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Multiple studies have identified transcriptome subtypes of high-grade serous ovarian carcinoma (HGSOC), but their interpretation and translation are complicated by tumor evolution and polyclonality accompanied by extensive accumulation of somatic aberrations, varying cell type admixtures, and different tissues of origin. In this study, we examined the chronology of HGSOC subtype evolution in the context of these factors using a novel integrative analysis of absolute copy-number analysis and gene expression in The Cancer Genome Atlas complemented by single-cell analysis of six independent tumors. Tumor purity, ploidy, and subclonality were reliably inferred from different genomic platforms, and these characteristics displayed marked differences between subtypes. Genomic lesions associated with HGSOC subtypes tended to be subclonal, implying subtype divergence at later stages of tumor evolution. Subclonality of recurrent HGSOC alterations was evident for proliferative tumors, characterized by extreme genomic instability, absence of immune infiltration, and greater patient age. In contrast, differentiated tumors were characterized by largely intact genome integrity, high immune infiltration, and younger patient age. Single-cell sequencing of 42,000 tumor cells revealed widespread heterogeneity in tumor cell type composition that drove bulk subtypes but demonstrated a lack of intrinsic subtypes among tumor epithelial cells. Our findings prompt the dismissal of discrete transcriptome subtypes for HGSOC and replacement by a more realistic model of continuous tumor development that includes mixtures of subclones, accumulation of somatic aberrations, infiltration of immune and stromal cells in proportions correlated with tumor stage and tissue of origin, and evolution between properties previously associated with discrete subtypes.Significance:This study infers whether transcriptome-based groupings of tumors differentiate early in carcinogenesis and are, therefore, appropriate targets for therapy and demonstrates that this is not the case for HGSOC.

Supplementary Materials & Methods. Supplemental Tables 1-3 and Supplemental Figures 1-19.

Objective Several adjustments occur after nephrectomy (NT) in the donor's remnant kidney. We investigated kidney donors 10 years after NT and compared several parameters before and after transplantation. Methods A total of 42 kidney donors of the University of Luebeck's Transplant Center were scheduled for a 10-year follow-up and were offered several investigations: laboratory tests, urinalysis and kidney ultrasound examination including determination of kidney volume (KV), resistive index (RI) and pulsatility index (PI). Moreover, a 24-hour ambulatory blood pressure monitoring (ABPM) was performed. A review of the medical records allowed comparison of the investigated parameters before (t0), 1 month after (t0.1), and 10 (t10) years after NT. Results Creatinine clearance decreased from 94.3 ± 23 (t0) to 52.4 ± 22 mL/min/1.73 m2 (t0.1) and increased to 78.2 ± 19 mL/min/1.73 m2 after 10 years (t10). Tubular proteinuria (α1-microglobuline) increased from 6.1 ± 1.5 (t0) to 63 ± 4.8 (t0.1) (P Conclusions NT leads to hypertrophy of the remnant kidney associated with an increase of organ volume and creatinine clearance after 10 years of follow-up. Our results indicate an excellent prognosis for the kidney donors without any signs of renal damage.

The diagnosis and therapy of obstructive inflammatory disorders of the salivary glands have changed in the past decades following the introduction of sialoendoscopy. The aims of the present study were to analyze the relevance of sialoendoscopy using our own data and to compare the results to those of other studies. A retrospective analysis of 70 patients was performed, who were treated for obstructive disorders of the parotid and/or submandibular gland in whom sialoendoscopy was indicated. Two categories of interventions were considered: diagnostic interventional sialoendoscopy and endoscope-assisted interventions. Interventional sialoendoscopy procedures requiring extirpation of the gland were included in the analysis, as were abnormal intraductal processes that were detected during endoscopy. Treatment was successful in 58 of 67 (86.6 %) procedures (sialoendoscopy without surgical intervention n = 59; endoscope-assisted surgical intervention n = 8). Based on the underlying disease, the success rate was 88.6 % (n = 39) in patients with obstructive sialadenitis without sialolithiasis and 86.6 % (n = 19) in patients with sialolithiasis. It was not possible to draw definitive conclusions on the underlying disease from the observed pathological intraductal changes. Sialoendoscopy is an effective and safe diagnostic and therapeutic option with low complication rate. However, limiting factors such as the size or the position of potentially removable obstacles must be taken into consideration. The rate of gland extirpations can be reduced using sialoendoscopy.

Es gibt nur wenige Daten uber vergleichende Langzeitverlaufe bei Patienten mit fazialen Dyskinesien. Hier wurden verschiedene Injektionsparameter untersucht. Es wird uber die Langzeitdynamik der Botulinumtoxin-Therapie beim Blepharospasmus, Spasmus facialis und bei Synkinesien nach Fazialisdefektheilung vergleichend berichtet. 80 Patienten (Blepharospasmus n=30, Spasmus facialis n=31, Synkinesien n=19) wurden ausgewertet. Alle hatten mindestens 10 Injektionen hinter sich. Die Entwicklung des zeitlichen Verlaufs der mittleren Gesamtdosis sowie bei jeder Indikation der mittleren Dosis, der mittleren Zahl der Injektionspunkte und die Dosisentwicklung pro Injektionspunkt wurde retrospektiv untersucht. Es fand sich eine kontinuierliche mittlere Dosiserhohung uber die Zeit. Dieses lies sich bei jeder Indikation zeigen. Beim Spasmus facialis und bei Synkinesien nach einer Fazialisdefektheilung ist uber die Zeit auch eine deutliche Steigerung der Injektionspunktezahl zu verzeichnen. Die Dosisentwicklung pro Punkt zeigte den hochsten mittleren Anstieg bei Blepharospasmus-Patienten (zwischen der 1. und 25. Injektion). Bei Patienten mit einem Spasmus facialis und Synkinesien war dieses Phanomen nicht gegeben. Somit ist – anders als beim Spasmus facialis und bei Synkinesien nach einer Fazialisdefektheilung – die Dosissteigerung beim Blepharospasmus primar durch eine Dosiserhohung einzelner konstanter Injektionspunkte zu erklaren, wahrend bei Patienten mit einem Spasmus facialis und mit Synkinesien eine Erhohung der Injektionspunkteanzahl fur die Dosiserhohung relevant ist. Diese neuen Aspekte der Injektions-Parameter versetzen den Therapeuten in die Lage, die Dynamik des jeweiligen Krankheitsbildes besser zu verstehen und Behandlungsplane zu optimieren.

Uberschiesende Gesichtsbewegungen konnen zur sozialen Stigmatisierung und Isolierung fuhren. Abhilfe schaffen kann hier die lokale Injektion von Botulinumtoxin, um diese unwillkurlichen Bewegungen zu therapieren.

Schwitzen kann zu Problemen fuhren bei Tragern von Horgeraten, aktiven Mittelohr- und Cochleaimplantaten als Funktionsminderung oder als Minderung des Tragekomforts. Wir berichten uber 2 Patientinnen (Patientin 1: Horgeratetragerin; Patientin 2: Tragerin einer Vibrant Soundbridge), die den Ausfall der Horgerate bzw. Einschrankungen beim Tragen des Audioprozessors erfuhren. Es wurden intrakutane Injektionen mit Botulinumtoxin A (laterale Kopfhaut) durchgefuhrt mit dem Resultat einer deutlichen Besserung. Die Horhilfen konnten ohne Einschrankungen kontinuierlich genutzt werden. Intrakutane Injektionen von Botulinumtoxin stellen eine gute Therapieoption zur Reduktion der Schweisproduktion als Ursache fur Einschrankungen von Funktion und Tragekomfort bei Horgeraten, aktiven Mittelohr- und Cochleaimplantaten dar.

Unwillkurliche Gesichtsbewegungen werden durch verschiedene Ursachen hervorgerufen. In dem folgenden Artikel werden der Blepharospasmus, der Spasmus facialis sowie Synkinesien nach Fazialisdefektheilung beschrieben. Unterschiedliche Ursachen, klinische Symptome und Diagnostik werden erlautert. Anschliesend wird ein fur die drei Krankheiten gemeinsames Therapiekonzept dargelegt. Die uberschiesenden Gesichtsbewegungen konnen uber die lokale Injektion von Botulinumtoxin in ihrem Ausmas reduziert oder ganz unterdruckt werden.

In Deutschland gibt es keine Daten uber die Verbreitung und Anwendungsbereiche von Botulinumtoxin (BoNT) an HNO-Kliniken. Mit dem Ziel, eine Ubersicht zur aktuellen Anwendung von BoNT an HNO-Kliniken zu erhalten, wurde die im Folgenden beschriebene Umfrage durchgefuhrt. An 150 HNO-Kliniken wurde ein standardisierter Fragebogen gesendet. In der Auswertung wurde zwischen Universitatskliniken und stadtischen Hausern unterschieden. Auserdem erfolgte auch eine Auswertung der Gesamtheit aller antwortenden Kliniken. Die Rucklaufquote betrug 62%. Es nutzen 75% aller antwortenden Kliniken BoNT als Therapieoption. Am haufigsten werden „Off-label-use“-Indikationen behandelt (15 von 20 Indikationen: 75%). Die haufigste genannte Indikation ist das Frey-Syndrom, gefolgt von Hypersalivation bei Speichelfistel nach Parotidektomie, Dysphagie, asthetischen Anwendungen und laryngealer Dystonie. Botulinumtoxin als Therapieoption ist in der HNO-Heilkunde weit verbreitet und die Tendenz, diese Therapieoption anzubieten, hat in den letzten Jahren deutlich zugenommen. Aufgrund der unterschiedlichen Anwendungsbereiche der einzelnen Kliniken ware ein Verzeichnis aller BoNT-verwendenden Kliniken sinnvoll, um es Patienten zu erleichtern, die fur die jeweilige Indikation nachstgelegene Klinik zu finden.

Das spastische Entropium ist eine seltene Erkrankung, die uberwiegend in hoherem Lebensalter auftritt. Wir berichten uber einen 74-jahrigen an Demenz erkrankten Patienten, welcher mittels Injektionen von Botulinumtoxin in das Unterlid erfolgreich behandelt wurde und somit eine lidkorrigierende Operation umgehen konnte. Die symptomatische Therapie in Form von Unterlidinjektionen mit Botulinumtoxin sollte als Alternative fur Patienten mit erhohtem Risikoprofil fur eine Operation in Betracht gezogen werden.

Rare information exists about comparative long-term observations of patients with facial movement disorders. This retrospective analysis deals with the course of different parameters of injection over the time.In this study we compared the development of long-term botulinum toxin treatments of patients with blepharospasm, hemifacial spasm and synkinesis. 80 patients (n=30 blepharospasm, n=31 hemifacial spasm, n=19 synkinesis), who had at least 10 consultations for BTA-injections, were included in the retrospective analysis. The development for each entity in total dosage, increase in the number of injection points and change in dosages for each point were evaluated.The over-all dosage in all 3 clinical disorders and for each single disease itself increased continuously over the time. The amount of injection points increased in the treatment of hemifacial spasm and synkinesis. The dosage per point increased most in blepharospasm between the 1. and 25. injection, but was distinctly lower in patients with hemifacial spasm and synkinesis. The increase in dosage in blepharospasm is therefore, in contrast to the other indications, mostly caused by an increase in dosage per point. In patients with hemifacial spasm and synkinesis the escalation of dosage is mainly caused by an increase of the number of injection points.These new aspects of the dynamic in the treatment with botulinum toxin enable the physician to understand better the dynamic of these diseases, to optimize treatment protocols.

After laryngectomy, the transport of intranasal secretions is often inadequate due to the lack of the nasal ventilation. Consequently, persistent and disruptive anterior rhinorrhea may occur. We report the case of a 61-year-old man who had recently undergone a laryngectomy and who was successfully treated with bilateral injections of botulinum toxin into the anterior portion of the inferior turbinates. After treatment, rhinorrhea was clearly reduced. Therefore, symptomatic treatment of anterior rhinorrhea with local injections of botulinum toxin type A should be considered as an option to improve the quality of life in laryngectomized patients.

Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This reduces social interaction chances and burdens daily care. Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, and saliva aspiration. Therefore, a multidisciplinary S2k guideline was developed. Diagnostic tools such as fiberoptic endoscopic evaluation of swallowing and videofluoroscopic swallowing studies generate important data on therapy selection and control. Especially traumatic and oncologic cases profit from swallowing therapy programmes in order to activate compensation mechanisms. In children with hypotonic oral muscles, oralstimulation plates can induce a relevant symptom release because of the improved lip closure. In acute hypersalivation, the pharmacologic treatment with glycopyrrolate and scopolamine in various applications is useful but its value in long-term usage critical. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long lasting saliva reduction. Surgical treatment should be reserved for isolated cases. External radiation is judged as ultima ratio. Therapy effects and symptom severity has to be followed, especially in neurodegenerative cases. The resulting xerostomia should be critically evaluated by the responsible physician regarding oral and dental hygiene.

Einleitung/Problematik: Viele Patienten klagen nach einer Laryngektomie über stetiges Nasenlaufen, welches vor der Operation nicht bestand. Dies deckt sich mit unserer Beobachtung einer vermehrten postoperativen anterioren Rhinorrhoe. Das gebildete Nasensekret kann nicht ausgeschnaubt oder aktiv nach kranial transportiert werden. Hinzu kommt, daß durch den Wegfall des inspiratorischen Atemstroms die Verdunstung des Sekrets nicht erfolgen kann. Methode Ein Patient klagte unmittelbar nach der Laryngektomie über anhaltendes Nasenlaufen, so daß er ständig eine Nasenschleuder zum Abfangen des Sekretes trug. Nach Abschwellung und Lokalanästhesie der Nasenschleimhäute mit einer Kombination aus Xylometazolin und Tetracain injizierten wir links und rechts jeweils 15 Einheiten Botulinumtoxin Typ A (Präparat Botox®) in die untere Nasenmuschel. Ergebnis: In den Tagen nach der Injektion kam es zu einer deutlichen Abnahme des nasalen Sekretflusses. Ein ständiges Abtupfen des Sekretes von der Nase war nicht mehr nötig. Somit war auch das Tragen einer Nasenschleuder nicht mehr erforderlich. Die Lebensqualität des Patienten stieg dadurch merklich. Es traten keine Nebenwirkungen auf. Schlussfolgerung Die lokale intranasale Applikation von Botulinumtoxin Typ A ist geeignet, den nasalen Sekretfluß nach Laryngektomie zu reduzieren. Der Erstautor gibt keinen Interessenkonflikt an., GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; 9:Doc03; ISSN 1865-1038

Spastic entropion is a rare condition that predominantly affects older people. We report on a 74-year-old dementia patient who was successfully treated by botulinum toxin injections into the lower eyelid, thereby avoiding lid correction surgery. For patients with an increased risk of eyelid surgery, symptomatic therapy comprising botulinum toxin injections to the lower eyelid should be considered as an alternative treatment.

Background Salivary fistulas are a well-known sequel of parotidectomy, and successful treatment with bot- ulinum toxin has been demonstrated in individual cases. Here, we report on 12 patients with fistulas treated follow- ing parotidectomy for various indications. Methods and results Injection of botulinum toxin type A into the residual gland tissue was the initial treatment. After early intervention (within 6 weeks after development of the fistula), only one fistula remained (9 of 10 fistulas treated early only with botulinum toxin). One patient with early intervention did not want to wait for the botulinum toxin treatment to take effect and demanded early surgical revision, which was suc- cessful. In one patient with a permanent fistula, botulinum toxin treatment began 420 days after the operation and was unsuccessful. No side effects were evident after the treatment. Conclusion In summary, botulinum toxin injections into the parotid tissue remaining after surgery appear to be an effec- tive treatment for salivary fistulas following parotidectomy.

Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.

The production of sweat in the temporal skin region may be a serious problem for patients with hearing aids, active middle ear implants or cochlear implants. We report on two patients suffering from a loss of function of their hearing aid and a reduction of the "wear comfort" of an active middle ear implant. The patients underwent intracutaneous botulinum toxin (BTX) treatment of the temporal skin region. In both patients a distinct improvement of their complaints occurred, enabling them to use their hearing aids and active middle ear implants continuously. BTX injections are suited to improve sweat-caused complaints in patients with hearing aids, active middle ear implants and cochlear implants.

Involuntary facial movements are caused by various diseases. This article describes three of these diseases: blepharospasm, hemifacial spasm and facial synkinesis following facial nerve paralysis. The different etiologies, clinical symptoms and diagnosis are discussed. A common therapeutic approach for these three diseases is presented. Involuntary facial movements can be reduced or even completely suppressed by local injections of botulinum toxin.

Background. A man diagnosed with Stensen's duct stenosis exhibited recurrent parotid swelling, invariably during meals. Previous parotid duct dilations and percutaneous radiotherapy were ineffective. Botulinum toxin (BTX) injections were injected into the affected gland to regulate salivary flow and reduce parotid swelling. Methods. BTX (22.5 units) was injected into the affected gland. A second treatment with 30 units BTX was carried out 7 weeks later. Two further injections followed after 4 months, respectively. The results were scored by the patient and evaluated in an examination. Results. The patient reported the disappearance of parotid swelling after 2 weeks of injections. This effect was maintained for 5 weeks after the first treatment and for 4 months after the following 2 treatments. There were no side effects. Conclusion. Here we introduce BTX as a therapeutic option for the treatment of salivary duct stenosis when other therapies are ineffective and before opting for gland extirpation. © 2009 Wiley Periodicals, Inc. Head Neck, 2009

Hypersalivation bezeichnet einen ubermasigen Speichelfluss, der durch insuffiziente oromotorische Fahigkeiten, verminderte zentralnervose Kontrolle und Koordination oder gestorte Schluckablaufe zu einem Benassen des Betroffenen und seiner Umgebung fuhren kann. Dieses reduziert die sozialen Interaktionsmoglichkeiten und erhoht den Pflegeaufwand. Die Diagnostik und Therapie sollten fruhzeitig multidisziplinar erfolgen, weshalb eine S2k-Leitlinie zur Hypersalivationstherapie erarbeitet wurde. Schwerpunkte sind die Abklarung von Schluckstorungen mit Speichelaspiration und von orofazialen motorischen Defiziten. Die endoskopische Schluckdiagnostik und die Videofluoroskopie konnen wichtige Informationen zur Therapiekontrolle liefern. Insbesondere bei traumatischen oder tumortherapeutischen Defektstorungen sind schlucktherapeutische Ubungsmasnahmen zur Aktivierung von Kompensationsmechanismen zweckmasig. Vor allem bei Kindern mit hypotoner perioraler Muskulatur konnen Stimulationsplatten uber einen vermehrten Lippenschluss zur Symptomreduktion fuhren. Sinnvolle medikamentose Therapien bei akuter Hypersalivation sind insbesondere Glycopyrrolat und Scopolamin, jedoch ist die Langzeitanwendung kritisch zu betrachten. Zuletzt hat sich die Injektion von Botulinumtoxin in die Speicheldrusen als effektive und sichere Behandlungsform mit einer lang anhaltenden Speichelreduktion erwiesen. Chirurgische Eingriffe der Speicheldrusen bleiben zunehmend Einzelfallen vorbehalten. Die externe Bestrahlung der Speicheldrusen gilt als ultima ratio. In der Nachsorge sind Therapieeffekte zu erfassen; insbesondere bei neurodegenerativen Erkrankungen ist die individuelle Dynamik der Symptomverschlechterung zu berucksichtigen. Der Einfluss der resultierenden relativen Mundtrockenheit soll vom behandelnden Arzt in Hinblick auf die Mund- und Zahnhygiene evaluiert werden.