Proximal ulna non-union: treatment concept and postoperative outcome.

PURPOSE: Non-union of the proximal ulna is a serious complication after surgical treatment of olecranon and complex elbow fractures, frequently leading to poor functional outcome. To date, there is a lack of data regarding optimal treatment strategies and functional outcome parameters after surgical revision. METHODS: From 02/2010 to 12/2018, 31 patients undergoing surgical treatment of proximal ulna non-union could be included. Follow-up period was seven years (SD 2.5 years). All patients were clinically assessed using a clinical assessment tool set and standard elbow scores (MEPS, OES, DASH score). All complications and unplanned revision surgeries were recorded and all radiographic material was analyzed. RESULTS: Initial non-union procedures were performed at an average of 6.6 months (SD 3 months) after the index procedures. Those included the use of autologous spongiosa graft in all patients and concomitant compression re-osteosynthesis in 28 patients. Radiological consolidation was achieved in all patients. Overall, patients achieved a good to fair functional outcome with Mayo elbow performance score measuring 78.5 (SD 9.1), DASH score 34.7 (SD 14.4), and Oxford elbow score 31.2 (SD 6.6) points. Initial malreduction/implant-malposition could be identified as a main reason for the occurrence of the non-union. Furthermore, inferior postoperative outcome was detected in patients > 60 years and BMI > 30 kg/m2. CONCLUSION: Using a standardized protocol, bony union and acceptable functional outcomes can be achieved in proximal ulna non-unions. However, surgeons should be aware of potential risk factors and proper initial fracture reduction as key to achieve sufficient bone healing.

[Preparing for a pandemic]. / Vorbereitungen auf eine pandemische Welle.

On 16 March 2020 the government of Bavaria declared a state of emergency due to the coronavirus disease 2019 (COVID-19) pandemic. This confronted all clinics with completely new and difficult challenges. In accordance with the official requirements, pandemic officers were appointed at the Kempten Clinic and a clinical management team was established. It was important to keep a relevant proportion of employees off duty at all times, and thus to have a constant reserve available in the event of expected infection-related absences of physicians and nurses. These structural changes were complemented by staff briefings and the creation of a training program on the subject of COVID-19. Within a very short time, algorithms were designed and defined how to manage patients presenting in the hospital or in the emergency room. The surgical program was limited to operations that could not be postponed, such as extrauterine pregnancy or adnexal torsion, and oncological diagnoses without the possibility of primary systemic therapy. In the case of breast cancer, however, therapy was started in all cases in which primary systemic therapy (PST), whether cytotoxic or endocrinological, appeared possible and indicated. As of 1 April 2020, more than 50% of the usable beds in the Kempten Clinic were empty. The utilization of the intensive care unit had also been reduced so that higher numbers of patients requiring artificial respiration could have been cared for at any time.

Improved treatment outcome and lower skin toxicity with intensity-modulated radiotherapy vs. 3D conventional radiotherapy in anal cancer.

PURPOSE: Radiochemotherapy is the standard treatment for anal carcinoma (ACa). Intensity-modulated radiotherapy (IMRT) has been introduced, allowing focused irradiation of the tumor area. Whether physical benefits of IMRT translate to clinical benefits has not been sufficiently demonstrated. METHODS: We retrospectively reviewed data from 82 patients with newly diagnosed ACa. Patients treated with IMRT were compared with previous patients treated with conventional three-dimensional computational radiotherapy (3D-CRT). The influence of IMRT on complete remission and acute and chronic side effects was analyzed in univariate and multivariate analyses. RESULTS: 39/40 patients treated with IMRT were in complete remission after 1 year compared to 31/39 patients treated with 3D-CRT (p = 0.014). Multivariate analysis confirmed tumor T stage as well as lack of IMRT treatment as risk factors for persistent tumor at 6 months. No significant benefits of IMRT were apparent at later timepoints (median follow up 52 months, IQR: 31.5-71.8 months). Patients treated with IMRT had a significantly lower degree of skin toxicity (median 2 vs. 3 in a scale ranging from 0 to 3, p = 0.00092). Rates of hematological toxicity/proctitis were not reduced and rates of acute diarrhea increased (p = 0.034). Median length of hospitalization tended to be shorter in patients treated with IMRT (n. s.). CONCLUSION: We present a real-world experience of shifting radiation technique from conventional 3D-CRT to IMRT. IMRT patients had better tumor control at 1 year and lower degrees of skin toxicity. Our data indicate that IMRT can enable therapies with lower side effects with equal or better oncological results for patients with ACa.

Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2.

BACKGROUND: A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure. METHODS: The long-term effects of EVE on renal function (∼4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5 mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10 mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3 months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS: A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88 mL/min/1.73 m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests. CONCLUSIONS: The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients.ClinicalTrials.gov identifiers NCT00789828 and NCT00790400.

Renal angiomyolipoma in patients with tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increase disease Awareness.

BACKGROUND: Renal angiomyolipoma occurs at a high frequency in patients with tuberous sclerosis complex (TSC) and is associated with potentially life-threatening complications. Despite this frequency and severity, there are no large population-based cohort studies. Here we present baseline and follow-up data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with an aim to provide detailed clinical characteristics of renal angiomyolipoma among patients with TSC. METHODS: Patients of any age with a documented clinic visit for TSC within 12 months or who were newly diagnosed with TSC before participation in the registry were eligible. Data specific to renal angiomyolipoma included physical tumour characteristics (multiple, bilateral, lesion size and growing lesions), clinical signs and symptoms, and management. The effects of age, gender and genotype on the prevalence of renal angiomyolipoma were also evaluated. RESULTS: Renal angiomyolipoma was reported in 51.8% of patients at baseline, with higher frequency in female patients (57.8% versus 42.2%). The median age at diagnosis was 12 years. Prevalence of angiomyolipoma was higher in patients with TSC2 compared with TSC1 mutations (59.2% versus 33.3%, P < 0.01). Of the 1031 patients with angiomyolipoma at baseline, multiple lesions were reported in 88.4% and bilateral in 83.9% of patients, while the size of angiomyolipoma was >3 cm in 34.3% of patients. Most patients were asymptomatic (82%). Frequently reported angiomyolipoma-related symptoms included bleeding, pain, elevated blood pressure and impaired renal function. Embolization and mammalian target of rapamycin inhibitors were the two most common treatment modalities. CONCLUSIONS: The TOSCA registry highlights the burden of renal angiomyolipoma in patients with TSC and shows that renal manifestations are initially asymptomatic and are influenced by gender and genotype. Furthermore, the occurrence of significant problems from angiomyolipoma in a minority of younger patients suggests that surveillance should begin in infancy or at initial diagnosis.

Effect of cocoa on the brain and gut in healthy subjects: a randomised controlled trial.

Dark chocolate is claimed to have effects on gastrointestinal function and to improve well-being. This randomised controlled study tested the hypothesis that cocoa slows gastric emptying and intestinal transit. Functional brain imaging identified central effects of cocoa on cortical activity. Healthy volunteers (HV) ingested 100 g dark (72 % cocoa) or white (0 % cocoa) chocolate for 5 d, in randomised order. Participants recorded abdominal symptoms and stool consistency by the Bristol Stool Score (BSS). Gastric emptying (GE) and intestinal and colonic transit time were assessed by scintigraphy and marker studies, respectively. Combined positron emission tomography-computed tomography (PET-CT) imaging assessed regional brain activity. A total of sixteen HV (seven females and nine males) completed the studies (mean age 34 (21-58) years, BMI 22·8 (18·5-26·0) kg/m2). Dark chocolate had no effect on upper gastrointestinal function (GE half-time 82 (75-120) v. 83 (60-120) min; P=0·937); however, stool consistency was increased (BSS 3 (3-5) v. 4 (4-6); P=0·011) and there was a trend to slower colonic transit (17 (13-26) v. 21 (15-47) h; P=0·075). PET-CT imaging showed increased [18F]fluorodeoxyglucose (FDG) in the visual cortex, with increased FDG uptake also in somatosensory, motor and pre-frontal cortices (P<0·001). In conclusion, dark chocolate with a high cocoa content has effects on colonic and cerebral function in HV. Future research will assess its effects in patients with functional gastrointestinal diseases with disturbed bowel function and psychological complaints.

[The acid pocket - a novel target for the treatment of gastro-esophageal reflux disease]. / Die Acid Pocket: ein neues Ziel für die Behandlung der gastroösophagealen Refluxkrankheit.

Increased acid reflux after meals is a key feature of gastro-esophageal reflux disease (GERD) and is the most important cause for patient symptoms, particularly heartburn and acid regurgitation. Chronic acid exposure also predisposes to associated pathologies including reflux esophagitis, esophageal stricture, Barrett's esophagus, and Barrett's carcinoma (esophageal adenocarcinoma). The severity of esophageal symptoms and mucosal damage is related to two key factors, (i) the acidity of the refluxate, which depends primarily on the gastric secretory output and its distribution within the stomach, and (ii) the frequency and duration of reflux events which depends on the efficacy of the reflux barrier at the gastro-esophageal junction and the esophageal clearance function. The concept of the acid pocket is an attempt to bring these two factors into a unified patho-mechanism.The acid pocket describes an area of unbuffered, highly acidic, gastric secretion in the proximal stomach adjacent to the esophago-gastric junction (GEJ) which forms in the postprandial period and is the source of acid refluxate into the esophagus. It is observed both in healthy individuals as well as in reflux patients. However, the presence of a hiatus hernia and/or a weak lower esophageal sphincter in patients allows the acid pocket to encroach on the gastro-esophageal junction. This results in very high acid exposure of the squamous epithelium of the distal esophagus, leading to mucosal damage and symptoms. Recently, the acid pocket has been proposed as a target for pharmacological and surgical therapies of GERD. Proton pump inhibitors and related medications reduce its acidity; whereas, alginate preparations, prokinetics, and fundoplication displace it away from the gastro-esophageal junction.

Surveillance of anal carcinoma after radiochemotherapy : A retrospective analysis of 80 patients.

BACKGROUND: Surveillance after radiochemotherapy of anal carcinoma (ACa) with curative intent is recommended in guidelines, but data regarding the effectiveness of follow-up are lacking. We aimed to assess the performance of an ACa surveillance program in a real-life setting. METHODS: We retrospectively summarized clinical history, physical findings, and follow-up investigations (endoanal ultrasound, endoscopy, CT scan) obtained during 42 months (±27 months) from 80 patients after radiochemotherapy of ACa. RESULTS: In 7/80 cases (8.8%) an incomplete response to therapy was identified at or before the 6­month time point after the end of treatment; 4 of the 7 cases were identified during scheduled follow-up. In 6 cases (7.5%), recurrent disease was found after the 6­month time point. Recurrence was systemic in 5 cases and local/inguinal in 1 case. In 3 of the 6 cases (50%), recurrence was identified during scheduled follow-up. In one asymptomatic patient, a single liver metastasis was detected during scheduled follow-up and the patient remains free of disease 19 months after surgery. Surveillance resulted in a high rate of false-positive findings (70 findings in 604 investigations), of which only 14 could be confirmed. CONCLUSION: Scheduled follow-up after treatment of ACa detected recurrent disease at systemic sites, enabling potentially curative treatment in a single case. Effectiveness of abdominal imaging during follow-up after ACa treatment should be tested in a prospective trial.

Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are recommended as first-line treatment of renal angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sporadic LAM), but follow-up is limited. Longer term efficacy and tolerability data from a Phase 3, double-blind, placebo-controlled trial are presented. METHODS: Following favorable results from the primary analysis (data cutoff 30 June 2011) of the EXIST-2 trial, patients still receiving study treatment were allowed to enter an open-label extension. Everolimus was initiated at 10 mg once daily and titrated based on tolerability. The primary outcome was angiomyolipoma response rate (≥ 50% reduction from baseline in target lesion volumes). Safety was a secondary endpoint. RESULTS: As of the cutoff date (1 May 2013), 112 patients had received everolimus, and the response rate in 107 patients with angiomyolipoma (median duration of medication exposure of 28.9 months) was 54%. The proportion of patients achieving angiomyolipoma reductions of ≥ 30% and ≥ 50% increased over time, reaching 81.6% (62/76) and 64.5% (49/76), respectively, by Week 96. No everolimus-treated patients experienced renal bleeding. The long-term safety profile was consistent with previous reports; adverse events (AEs) were mostly Grade 1/2, and there were no new safety issues. The frequency of emerging AEs and severe AEs lessened over time. CONCLUSIONS: Longer term everolimus treatment appeared safe and effective in patients with TSC- or sporadic LAM-associated renal angiomyolipoma not requiring surgical intervention. Continued reduction in angiomyolipoma volume was demonstrated, and there was no angiomyolipoma-related bleeding; AEs were predictable and generally manageable. TRIAL REGISTRATION: clinicaltrialsgov identifier: NCT00790400 (http://clinicaltrials.gov/ct2/show/NCT00790400).

Presenting symptoms predict local staging of anal cancer: a retrospective analysis of 86 patients.

BACKGROUND: Incidence of anal carcinoma (AC) is increasing and timely diagnosis is critical for efficient therapy. However, there is a paucity of recent studies addressing clinical symptoms and physical findings of anal carcinoma. METHODS: We performed a retrospective study reviewing history, symptoms and physical findings from 86 patients with newly diagnosed AC. We analyzed frequency of symptoms and physical findings according to T and TNM stage and their predictive value regarding tumor stage. RESULTS: Most patients presented with T2 (37 %) or T3 (29 %) cancer. 85 of 86 patients were symptomatic with anal bleeding (78 %), anal/perianal pain (63 %), weight loss (31 %) and foreign body sensation (22 %). 95 % of patients had ≥1 finding on physical examination including a visible tumor, palpable resistance and pain/blood during digital rectal examination. Patients with locally advanced disease (T3/T4) presented with more symptoms (p < 0.01) and more physical findings (p = 0.04) than patients with T1/T2 disease. On multivariate regression analysis perianal pain, painful defecation and weight loss were significantly associated with T3/T4 disease. CONCLUSION: Clinical symptoms and physical findings are present in nearly all AC patients. Pain referred to the perianal region, painful defecation and weight loss have predictive value for locally advanced disease.

Assessment of Obstructive Defecation by High-Resolution Anorectal Manometry Compared With Magnetic Resonance Defecography.

BACKGROUND & AIMS: Patients with obstructive defecation have abnormalities of anorectal function and/or structure. Conventional anorectal manometry (ARM) can identify abnormal function and behavior (dyssynergia); however, agreement between manometry and defecography is only fair. High-resolution (HR)-ARM may improve diagnostic agreement by differentiating pressure effects caused by dyssynergia and obstruction. We compared HR-ARM findings with magnetic resonance (MR) defecography in the clinical assessment of patients with symptoms of obstructive defecation defined by Rome III criteria. METHODS: HR-ARM (Manoscan AR 360; Given Imaging, Yoqeam, Israel) assessed anal sphincter function and pressure during simulated defecation. Abnormal manometric findings were classified according to the Rao system and compared with MR defecography as the reference standard. RESULTS: A total of 188 consecutive patients (155 women; age, 19-93 y) with obstructive defecation underwent a full investigation. Compared with patients with dyssynergia on MR imaging (n = 66), patients with structural pathology (n = 87) had lower resting (P < .003) and squeeze pressures (P < .011), but a higher rectoanal pressure gradient (P < .0001) on HR-ARM. High intrarectal pressure with a steep, positive pressure gradient consistent with outlet obstruction on HR-ARM was present in 24 patients with intra-anal intussusception on MR imaging. This pattern was not observed in other patients. Interobserver agreement was substantial for HR-ARM diagnoses (κ = 0.67; 95% confidence interval, 0.559-0.779). Diagnostic accuracy for dyssynergia was 82% compared with MR imaging (sensitivity, 77% [51 of 66]; specificity, 85% [104 of 122]). CONCLUSIONS: The diagnostic agreement between anorectal HR-ARM and MR defecography is high and pressure measurements accurately identify recto-anal dyssynergia and intra-anal outlet obstruction by structural pathology as causes of obstructive defecation.

Validation of a golden angle radial sequence (GOLD) for abdominal T1 mapping during free breathing: demonstrating clinical feasibility for quantifying gastric secretion and emptying.

PURPOSE: To validate a magnetic resonance imaging sequence suitable for quantitative assessment of acid suppression by a proton pump inhibitor (PPI) on gastric secretion and emptying in clinical practice. METHODS: A golden angle radial sequence (GOLD) was validated in a series of in vitro and in vivo experiments and clinical feasibility was shown in two studies. The impact of free breathing and image plane orientation on T1 values was evaluated in a controlled in vivo experiment. The free-breathing GOLD sequence was compared against a standard breath-hold gradient echo sequence for gastric half emptying time in 23 subjects during a gastric emptying study. Pilot data from five subjects assessed the sensitivity of the GOLD sequence to detect changes in acid secretion volume produced by PPI treatment. RESULTS: The coronal free-breathing GOLD sequence and the axial breath-hold standard gradient echo sequence showed good agreement of the gastric half emptying time (6 ± 3 min, P = 0.053). The GOLD sequence demonstrated sensitivity to reduction of gastric secretion volumes induced by PPI treatment (55 ± 5 mL, P < 0.001). CONCLUSION: The GOLD sequence allowed for free breathing, multislice, combined imaging and T1 mapping of the stomach content. GOLD presents a promising multipurpose, noninvasive imaging tool for monitoring gastric function in clinical studies.

Volume, distribution and acidity of gastric secretion on and off proton pump inhibitor treatment: a randomized double-blind controlled study in patients with gastro-esophageal reflux disease (GERD) and healthy subjects.

BACKGROUND: Postprandial accumulation of gastric secretions in the proximal stomach above the meal adjacent to the esophagogastric junction (EGJ), referred to as the 'acid pocket', has been proposed as a pathophysiological factor in gastro-esophageal reflux disease (GERD) and as a target for GERD treatment. This study assessed the effect of proton pump inhibitor (PPI) therapy on the volume, distribution and acidity of gastric secretions in GERD and healthy subjects (HS). METHODS: A randomized, double blind, cross-over study in 12 HS and 12 GERD patients pre-treated with 40 mg pantoprazole (PPI) or placebo b.i.d. was performed. Postprandial secretion volume (SV), formation of a secretion layer and contact between the layer and the EGJ were quantified by Magnetic Resonance Imaging (MRI). Multi-channel pH-monitoring assessed intragastric pH. RESULTS: A distinct layer of undiluted acid secretion was present on top of gastric contents in almost all participants on and off high-dose acid suppression. PPI reduced SV (193 ml to 100 ml, in HS, 227 ml to 94 ml in GERD; p < 0.01) and thickness of the acid layer (26 mm to 7 mm, 36 mm to 9 mm respectively, p < 0.01). No differences in secretion volume or layer thickness were observed between groups; however, off treatment, contact time between the secretion layer and EGJ was 2.6 times longer in GERD compared to HS (p = 0.012). This was not the case on PPI. CONCLUSIONS: MRI can visualize and quantify the volume and distribution dynamics of gastric secretions that form a layer in the proximal stomach after ingestion of a liquid meal. The secretion volume and the secretion layer on top of gastric contents is similar in GERD patients and HS; however contact between the layer of undiluted secretion and the EGJ is prolonged in patients. High dose PPI reduced secretion volume by about 50% and reduced contact time between secretion and EGJ towards normal levels. TRIAL REGISTRATION: NCT01212614.

Inflammatory Characteristics of Monocytes from Pediatric Patients with Tuberous Sclerosis.

OBJECTIVE: Therapeutic options for the tuberous sclerosis complex (TSC) syndrome showed varying outcomes. Malfunctional tsc1/tsc2 genes leave mTOR uninhibited, a positive downstream modulator of the innate proinflammatory immune system, which has not yet been described in pediatric patients with TSC. METHODS: Using polymerase chain reaction (PCR) gene expression levels of monocytes after cultivation with lipopolysaccharide (LPS) or with LPS + mTOR inhibitor rapamycin, patients with TSC (n = 16) were compared with healthy subjects (n = 20). RESULTS: Compared with monocytes from healthy controls, LPS showed a more prominent gene expression pattern in patients with TSC (CCL24, CXCL10, IL-6, IL-10, and IL-1B). Proinflammatory reactions against LPS were modulated by rapamycin. With LPS + rapamycin monocytes from patients with TSC showed gene expression patterns different from healthy subjects. Furthermore, developmental differences were discernible in patients with TSC, compared with gene expression levels for patients 0 to 5 years to those 6 to 11 years of age, the latter with marked expression of IL-6 IL-1A, IL-1B, RIPK2, but also IL-10. CONCLUSION: The effects of LPS, even more of LPS with rapamycin on monocytes from patients with TSC suggested that inflammatory processes are distinct from those in healthy subjects. Furthermore, reaction to rapamycin indicates age-related gene expression levels. Our findings offer a model to decipher the unknown and varying gene expression pattern induced by rapamycin.

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata. METHODS: In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400. RESULTS: 118 patients (median age 31·0 years; IQR 18·0­61·0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31­53%]) for everolimus and 0% (0 of 39 [0­9%]) for placebo (response rate difference 42% [24­58%]; one-sided Cochran-Mantel-Haenszel test p<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]). INTERPRETATION: Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. FUNDING: Novartis Pharmaceuticals.

Association of oestrogen-containing contraceptives with pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex--findings from a survey.

OBJECTIVES About 30-40% of women with tuberous sclerosis complex (TSC) develop pulmonary lymphangioleiomyomatosis (LAM). Oestrogen seems to be involved in LAM pathogenesis and oestrogen-containing contraception should be avoided in women with known LAM. However, there is very little data on the use of contraceptives in TSC patients. METHODS We conducted a survey on the use of contraception and disease characteristics. The questionnaire was forwarded to all adult female TSC patients listed in the database of a German patient organisation. RESULTS Data from 39 such patients could be analysed. Of these, 15 were diagnosed with LAM. Twenty-five patients (65%) confirmed current or past use of oestrogen-containing contraceptives. We found a suggestive correlation between the history of oestrogen-containing contraception, and LAM (Odds ratio: 6.500; 95% confidence interval: 1.199-35.230). However, oestrogen use was not associated with LAM complications. CONCLUSIONS Based on our findings, oestrogen-containing contraceptives should be resorted to by these patients only with great caution, and avoided whenever possible.

Complex elbow fracture-dislocations- what factors are associated with a poor post-operative outcome?

PURPOSE: Despite standardized treatment algorithms, patients with complex elbow fracture-dislocation frequently suffer from poor post-operative elbow function leading to reduced quality of life. Up to now, there is no valuable data regarding risk factors that lead to poor post-operative outcome after surgical reconstruction of complex elbow fracture-dislocations. METHODS: From 06/2010 to 12/2020 134 patients (51.3 ± 15.1 years, 44% women) undergoing surgical treatment of complex elbow fracture-dislocations could be included in this study. Follow-up period was 4.4 years (SD 2.5). All patients were clinically evaluated for elbow movement, elbow stability and common elbow scores (MEPS, OES, DASH-Score). Potential risk factors for poor post-operative outcome were identified using bi- and multivariate analyses. RESULTS: Overall good post-operative outcome has been achieved, mean MEPS was 88.8 ± 17.6. Post-operative complications occurred in 31.3% of the cases, while 25.4% required surgical revision. Patients with transolecranon dislocation fractures showed the significantly worst functional outcomes (p = 0.01). In addition, it has been shown that a patient's age of more than 70 years (OR = 10, p = 0.003) and a BMI of more than 35 kg/m2 (OR = 7.6, p = 0.004) are independent risk factors for a poor post-operative outcome. In contrast, gender and time to surgery showed no significant influence on post-operative outcome. CONCLUSION: In most cases, good post-operative functional results can be achieved using standardized treatment protocols. However, complication and revision rates remain high. Patients older than 70 years of age or with a BMI over 35 kg/m2 are at risk for an inferior outcome and require close follow-up monitoring.

Patients' and physicians' awareness of clinical symptoms and disease severity in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare inherited disease with the potential to affect virtually every organ system. Clinical presentation is age- and partly sex-dependent and varies broadly with respect to disease manifestations including treatment-refractory epilepsy, intellectual disability and TSC-associated neuropsychiatric disorders, chronic kidney disease or progressive lung function decline. Given the complexity of this disease, multidisciplinary care in specialized TSC centres is recommended. We aimed to elucidate the state of knowledge of patients/caregivers and physicians on individual disease manifestations. We further examined whether the association to a TSC centre has an impact on the comprehensive consideration of potential disease manifestations. Therefore, a survey was performed in a cohort of German TSC patients and their physicians. Complete information was available for 94 patients with a median age of 18 years [range 1-55] and a sex distribution of 53.2% (male): 48.8% (female). Using almost identical questionnaires for patients/caregivers and their respective physician, there was a good correlation for disease assessments associated with relevant morbidity and mortality like epilepsy, renal angiomyolipoma, cardiac rhabdomyomas or intellectual disability. Correlation was moderate for several neuropsychiatric disorders and only poor for hypomelanotic macules, dental pits or retinal achromic patches. Estimation of overall disease severity using a numeric rating scale correlated highly significantly (Pearson correlation coefficient = 0.767; p < 0.001) between patients/caregivers and physicians. In general, physicians more likely quoted items as 'unknown' than patients (822 answers vs. 435 answers in the respective groups). Questionnaires completed by physicians who were associated with a specialized TSC centre declared a significantly lower proportion of items as unknown (mean 8.7% vs. 20.5%; p < 0.001). These findings indicate that patients treated by specialized TSC centres seem to obtain a more comprehensive surveillance. Furthermore, it shows that there were reasonable surveillance strategies in general and sufficient patient/caregiver interaction and education in the examined cohort. However, for the most prominent disease characteristics there was a good awareness within both the patients/caregivers and the physicians group.

A multicenter, matched case-control analysis comparing burden of illness among patients with tuberous sclerosis complex related epilepsy, generalized idiopathic epilepsy, and focal epilepsy in Germany.

BACKGROUND: Depending on the underlying etiology and epilepsy type, the burden of disease for patients with seizures can vary significantly. This analysis aimed to compare direct and indirect costs and quality of life (QoL) among adults with tuberous sclerosis complex (TSC) related with epilepsy, idiopathic generalized epilepsy (IGE), and focal epilepsy (FE) in Germany. METHODS: Questionnaire responses from 92 patients with TSC and epilepsy were matched by age and gender, with responses from 92 patients with IGE and 92 patients with FE collected in independent studies. Comparisons were made across the main QoL components, direct costs (patient visits, medication usage, medical equipment, diagnostic procedures, ancillary treatments, and transport costs), indirect costs (employment, reduced working hours, missed days), and care level costs. RESULTS: Across all three cohorts, mean total direct costs (TSC: €7602 [median €2620]; IGE: €1919 [median €446], P < 0.001; FE: €2598 [median €892], P < 0.001) and mean total indirect costs due to lost productivity over 3 months (TSC: €7185 [median €11,925]; IGE: €3599 [median €0], P < 0.001; FE: €5082 [median €2981], P = 0.03) were highest among patients with TSC. The proportion of patients with TSC who were unemployed (60%) was significantly larger than the proportions of patients with IGE (23%, P < 0.001) or FE (34%, P = P < 0.001) who were unemployed. Index scores for the EuroQuol Scale with 5 dimensions and 3 levels were significantly lower for patients with TSC (time-trade-off [TTO]: 0.705, visual analog scale [VAS]: 0.577) than for patients with IGE (TTO: 0.897, VAS: 0.813; P < 0.001) or FE (TTO: 0.879, VAS: 0.769; P < 0.001). Revised Epilepsy Stigma Scale scores were also significantly higher for patients with TSC (3.97) than for patients with IGE (1.48, P < 0.001) or FE (2.45, P < 0.001). Overall Quality of Life in Epilepsy Inventory-31 items scores was significantly lower among patients with TSC (57.7) and FE (57.6) than among patients with IGE (66.6, P = 0.004 in both comparisons). Significant differences between patients with TSC and IGE were also determined for Neurological Disorder Depression Inventory for Epilepsy (TSC: 13.1; IGE: 11.2, P = 0.009) and Liverpool Adverse Events Profile scores (TSC: 42.7; IGE: 37.5, P = 0.017) with higher score and worse results for TSC patients in both questionnaires. CONCLUSIONS: This study is the first to compare patients with TSC, IGE, and FE in Germany and underlines the excessive QoL burden and both direct and indirect cost burdens experienced by patients with TSC.