Klinikum Fulda

OBJECTIVES: To develop recommendations for the management of adult and paediatric lupus nephritis (LN). METHODS: The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus. RESULTS: Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III-IV(A) or (A/C) (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults. CONCLUSIONS: Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.

PURPOSE Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene ( FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD–positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD–positive AML.

BACKGROUND: The present article is a report of our animal experiments and also of the first clinical results of a new treatment for coronary heart disease using the human growth factor FGF-I (basic fibroblast growth factor) to induce neoangiogenesis in the ischemic myocardium. METHODS AND RESULTS: FGF-I was obtained from strains of Escherichia coli by genetic engineering, then isolated and highly purified. Several series of animal experiments demonstrated the apathogenic action and neoangiogenic potency of this factor. After successful conclusion of the animal experiments, it was used clinically for the first time. FGF-I (0.01 mg/kg body weight) was injected close to the vessels after the completion of internal mammary artery (IMA)/left anterior descending coronary artery (LAD) anastomosis in 20 patients with three-vessel coronary disease. All the patients had additional peripheral stenoses of the LAD or one of its diagonal branches. Twelve weeks later, the IMA bypasses were selectively imaged by intra-arterial digital subtraction angiography and quantitatively evaluated. In all the animal experiments, the development of new vessels in the ischemic myocardium could be demonstrated angiographically. The formation of capillaries could also be demonstrated in humans and was found in all cases around the site of injection. A capillary network sprouting from the proximal part of the coronary artery could be shown to have bypassed the stenoses and rejoined the distal parts of the vessel. CONCLUSIONS: We believe that the use of FGF-I for myocardial revascularization is in principle a new concept and that it may be particularly suitable for patients with additional peripheral stenoses that cannot be revascularized surgically.

Reagent-supported thromboelastometry (TEM) with the ROTEM Whole Blood Haemostasis Analyser is an enhancement of thromboelastography, a method that is increasingly used for the point of care monitoring of acute perioperative bleeding disorders. We investigated the reference ranges of two activated tests (INTEM and EXTEM) and a test analysing specifically the fibrin component of coagulation (FIBTEM) in a multi-centre approach. The reference ranges obtained for the clotting time (CT), clot formation time (CFT), alpha angle (ALP), maximum clot firmness (MCF) and clot lysis parameters were comparable from centre to centre. INTEM: CT equals; 137-246 s, CFT equals; 40-100 s, MCF equals; 52-72 mm. EXTEM: CT equals; 42-74 s, CFT equals; 46-148 s, MCF equals; 49-71 mm. FIBTEM: MCF equals; 9-25 mm. ROTEM whole blood coagulation correlated weakly with a trend towards enhanced coagulation in females compared with males and in advanced age. The repeatability (within-run imprecision) of the results was dependent on the test with the following coefficients of variation: 1-5% (clot firmness, alpha angle), 3-12% (CT, CFT), 6-13% (FIBTEM clot firmness). Citrated blood samples were stable for ROTEM analysis stored within 6 h from drawing. In summary, the data showed that ROTEM thromboelastometry yields consistent values between centres and that providing general orientating reference ranges seems to be possible.

IMPORTANCE: Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. OBJECTIVE: To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection. DESIGN, SETTING, AND PARTICIPANTS: The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013. INTERVENTIONS: Patients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. RESULTS: In total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n = 51), 63 (28-79) years in arm B (n = 60), and 65 (23-83) years in arm C (n = 127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P < .001). The response rate for arm B was 60% (complete, 10%; partial, 50%), which is higher than the 43.3% for arm C. In arm B, 36 of 60 patients (60%) proceeded to surgery. The median overall survival was 31.3 months (95% CI, 18.9-upper level not achieved) for patients who proceeded to surgery and 15.9 months (95% CI, 7.1-22.9) for the other patients. CONCLUSIONS AND RELEVANCE: Patients with limited metastatic disease who received neoadjuvant chemotherapy and proceeded to surgery showed a favorable survival. The AIO-FLOT3 trial provides a rationale for further randomized clinical trials. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00849615.

The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.

RATIONALE: Indacaterol is the first once-daily, long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To demonstrate greater efficacy of indacaterol versus placebo on FEV(1) at 24 hours post dose (trough) after 12 weeks, to compare efficacy with placebo and tiotropium, and to evaluate safety and tolerability over 26 weeks. MEASUREMENTS: Patients with moderate-to-severe COPD were randomized to double-blind indacaterol 150 or 300 microg or placebo, or open-label tiotropium 18 microg, all once daily, for 26 weeks. The primary efficacy outcome was trough FEV(1) at 12 weeks. Additional analyses (not adjusted for multiplicity) included transition dyspnea index (TDI), health status (St George's Respiratory Questionnaire [SGRQ]), and exacerbations. Serum potassium, blood glucose, and QTc interval were measured. RESULTS: A total of 1,683 patients (age, 63.3 yr; post-bronchodilator FEV(1), 56% predicted; FEV(1)/FVC, 0.53) were randomized to the four treatment arms. Trough FEV(1) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium (all P < 0.001 vs. placebo). At Week 26, for indacaterol 150/300 microg, respectively, versus placebo, TDI increased (1.00/1.18, P < 0.001) and SGRQ total score decreased (-3.3/-2.4, P < 0.01); corresponding results with tiotropium were 0.87 (P < 0.001) for TDI and (-1.0, P = not significant) for SGRQ total score. The incidence of adverse events, low serum potassium, high blood glucose, and prolonged QTc interval was similar across treatments. CONCLUSIONS: Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD. Clinical trial registered with clinicaltrials.gov (NCT 00463567).

OBJECTIVE: To evaluate the new magnetic resonance imaging (MRI) method of dynamic MRI with fast imaging in the diagnosis of sacroiliitis among patients with spondylarthropathy. METHODS: Fifteen patients with a history of inflammatory back pain without radiographic evidence of grade II or greater sacroiliitis (group 1), 25 patients with definite ankylosing spondylitis (group 2), and 12 patients with noninflammatory spinal pain (controls) (group 3) were examined. Dynamic MRI with fast imaging was performed after intravenous bolus injection of the contrast agent gadolinium-diethylenetriamine pentaacetic acid. The degree of enhancement was graded as representing acute sacroiliitis, latent sacroiliitis, or no sacroiliitis. RESULTS: Acute sacroiliitis was detected in 22 of 30 sacroiliac (SI) joints in group 1 patients and in 27 of 50 SI joints in group 2 patients; latent sacroiliitis was seen in 25 of 80 SI joints in patients from groups 1 and 2. No group 3 patient was found to have sacroiliitis. CONCLUSION: Early sacroiliitis can be demonstrated by dynamic MRI in spondylarthropathy patients in whom abnormalities are not revealed by conventional radiography.

OBJECTIVE: A study was undertaken to evaluate clinical and procedural factors associated with outcome and recanalization in endovascular stroke treatment (EVT) of basilar artery (BA) occlusion. METHODS: ENDOSTROKE is an investigator-initiated multicenter registry for patients undergoing EVT. This analysis includes 148 consecutive patients with BA occlusion, with 59% having received intravenous thrombolysis prior to EVT. Recanalization (defined as Thrombolysis in Cerebral Infarction [TICI] score 2b-3) and collateral status (using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral grading system) were assessed by a blinded core laboratory. Good (moderate) outcome was defined as a modified Rankin Scale score of 0 to 2 (0-3) assessed after at least 3 months (median time to follow-up = 120 days). RESULTS: Thirty-four percent had good and 42% had moderate clinical outcome; mortality was 35%. TICI 2b-3 recanalization was achieved by 79%. Age, hypertension, National Institutes of Health Stroke Scale scores, collateral status, and the use of magnetic resonance imaging prior to EVT predicted clinical outcome, the latter 3 remaining independent predictors in multivariate analysis. Independent predictors of recanalization were better collateral status and the use of a stent retriever. However, recanalization did not significantly predict clinical outcome. INTERPRETATION: Beside initial stroke severity, the collateral status predicts clinical outcome and recanalization in BA occlusion. Our data suggest that the use of a stent retriever is associated with high recanalization rates, but recanalization on its own does not predict outcome. The role of other modifiable factors, including the choice of pretreatment imaging modality and time issues, warrants further investigation.

BACKGROUND AND AIMS: Gastro-oesophageal reflux disease (GERD) can be associated with a variety of extra-oesophageal disorders (EED) such as chronic cough, asthma, laryngeal disorder or chest pain. The aim of the study was to estimate and compare the prevalence of EED in a population with symptomatic GERD presenting as either erosive reflux disease (ERD) or non-erosive reflux disease (NERD). METHODS: Baseline data were collected from a prospective, multicentre, open cohort study (ProGERD) in which patients will be followed for 5 years after initial treatment with esomeprazole. Within the framework of this trial, all patients underwent gastroscopy and filled out a questionnaire designed to assess EED. The influence of potential prognostic factors on the prevalence of EED was analysed by multivariate (stepwise logistic regression) analysis. RESULTS: 6215 patients (3303 male, 2912 female; mean age 54 years) presenting with heartburn were included. EED was detected in 32.8% of all patients. The proportion was significantly higher (P = 0.0002) in ERD patients (34.9%) than in NERD patients (30.5%). As judged from the multivariate analysis, female gender, age, oesophagitis of LA grade C/D, duration of GERD disease greater than 1 years and smoking were significantly associated with EED. ERD patients with oesophagitis of LA grade A or B did not have a significantly higher risk of EED than patients with NERD. CONCLUSIONS: Patients with GERD have a high probability of experiencing EED, which may be associated with a number of prognostic factors such as duration and severity of GERD. Extra-oesophageal disorders are slightly, but statistically, more prevalent in ERD than in NERD patients.

OBJECTIVES/HYPOTHESIS: To validate the endonasal surgical approach to frontal sinus in inflammatory sinus disease, trauma, and selective tumor surgery, and to define the role of external approaches to the frontal sinus. Endonasal frontal sinusotomy can range from endoscopic removal of obstructing frontal recess cells or uncinate process to the more complex unilateral or bilateral removal of the frontal sinus floor as described in the Draf II-III drainage procedures. In contrast, the osteoplastic frontal sinusotomy remains the "gold standard" for external approaches to frontal sinus disease. METHODS: A retrospective review of 1286 patients undergoing either endonasal or external frontal sinusotomy by the authors at four university teaching programs from 1977. Prior author reports were updated and previously unreported patient series were combined. RESULTS: Six hundred thirty-five patients underwent type I frontal sinusotomy, 312 type II sinusotomy, and 156 type III sinusotomy. A successful result was seen in these groups, 85.2% to 99.3%, 79% to 93.3%, and 91.5% to 95%, respectively. External frontal sinusotomy or osteoplastic frontal sinusotomy was successfully performed in 187 of 194 patients. Clinical symptoms, endoscopic findings, computed tomography, and magnetic resonance image scanning, and reoperation rate measured postoperative success. CONCLUSIONS: A stepwise approach to the surgical treatment of frontal sinusitis, trauma, and selective benign tumors yields successful results as defined by specific criteria which vary from 79% to 97.8%. The details of specific techniques are discussed, essential points emphasized, and author variations noted.

AIMS: To determine the strength of evidence for preoperative statin use for prevention of adverse postoperative outcomes in patients undergoing cardiac surgery. METHODS AND RESULTS: After literature search in major databases, 19 studies were identified [three RCT (randomized prospective clinical trials), 16 observational] that reported outcomes of 31 725 cardiac surgery patients with (n = 17 201; 54%) or without (n = 14 524; 46%) preoperative statin therapy. Outcomes that were analysed included early all-cause mortality (30-day mortality), myocardial infarction (MI), atrial fibrillation (AF), stroke and renal failure. Odds ratio (OR) with 95% confidence intervals (95%CI) were reported using fixed or random effect models and publication bias was assessed. Preoperative statin therapy resulted in a 1.5% absolute risk reduction (2.2 vs. 3.7%; P < 0.0001) and 43% odds reduction for early all-cause mortality (OR 0.57; 95%CI: 0.49-0.67). A significant reduction (P < 0.01) in statin pretreated patients was also observed for AF (24.9 vs. 29.3%; OR 0.67, 95%CI: 0.51-0.88), stroke (2.1 vs. 2.9%, OR 0.74, 95%CI: 0.60-0.91), but not for MI (OR 1.11; 95%CI: 0.93-1.33) or renal failure (OR 0.78, 95%CI: 0.46-1.31). Funnel plot and Egger's regression analysis (P = 0.60) excluded relevant publication bias. CONCLUSION: Our meta-analysis provides evidence that preoperative statin therapy exerts substantial clinical benefit on early postoperative adverse outcomes in cardiac surgery patients, but underscores the need for RCT trials.

AIMS: To determine the impact of gastro-oesophageal reflux disease (GERD) on the quality of life, to assess changes in the quality of life during treatment with esomeprazole and to define factors that can predict these changes. METHODS: Patients with GERD (n=6215) were included in a prospective cohort study (ProGERD). All patients underwent endoscopy and received esomeprazole. At baseline and after 2 weeks of treatment, symptoms and quality of life were assessed. Factors that influenced changes in the quality of life were determined by multiple regression analyses. RESULTS: At baseline, the quality of life in GERD patients was lower than that in the general population, and was similar to that in patients after acute coronary events. No differences in symptoms or quality of life were observed between the subgroups of patients with non-erosive GERD, erosive GERD and Barrett's oesophagus. After treatment with esomeprazole, the symptoms and quality of life were improved in all subscales within 2 weeks (P<0.001). The mean score of the disease-specific quality of life instrument (Quality of Life in Reflux and Dyspepsia Patients) increased from 4.6 to 6.2 points, representing a highly relevant clinical improvement. The generic quality of life (SF-36) reached levels similar to those in the general population, but, again, no difference was found between the three different subgroups of GERD patients. The main factors associated with an improvement in the quality of life after treatment were symptom relief, severe erosive reflux disease, absence of extra-oesophageal disorders, avoidance of non-steroidal anti-inflammatory drug intake and positive Helicobacter pylori status. CONCLUSIONS: GERD causes a significant impairment in the quality of life that can be attenuated or normalized within a time period as short as 2 weeks by treatment with esomeprazole. These findings were similar across the whole GERD patient spectrum.

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

BACKGROUND: Glial fibrillary acidic protein (GFAP) is a biomarker candidate indicative of intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke. GFAP is released rapidly in the presence of expanding intracerebral bleeding, whereas a more gradual release occurs in ischemic stroke. In this study the diagnostic accuracy of plasma GFAP was determined in a prospective multicenter approach. METHODS: Within a 1-year recruitment period, patients suspected of having acute (symptom onset<4.5 h before admission) hemispheric stroke were prospectively included into the study in 14 stroke centers in Germany and Switzerland. A blood sample was collected at admission, and plasma GFAP was measured by use of an electrochemiluminometric immunoassay. The final diagnosis, established at hospital discharge, was classified as ICH, ischemic stroke, or stroke mimic. RESULTS: The study included 205 patients (39 ICH, 163 ischemic stroke, 3 stroke mimic). GFAP concentrations were increased in patients with ICH compared with patients with ischemic stroke [median (interquartile range) 1.91 μg/L (0.41-17.66) vs 0.08 μg/L (0.02-0.14), P<0.001]. Diagnostic accuracy of GFAP for differentiating ICH from ischemic stroke and stroke mimic was high [area under the curve 0.915 (95% CI 0.847-0.982), P<0.001]. A GFAP cutoff of 0.29 μg/L provided diagnostic sensitivity of 84.2% and diagnostic specificity of 96.3% for differentiating ICH from ischemic stroke and stroke mimic. CONCLUSIONS: Plasma GFAP analysis performed within 4.5 h of symptom onset can differentiate ICH and ischemic stroke. Studies are needed to evaluate a GFAP point-of-care system that may help optimize the prehospital triage and management of patients with symptoms of acute stroke.

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care.

OBJECTIVE: To evaluate the intraoperative and late complications of osteoplastic sinus surgery with fat obliteration with long-term magnetic resonance imaging (MRI) follow-up. METHODS: The operative records of all patients who underwent osteoplastic frontal sinus surgery with fat obliteration between January 1, 1986 and December 31, 1997 were reviewed and the postoperative clinical course and magnetic resonance imaging (MRI) scans were analyzed if available. MRI analyses revealed that changes in the distribution of fatty and fibrous tissue, the development of necrosis or oil cysts, recurrences, inflammatory complications, and mucoceles were time-dependent occurrences. RESULTS: Eighty-two operative records were evaluated and 59 patients were followed 1 to 12 years after surgery. Eighty-six MRI scans in 51 patients were available for analysis. The most frequent intraoperative complications were exposure of orbital fat (19.5%), unintentional fracture of the anterior wall (19.5%), incorrect placement of the anterior wall (17%), and dural injury (9.8%). Persistent changes of the frontal contour (embossment, depression) occurred in 10.2% and the esthetic result was unfavorable in 5.1% of the cases. Mucoceles could be detected in 5 of 51 cases (9.8%). The amount of adipose tissue detectable in the last scan was less than 20% in the majority of cases (53%), and more than 60% in only 18% of the cases. The amount of adipose tissue decreased significantly with time (the median half-life was 15.4 mo). CONCLUSIONS: Osteoplastic frontal sinus surgery with fat obliteration is very useful and successful in patients in whom the frontal sinus is not accessible via an endonasal approach or the natural drainage cannot be reestablished. MRI is currently the most valuable diagnostic tool to evaluate the frontal sinus after obliteration with adipose tissue. The method has some limitations with regard to detection of small recurrent mucoceles and differentiating vital adipose tissue from fat necroses in the form of oil cysts. In these difficult cases, long-term MRI follow-up is necessary.

OBJECTIVES: Gastroesophageal reflux disease can be divided into three categories: nonerosive GERD (NERD), erosive GERD (ERD), and Barrett's esophagus. A shift among these categories rarely occurs. The aim of the present study was to elucidate potential patient-associated risk factors associated with ERD. METHODS: A total of 6,215 patients with troublesome heartburn were recruited to a large, prospective, multicenter open cohort study comprising an initial treatment phase and a 5-yr follow-up phase. Each center planned to recruit an equal number of patients with NERD and ERD. All patients underwent an interview based on standardized questionnaires, a physical examination, and endoscopy with biopsies. Data were analyzed by multiple logistic regression analysis. RESULTS: Risk factor analysis was performed on 5,289 patients (NERD: n = 2,834; ERD: n = 2,455), which was the intent-to-treat population excluding patients with suspected/proven complicated reflux disease. Stepwise regression analysis identified the following independent predictors of ERD: male gender, overweight, regular use of alcohol, a history of GERD >1 yr, and smoker or ex-smoker. A higher level of education and a positive Helicobacter pylori (H. pylori) status were associated with a lower risk of ERD. CONCLUSIONS: Some patient-associated factors increase the risk of erosive esophagitis as opposed to nonerosive reflux disease. However, no single factor or combination of factors is capable of predicting mucosal damage with clinically sufficient certainty. Thus, endoscopy is still required in all GERD patients if valid information on the state of the esophageal mucosa is needed.

The new IASP diagnostic criteria for complex regional pain syndrome (CRPS) (aka “the Budapest Criteria”3; Table 1) have improved the diagnostic specificity for CRPS while maintaining good sensitivity. Internationally, these criteria are now in common use. The IASP CRPS Special Interest Group convened a workshop of CRPS experts in Valencia/Spain in September 2019 to review perceived ambiguities in the diagnostic text and issues identified in applying these criteria in both the research and clinical contexts. After this review, workshop attendees discussed and reached a consensus regarding adaptations to the diagnostic taxonomy text. This process resulted in pragmatic updates to CRPS assessment instructions and the associated text in the IASP taxonomy. The wording of the diagnostic criteria themselves was not altered so as to avoid invalidating the criteria. Table 1 - New IASP diagnostic criteria for complex regional pain syndrome (“Budapest criteria”2) (A–D must apply). A. The patient has continuing pain which is disproportionate to any inciting eventB. The patient reports at least one symptom in 3 or more of the categoriesC. The patient displays at least one sign in 2 or more of the categoriesD. No other diagnosis can better explain the signs and symptoms □□□□ Category Symptom (the patient reports a problem) Sign (you can see or feel a problem on examination) 1 “Sensory” Allodynia (to light touch/brush stoke and/or temperature sensation and/or deep somatic pressure and/or joint movement), and/or hyperalgesia (to pinprick) Reported hyperesthesia also qualifies as a symptom□ □ 2 “Vasomotor” Temperature asymmetry and/or skin colour changes and/or skin colour asymmetry □ □ 3 “Sudomotor/oedema” Oedema and/or sweating changes and/or sweating asymmetry □ □ 4 “Motor/trophic” Decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair/nail/skin) □ □ Adapted from https://www.rcplondon.ac.uk/guidelines-policy/complex-regional-pain-syndrome-adults with permission. The results of this meeting were also used as a justification to update the new ICD-11 text regarding CRPS and its diagnosis. This focus on incorporating changes into the ICD-11 was triggered by the current absence of plans to further update the existing CRPS IASP taxonomy. A consensus proposal was sent to WHO for amending ICD-11 CRPS-related text.5 WHO has already accepted some adaptations (marked with # below). Here, we summarise all the proposed changes. The proposed wording of all new text for CRPS in the ICD-11 development version is attached in the web appendix (Online appendix, available at http://links.lww.com/PAIN/B358). Changes concern 3 areas: (a) diagnostic parenting under ICD-11, (b) CRPS subtypes, and (c) the diagnostic procedure. (a) Diagnostic parenting under ICD-11: The current first parent classification of CRPS in the ICD-11 is “focal or segmental autonomic disorder” (ICD-11 BD8A). We consider this classification to be a mistake based on the historic misunderstanding of CRPS as primarily an autonomic disorder. The past 3 decades of CRPS experimental and clinical research clearly demonstrate that this is not the case. We therefore have proposed that the correct parent is “chronic primary pain.” This proposal is also supported by the American Autonomic Society. (b) CRPS subtypes: (i) CRPS II as defined in the IASP criteria is associated with discrete peripheral nerve damage as indicated by neurological examination, electrodiagnostic testing, or other quasi-objective testing. We now clarify that the diagnostic signs of CRPS II must extend beyond any identified injured nerve territory. Nerve lesion itself may cause separate CRPS-concomitant symptoms and signs, including neuropathic pain, paraesthesias, numbness, and autonomic dysfunction restricted to the injured nerve territory. CRPS II should therefore not be classed as a neuropathic pain condition in accordance with current criteria #.4 Diagnostic signs of CRPS I (without discrete nerve damage) and II are identical. The clinical relevance and implications of subgrouping CRPS into these 2 subtypes remain unclear at present.# (ii) We have introduced a third CRPS subtype and have also modified the description of the current diagnostic label CRPS Not Otherwise Specified (NOS) to minimise any confusion with using this latter term. Patients previously documented as having fully met CRPS criteria (either CRPS I or CRPS II, Table 1) but who currently display CRPS features insufficient to fully meet the diagnostic criteria should be classified into the new CRPS subtype, “CRPS with Remission of Some Features.” These patients should not be classified as having CRPS NOS. Notably, a reduction in the number of CRPS diagnostic signs and symptoms does not necessarily constitute an improvement in the lived experience of CRPS; these patients may not have improved pain nor are they usually free of all CRPS-related signs and symptoms. CRPS with Remission of Some Features is a third formal subtype of CRPS, which by necessity overlaps with either CRPS I or II. At what point CRPS changes from being an ongoing condition potentially requiring continued clinical management (ie, CRPS with Remission of Some Features) to being considered resolved is a topic that will need to be addressed in future research. (iii) The term “CRPS-NOS” in the current IASP criteria has been retained exclusively for application to patients who have never been documented to fulfil the new IASP CRPS criteria (Table 1). That is, they now display some but not all features of CRPS required for formal diagnosis, and no other diagnosis better explains the clinical features. (iv) Warm/cold CRPS and early/persistent CRPS are overlapping presentations that are clinically observed. The group did not consider there to be sufficient evidence yet to create formal CRPS subgroups according to these features. However, there was consensus that research and clinical reports should include this information when describing individual patients, study inclusion criteria, or research participants (clinical experience and research suggest that a substantial proportion of individuals who develop acute CRPS improve or resolve, with a smaller subgroup that fails to substantially improve even with standard care. This transition of CRPS to a more prolonged and difficult to manage condition seems to occur during the first 12-18 months after onset, although there is no widely accepted demarcation point for this distinction. The word “persistent” is used here as a descriptive term for this subgroup of prolonged and intractable CRPS. Use of the alternative term “chronic” is preferred by some CRPS experts. However, we note that the term “chronic” is also broadly used across all pain conditions to refer to pain lasting more than 3 months after tissue injury to distinguish it from “acute” pain. To avoid incorrect implications of the word ‘chronic’ to be understood as a >3 months' pain duration in patients with CRPS, the word “persistent” is used to refer to such prolonged CRPS. For clarity, ‘persistent’ does not necessarily indicate the condition will persist indefinitely—a minority of patients with persistent CRPS will naturally improve).# (c) The diagnostic procedure ICD-11 includes additional text to clarify diagnostic terms and procedures. The purpose of that text, pragmatic clarification of the diagnostic process, bears resemblance to that of the IASP taxonomy and associated text (https://www.iasp-pain.org/files/Content/ContentFolders/Publications2/ClassificationofChronicPain/Part_II-A.pdf), which is not currently being updated. This ICD-11 supplemental text has now been updated for CRPS. The following key points are now all implemented (except viii): (i) All patients should be asked systematically about all symptoms listed in the criteria at each formal diagnostic evaluation, even if they have not previously reported certain symptoms. This is recommended because CRPS signs and symptoms are clinically observed to fluctuate over time.# (ii) Clarification of the terms “asymmetry” and “changes” as used in the current IASP CRPS criteria (Table 1): For unilateral CRPS, assess asymmetry by comparing the affected side to the unaffected side. For (much rarer) bilateral and symmetrical CRPS, assess changes in the affected limbs relative to an unaffected limb in the patient or to the limbs of a typical healthy individual. Asymmetry is based on clinical judgment only, rather than any prespecified criteria.# (iii) For evaluating possible spreading of CRPS beyond a single limb, the full diagnostic criteria must be applied to each limb individually. True spreading of CRPS is defined as CRPS that meets full new IASP/ICD-11 diagnostic criteria (Table 1) for multiple limbs—extension of pain alone to other limbs, which is not unusual, in the absence of other CRPS features is not formally considered to be spreading CRPS.# (iv) Hyperalgesia (note that other definitions of hyperalgesia and allodynia exist for use in other chronic pain conditions)4 is a clinical observation in which a painful stimulus evokes more pain than it normally would. The group recommended standard testing for hyperalgesia by comparing the response to a single pinprick applied in the center of the most affected region to the response to an identical pinprick at the corresponding location on the unaffected limb, or an equivalent control site in the case of bilateral CRPS. The test is positive if reported pain is more intense or lasts longer on the affected limb.# (v) Allodynia is a clinical observation in which pain is evoked by a stimulus that is not normally painful. Stimuli used in clinical allodynia assessment can include light touch, vibration, cool or warm temperature, deep tissue or joint pressure in the affected area, or joint movement. Only one of these is required to confirm whether allodynia is present or absent. Suggested clinical assessment procedures are now outlined as below in the revised text: “allodynia to light touch as tested by light manual touch (or brush); allodynia to tissue pressure as assessed by pressure applied to a joint or other tissue using the evaluator's finger with just enough pressure to make the fingernail bed of the evaluator blanch (turn white) (equating to a pressure of below 100g/cm2, and a load of no more than 500 g; this is substantially less than the pressure recommended for the examination of tender points [4 kg/cm2]),6 allodynia to vibration as assessed using a graded tuning fork over bony prominence on the affected limb; allodynia to cool or warm temperature.”# (vi) Temperature asymmetry is assessed in the affected area and compared with the corresponding area on the contralateral extremity, or a suitable control site in the case of bilateral CRPS. Such asymmetry should be obvious to the touch of the dorsum of the hand of the examiner.# (vii) Obvious color asymmetry of a regional nature (ie, hand, foot, knee, or larger region). Please specify the nature of the color changes, eg, red, blue, pale, or mottled.# (viii) A rare limitation of the CRPS diagnostic criteria is noted: In some cases, an objective CRPS diagnostic sign such as color or temperature asymmetry may be observed by the examiner without the patient reporting the corresponding subjective symptom. This may occur, for example, because the patient cannot feel a temperature change, or a color change is difficult to see (this similarly applies to swelling). This situation may result in a patient's diagnostic symptom-category count dropping below the threshold of 3 required for formal diagnosis, despite the patient objectively displaying sufficient clinical features for diagnosis. In these instances, because of the statistical methods on which the IASP criteria were developed and validated, the obvious common-sense approach that ‘signs override symptoms’ (ie, a sign automatically generates a tick also as a symptom) cannot automatically apply. A related challenge arises also where a patient has impaired vision and is therefore unable to ascertain objective color changes; in these rare cases, a pragmatic solution must be found in which common sense prevails. It is hoped that the modified ICD-11 text clarifies important pragmatic aspects of CRPS assessment and diagnosis, and that it will enhance usability of these criteria in both clinical and research settings. All changes and clarifications marked with a # above have already been incorporated into the ICD-11 CRPS text and should be applied in the CRPS diagnostic process immediately. Future research should (1) clarify whether CRPS type 1 and 2 are indeed separate entities or are better merged; (2) assess whether introduction of further subgroups such as warm-cold and early-persistent CRPS is useful (eg, for predicting treatment responses); (3) ascertain the utility of biomarkers for supporting the clinical CRPS diagnosis1; and (4) define “resolved CRPS.” Conflict of interest statement The authors have no conflicts of interest to declare. Appendix A. Supplemental digital content Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/B358. Supplemental video content A video abstract associated with this article can be found at http://links.lww.com/PAIN/B329.

Technical aspects of intraluminal pH-metry in man: current status and recommendationsIn April 1986 a discussion meeting entitled 'Technical aspects of intraluminal pH-metry using pH-electrodes in man' was held in Zurich, Switzerland.The meeting brought together specialists in theoretical aspects of pH-recording, design and manufacture of equipment, and clinical application of this technique.The aim was to define the actual level of knowledge of pH monitoring in the upper gastrointestinal tract and to provide recommendations for its practical use.In view of the increasing use of intraluminal pH-metry it was considered timely to hold a discussion with the focus primarily on equipment and experimental design because under- standing these factors is essential for application of pH-metry to research and routine clinical investigation.The meeting was organised in a format designed to maximise discussion and arrive at a consensus view.Before the meeting, participants submitted up to three concise statements on assigned topics, which were then precirculated to all 41 delegates.Fifty nine topics ranging from 'Interference of external factors with pH-measurements -temperature' to 'Specific problems of duodenal pH-metry -normal values' were addressed.There were no formal presentations and the entire meeting was devoted to discussion leading to modification, addition or replacement of these statements.Finally, delegates voted (agree, disagree, no opinion) on all statements and on the overall importance of a particular topic.These statements form the basis of this text with the voting being used to define the balance and emphasis of the article.Thus, the purpose of this article is to reflect the conclusions of the meeting and to incorporate a series of precise and unambiguous recommendations.As such certain of the statements may appear more dogmatic than in a conventional review article. Equipment pH-ELECTRODEIntraluminal pH can be measured by either a glass, plastic or ISFET (ion sensitive field effect transistor) combination electrode (containing both sensing and reference elements) or a unipolar (sensing electrode alone) monocrystalline antimony electrode connected to a pH-meter via cable.Combination glass telemetry capsules are also available which avoid potential problems associated with the cable but are more susceptible to errors caused by electromagnetic fields.Combination glass electrodes predominate'3 although monocrystalline antimony electrodes are being used increasingly for oesophageal pH-metry.4Currently, combination glass 1177