) plus bevacizumab 7.5 mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m(2) BID for 14d (d1-14), irinotecan 200 mg/m(2) (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). Patients included into this trial are required to consent to the analysis of tumour tissue and blood for translational investigations. In Arm A, treatment escalation from Cape-Bev to CAPIRI-Bev is recommended in case of progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to Cape-Bev is possible after 6 months of treatment or in case of irinotecan-associated toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The primary endpoint is time to failure of strategy (TFS). Secondary endpoints are overall response rate (ORR), overall survival, progression-free survival, safety and quality of life. CONCLUSION: The AIO KRK 0110 trial is designed for patients with disseminated, but asymptomatic mCRC who are not potential candidates for surgical resection of metastasis. Two bevacizumab-based strategies are compared: one starting as single-agent chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and another starting with combination chemotherapy (CAPIRI-Bev) and allowing de-escalation to Cape-Bev and subsequent re-escalation if necessary. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01249638 EudraCT-No.: 2009-013099-38.

Anterior cruciate ligament reconstruction: drilling a femoral posterolateral tunnel cannot be accomplished using an over-the-top step-off drill guide.

The objective of this study was to evaluate the position of a K-wire drilled into the lowest and most shallow position possible in the femoral footprint of the anterior cruciate ligament (ACL) with an over-the-top drill guide and to compare this position in relation to the total length of the femoral footprint. In eight specimens, the K-wire was drilled through the guide from the medial side to mimic the anteromedial portal used during arthroscopy. The distances between the K-wire and the farthest points of the anteromedial (AM) and posterolateral (PL) end of the ACL footprint were measured. The median ACL footprint was 15 mm (range 14-18). The median distance from the K-wire was 5 mm (range 3-8) to the AM end of the footprint and 10 mm (range 9-15) to the PL end of the footprint. The K-wire did not reach the middle of the ACL footprint length in any of the specimens. The posterior border of the articular cartilage on the lateral femoral condyle prevented the drill guide from being placed in a lower and more shallow position. The results of this study showed that a tunnel drilled using an over-the-top drill guide and placed in the lowest and most shallow position possible within the ACL footprint is almost exclusively situated in the AM bundle origin.

[Ears "made of stone" - unusual secondary phenomenon of undersubstituted adrenal insufficiency]. / Ohren "aus Stein" - ungewöhnlicher Begleitbefund aufgrund einer untersubstituierten Nebenniereninsuffizienz.

HISTORY AND CLINICAL FINDINGS: A 69-year-old man was admitted with cough, fever and dyspnea. For years, an adrenal insufficiency has been substituted with low-dose hydrocortisone. The hypotensive and tachycardic patient exhibited remarkable stony hard ears. INVESTIGATIONS: Elevated inflammatory markers and the clinical picture point to a pulmonary focus of infection. Radiographs of the ears show trabecular structures as a sign of true ossification. DIAGNOSIS, TREATMENT AND COURSE: Addisonian crisis due to pulmonary infection was treated successfully with steroids, antibiotics and intravenous fluids. The auricular ossification was interpreted as a secondary phenomenon of undersubstituted adrenal insufficiency. CONCLUSION: Adrenal insufficiency should be considered when auricular ossification is encountered. The pathogenesis of this phenomenon is complex and not well understood.

Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors.

Cellular differentiation entails loss of pluripotency and gain of lineage- and cell-type-specific characteristics. Using a murine system that progresses from stem cells to lineage-committed progenitors to terminally differentiated neurons, we analyzed DNA methylation and Polycomb-mediated histone H3 methylation (H3K27me3). We show that several hundred promoters, including pluripotency and germline-specific genes, become DNA methylated in lineage-committed progenitor cells, suggesting that DNA methylation may already repress pluripotency in progenitor cells. Conversely, we detect loss and acquisition of H3K27me3 at additional targets in both progenitor and terminal states. Surprisingly, many neuron-specific genes that become activated upon terminal differentiation are Polycomb targets only in progenitor cells. Moreover, promoters marked by H3K27me3 in stem cells frequently become DNA methylated during differentiation, suggesting context-dependent crosstalk between Polycomb and DNA methylation. These data suggest a model how de novo DNA methylation and dynamic switches in Polycomb targets restrict pluripotency and define the developmental potential of progenitor cells.

Compartment syndrome of the foot: an experimental approach to pressure measurement and release.

INTRODUCTION: Using a cadaver model and multiple continuous compartment pressure measurement, we sought to determine the pressure distribution in different osseofascial spaces of the foot and determine the quickest and most effective technique of pressure release. MATERIALS AND METHODS: The compartment pressures were measured (in mmHg) in five different osseofascial spaces of each foot. In stepwise manner, warmed saline was injected only into the central compartment only. Three experimental approaches to fasciotomy were studied. RESULTS: We recognized a simultaneous exponential increase of all foot compartments in all experimental models. With a medial fasciotomy technique first, a flexor brevis compartment incision was necessary to release pressures in the central compartments. Following this procedure, pressure was released in the tarsal tunnel and in the intermetatarsal area immediately. Pressure reduction in the central flexor space and in the tarsal tunnel was less effective with a dorsal fasciotomy technique. CONCLUSIONS: There is no pressure increase of a "single" osseofascial space in case of a foot compartment syndrome. If immediate pressure release is required, a medial fasciotomy technique including the central flexors should be favoured.

Testing strategies and follow-up for coeliac disease in a general internal medicine outpatient department from 2000 to 2005.

PRINCIPLES: Coeliac disease (gluten sensitive enteropathy) is a genetically determined disorder with an incidence in the general population that is comparable to type 2 diabetes mellitus. Awareness of this fact and of the often atypical and oligosymptomatic manifestations is only now gaining ground in the medical profession. A high index of suspicion is important in order to minimise diagnostic and therapeutic delay. METHODS: Testing patterns and follow-up for coeliac disease in our institution have been analysed retrospectively for the past five years. The current literature was reviewed with respect to recommendations for clinical practice. RESULTS: A total of 271 patients were tested for coeliac disease over a period of five years. Only in 24 patients were positive results found; after further work-up, the final number of cases with certain or presumed coeliac disease was four. Followup was often difficult, many patients being lost after a single visit. CONCLUSIONS: This study showed that the number of tests ordered in our institution, more often for abdominal than atypical symptoms, has started to increase in the past two years. It also showed that screening tests have found their place in general clinical practice, while the final choice of tests needs to be determined in accordance with available guidelines and local resources. Upper endoscopy with small bowel biopsy remains the gold standard for diagnosis, but its place in follow-up is less certain. Coeliac disease is a disorder for which there is a definite treatment (gluten free diet); if it is left untreated diminished quality of life and potentially serious complications may ensue. Further education of the medical profession regarding coeliac disease, its incidence, presentation and treatment, is clearly indicated..

The added value of ECG-gating for the diagnosis of myocardial infarction using myocardial perfusion scintigraphy and artificial neural networks.

To assess the value of ECG-gating for the diagnosis of myocardial infarction using myocardial perfusion scintigraphy (MPS) and an artificial neural network. A total of 422 patients referred for MPS were studied using a one day (99m)Tc-tetrofosmin protocol. Adenosine stress combined with submaximal dynamic exercise was used. The images were interpreted by one of three experienced clinicians and these interpretations regarding the presence or absence of myocardial infarction were used as the standard. A fully automated method using artificial neural networks was compared with the clinical interpretation. Either perfusion data alone or a combination of perfusion and function from ECG-gated images were used as input to different artificial neural networks. After a training session, the two types of neural networks were evaluated in separate test groups using an eightfold cross-validation procedure. The neural networks trained with both perfusion and ECG-gated images had a 4-7% higher specificity compared with the corresponding networks using perfusion data only, in four of five segments compared at the same level of sensitivity. The greatest improvement in specificity, from 70% to 77%, was seen in the inferior segment. In the septal and lateral segments the specificity rose from 73% to 77% and from 81% to 85%, respectively. In the anterior segment, the increase in specificity from 93% to 94% by adding functional data was not significant. The addition of functional information from ECG-gated MPS is of value for the diagnosis of myocardial infarction using an automated method of interpreting myocardial perfusion images.