Inhibition of the Cyclin K-CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate cancer.

Androgen deprivation therapy (ADT) is the mainstay of the current first-line treatment concepts for patients with advanced prostate carcinoma (PCa). However, due to treatment failure and recurrence investigation of new targeted therapeutics is urgently needed. In this study, we investigated the suitability of the Cyclin K-CDK12 complex as a novel therapeutic approach in PCa using the new covalent CDK12/13 inhibitor THZ531. Here we show that THZ531 impairs cellular proliferation, induces apoptosis, and decreases the expression of selected DNA repair genes in PCa cell lines, which is associated with an increasing extent of DNA damage. Furthermore, combination of THZ531 and ADT leads to an increase in these anti-tumoral effects in androgen-sensitive PCa cells. The anti-proliferative and pro-apoptotic activity of THZ531 in combination with ADT was validated in an ex vivo PCa tissue culture model. In a retrospective immunohistochemical analysis of 300 clinical tissue samples we show that Cyclin K (CycK) but not CDK12 expression correlates with a more aggressive type of PCa. In conclusion, this study demonstrates the clinical relevance of the CycK-CDK12 complex as a promising target for combinational therapy with ADT in PCa and its importance as a prognostic biomarker for patients with PCa.

Infectious diseases in German military personnel after predominantly tropical deployments: a retrospective assessment over 13 years.

OBJECTIVES: Military deployments to the tropics are associated with specific infection risks. To add to the available epidemiological information, infectious disease risks in German military personnel returning from predominantly tropical deployments were assessed. METHODS: Since 2006, German soldiers returning from predominantly tropical deployments have been offered the opportunity of returnee screenings at the Department of Tropical Medicine and Infectious Diseases of the Bundeswehr Hospital Hamburg. Case files and diagnostic results recorded between 2006 and 2018 were retrospectively assessed to identify deployment-associated infectious disease risks. RESULTS: Along with high enteric colonisation rates with apathogenic protozoa and resistant Enterobacteriaceae, direct or indirect proof of infections among the 764 assessed cases comprised Plasmodium spp (n=37), Giardia duodenalis (n=21), Schistosoma spp (n=14), Yersinia enterocolitica (n=5), Strongyloides stercoralis (n=3), Campylobacter jejuni (n=1), Leishmania spp (n=1) and Salmonella enterica (n=1), as well as latent infections with Mycobacterium tuberculosis complex (n=8). The infections were mainly imported from the African region and Eastern Mediterranean region and high proportions of cases lacked typical symptoms. Reported side effect rates of antimalarial chemoprophylaxis for mefloquine (n=121), atovaquone/proguanil (n=49) and doxycycline (n=6) were 36.3%, 19.3% and 11.8%, respectively, while non-compliance rates were 12.9%, 13.0% and 5.9%, respectively. CONCLUSIONS: Considerable rates of infections with sometimes atypical or absent symptoms confirm a need for returnee screenings after tropical deployments. High reported side effect rates for mefloquine support its replacement by atovaquone/proguanil or doxycycline for antimalarial chemoprophylaxis.

N-Cadherin Distinguishes Intrahepatic Cholangiocarcinoma from Liver Metastases of Ductal Adenocarcinoma of the Pancreas.

Carcinomas of the pancreatobiliary system confer an especially unfavorable prognosis. The differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and its subtypes versus liver metastasis of ductal adenocarcinoma of the pancreas (PDAC) is clinically important to allow the best possible therapy. We could previously show that E-cadherin and N-cadherin, transmembrane glycoproteins of adherens junctions, are characteristic features of hepatocytes and cholangiocytes. We therefore analyzed E-cadherin and N-cadherin in the embryonally related epithelia of the bile duct and pancreas, as well as in 312 iCCAs, 513 carcinomas of the extrahepatic bile ducts, 228 gallbladder carcinomas, 131 PDACs, and precursor lesions, with immunohistochemistry combined with image analysis, fluorescence microscopy, and immunoblots. In the physiological liver, N-cadherin colocalizes with E-cadherin in small intrahepatic bile ducts, whereas larger bile ducts and pancreatic ducts are positive for E-cadherin but contain decreasing amounts of N-cadherin. N-cadherin was highly expressed in most iCCAs, whereas in PDACs, N-cadherin was negative or only faintly expressed. E- and N-cadherin expression in tumors of the pancreaticobiliary tract recapitulate their expression in their normal tissue counterparts. N-cadherin is a helpful marker for the differential diagnosis between iCCA and PDAC, with a specificity of 96% and a sensitivity of 67% for small duct iCCAs and 50% for large duct iCCAs.

Middle-ear effusion in children with cleft palate: congenital or acquired?

OBJECTIVE: Cleft palates are one of the most common congenital malformations. Because of the loss of Eustachian tube function, middle-ear ventilation is reduced. The aim of this study was to determine if middle-ear effusions were present at birth or at the three-month audiological evaluation. METHOD: A total of 53 children with a cleft palate were included. Data review included the results of newborn hearing screening, microscopic findings, a tympanometry, a free field audiometry and intra-operative findings. RESULTS: A total of 58.4 per cent of patients had a median, 26.4 per cent had a bilateral, 11.3 per cent had a unilateral and 3.8 per cent had a limited soft palate cleft. Newborn hearing screening showed a pass in 83.1 per cent of newborns bilaterally. The first ear microscopy showed a bilateral middle-ear effusion in 90.6 per cent of cases. During cleft surgery, bilateral paracentesis was performed in all cases, and in 90.6 per cent middle-ear effusion was sucked out. CONCLUSION: The majority of children with a cleft palate do not present with middle-ear effusion at birth. It develops within several days or weeks of life.

[Effects of the SARS-CoV­2 pandemic on the otolaryngology university hospitals in the field of research, student teaching and specialist training]. / Auswirkungen der SARS-CoV­2-Pandemie auf die universitäre Hals-Nasen-Ohren-Heilkunde im Bereich der Forschung, Lehre und Weiterbildung.

BACKGROUND: From spring 2020, SARS-CoV­2 began to spread worldwide, with what is now known as the first wave of the pandemic, starting in March 2020. This resulted in restructuring and shift of resources at many hospitals. The aim of our work was to detect the effects of the pandemic on the german Oto-Rhino-Laryngology (ORL) university hospitals in terms of research, student teaching and further specialist training. MATERIAL AND METHODS: The chairmen of the 39 ORL university hospitals in Germany were asked about the effects of the pandemic on research, student teaching and ORL specialist training (residency) in the period from March to April 2020 using a structured online survey. RESULTS: All 39 chairmen took part in the survey. Of these, 74.4% (29/39) stated that their research activities had deteriorated as a result of the pandemic. In 61.5% (24/39) pandemic-related research issues were addressed. All hospitals reported a restriction for in-house teaching and 97.5% (38/39) introduced new digital teaching methods. During the observation period, 74.4% of the chairmen did not see ORL specialist training (residency)at risk. CONCLUSION: Our results provide an insight into the heterogeneous effects of the pandemic. The fast processing of pandemic-related research topics and the introduction of innovative digital concepts for student teaching impressively demonstrates the great innovative potential and the ability of the ORL university hospitals to react quickly in order to maintain their tasks in research, student teaching and ORL specialist training in the best possible way even during the pandemic.

Influence of cochlear parameters on the current practice in cochlear implantation : Development of a concept for personalized medicine.

Since the introduction of cochlear implants into clinical routine, the interest in measuring cochlear parameters, particularly the cochlear duct length (CDL) has increased, since these can have an influence on the correct selection of the electrode. On the one hand, coverage of an optimal frequency band is relevant for a good audiological result, and on the other hand, cochlear trauma due to too deep insertion or displacement of the electrode must be avoided. Cochlear implants stimulate the spiral ganglion cells (SGC). The number of SGC and particularly their distribution can also have an influence on the function of a cochlear implant. In addition, the frequency assignment of each electrode contact can play a decisive role in the postoperative success, since the frequency distribution of the human cochlea with varying CDL shows substantial interindividual differences. The aim of this work is to provide an overview of the methods used to determine the cochlear parameters as well as of relevant studies on the CDL, the number and distribution of SGZ, and the frequency assignment of electrode contacts. Based on this, a concept for individualized cochlear implantation will be presented. In summary, this work should help to promote individualized medicine in the field of cochlear implants in the future, in order to overcome current limitations and optimize audiological outcomes.

[Influence of cochlear parameters on the current practice in cochlear implantation : Development of a concept for personalized medicine. German version]. / Einfluss cochleärer Parameter auf die aktuelle Cochleaimplantatversorgung : Entwicklung eines Konzepts für die personalisierte Medizin.

Since the introduction of cochlear implants into clinical routine, the interest in measuring cochlear parameters, particularly the cochlear duct length (CDL) has increased, since these can have an influence on the correct selection of the electrode. On the one hand, coverage of an optimal frequency band is relevant for a good audiological result, and on the other hand, cochlear trauma due to too deep insertion or displacement of the electrode must be avoided. Cochlear implants stimulate the spiral ganglion cells (SGC). The number of SGC and particularly their distribution can also have an influence on the function of a cochlear implant. In addition, the frequency assignment of each electrode contact can play a decisive role in the postoperative success, since the frequency distribution of the human cochlea with varying CDL shows substantial interindividual differences. The aim of this work is to provide an overview of the methods used to determine the cochlear parameters as well as of relevant studies on the CDL, the number and distribution of SGZ, and the frequency assignment of electrode contacts. Based on this, a concept for individualized cochlear implantation will be presented. In summary, this work should help to promote individualized medicine in the field of cochlear implants in the future, in order to overcome current limitations and optimize audiological outcomes.

Improved cancer detection in Waldeyer's tonsillar ring by 68Ga-FAPI PET/CT imaging.

PURPOSE: In cancer of unknown primary (CUP), positron emission tomography/computed tomography (PET/CT) with the glucose analog [18F]FDG represents the standard imaging approach for localization of the malignant primary. Frequently, however, [18F]FDG PET/CT cannot precisely distinguish between small occult tumors and chronic inflammation, especially in Waldeyer's tonsillar ring. To improve the accuracy for detecting primary tumors in the Waldeyer's tonsillar ring, the novel PET tracer [68Ga]Ga-FAPI-4 for specific imaging of fibroblast activation protein (FAP) expression was used as a more specific target for cancer imaging. METHODS: Eight patients with suspicion of a malignant tumor in Waldeyer's tonsillar ring or a CUP syndrome were examined. PET/CT scans with [18F]-FDG and [68Ga]Ga-FAPI-4 were performed for pre-operative tumor localization. After surgical resection, histopathological and immunohistochemical results were compared to PET/CT findings. RESULTS: Histopathology revealed a palatine or lingual tonsil carcinoma in all patients. In case of lymph node metastases smaller than 7 mm in size, the [18F]FDG PET/CT detection rate of cervical lymph node metastases was higher than that of [68Ga]FAPI PET/CT, while both tracers identified the primary tumors in all eight cases. The size of the primary and the lymph node metastases was directly correlated to the respective FAP expression, as detected by immunohistochemistry. The mean SUVmax for the primary tumors was 21.29 ± 7.97 for 18F-FDG and 16.06 ± 6.29 for 68Ga-FAPI, respectively (p = 0.2). The mean SUVmax for the healthy contralateral tonsils was 8.38 ± 2.45 for [18F]FDG and 3.55 ± 0.47 for [68Ga]FAPI (p < 0.001). The SUVmax ratio of [68Ga]FAPI was significantly different from [18F] FDG (p = 0.03). Mean TBRmax for the [68Ga]Ga-FAPI-4 tracer was markedly higher in comparison to [18F]FDG (10.90 vs. 4.11). CONCLUSION: Non-invasive imaging of FAP expression by [68Ga]FAPI PET/CT resulted in a better visual detection of the malignant primary in CUP, as compared to [18F]FDG imaging. However, the detection rate of lymph node metastases was inferior, presumably due to low FAP expression in small metastases. Nevertheless, by offering a detection method for primary tumors with the potential of lower false positive rates and thus avoiding biopsies, patients with CUP syndrome may benefit from [68Ga]FAPI PET/CT imaging.

Heartworm control in Grenada, West Indies: Results of a field study using imidacloprid 10% + moxidectin 2.5% and doxycycline for naturally-acquired Dirofilaria immitis infections.

Canine heartworm disease (CHD) results from infection with Dirofilaria immitis and while it is of global concern, it is most prevalent in tropical climates where conditions support the parasite and vector life cycles. Melarsomine dihydrochloride is the sole treatment for CHD recommended by the American Heartworm Society. However, in cases where cost or access to melarsomine precludes treatment of an infected dog, therapeutic alternatives are warranted. This randomized, controlled field study evaluated the adulticidal efficacy of a combination therapeutic protocol using 10 % imidacloprid + 2.5 % moxidectin spot-on and a single 28-day course of doxycycline and compared with that of a 2-dose melarsomine dihydrochloride protocol. Of 37 naturally-infected domestic dogs with class 1, 2 or early class 3 CHD enrolled in the study, 30 were evaluated for a minimum of 12 months. Seven dogs were withdrawn due to canine ehrlichiosis, non-compliance, or wrongful inclusion. Dogs were randomly assigned to a control (CP, n = 15) or investigational (IVP, n = 15) treatment group. CP dogs received two injections of melarsomine dihydrochloride (2.5 mg/kg) 24 -hs apart and maintained on monthly ivermectin/pyrantel. IVP dogs were treated with oral doxycycline (10 mg/kg twice daily for 28 days) and topical 10 % imidacloprid + 2.5 % moxidectin once monthly for 9 months. Dogs were evaluated up to 18 months - monthly for the first 9 months, then every 3 months. Parasiticidal efficacy was based on antigen status using the IDEXX PetChek® 34 Heartworm-PF Antigen test. By month 18, antigen was not detected in any study dog except one from the IVP group. One other IVP dog was persistently antigenemic and treated with melarsomine at month 12 according to the initial study protocol. Mean antigen concentration (based on optical density) decreased more rapidly in the CP group and by month 15 was 0.11 for the IVP and 0.07 for CP groups, with equivalent median concentrations (0.04) in both groups. Conversion following heat-treatment of antigen-negative samples occurred frequently and at similar rates in both treatment groups. Based on the bias of diagnostic tests towards detection of female worms, we conclude that monthly application of 10 % imidacloprid + 2.5 % moxidectin for 9 months combined with a course of doxycycline twice daily for 28 days resulted in effective therapy against female adults in CHD. This therapeutic option may be particularly useful in cases where financial constraint or access to melarsomine precludes treatment of an infected individual. This study was supported by Bayer Animal Health.

[Effects of the SARS-CoV-2 pandemic on the otorhinolaryngology university hospitals in the field of medical care]. / Auswirkungen der SARS-CoV-2-Pandemie auf die universitäre Hals-Nasen-Ohrenheilkunde im Bereich der Krankenversorgung.

INTRODUCTION: Since December 2019, the SARS-CoV-2 virus has been rapidly spreading worldwide. In Germany, an exponential increase in the number of infections was registered at the beginning of March 2020 and led to a call of the Ministry of Health to create more capacity for intensive medical treatment in hospitals. The aim of the present study was to determine the effects of the SARS-CoV-2 pandemic on Oto-Rhino-Laryngology (ORL) university hospitals regarding patient care. MATERIALS AND METHODS: An online survey was sent out to all chairmen of the 39 ORL university hospitals in Germany. The answers to the questions referred to the defined period from March 15th to April 15th 2020 and were carried out using the online survey tool "SurveyMonkey". 87 questions focused on general information, health care, and structural effects in the respective institution. RESULTS: All chairmen of the 39 university hospitals in Germany participated in the survey. The collected data prove the considerable impact on organizational, structural and medical aspects of patient care. For example, the surveyed clinics reported a decrease in outpatient cases by 73.8 % to 26.2 ±â€Š14.2 % and in surgical treatments by 65.9 % to 34.1 ±â€Š13.9 %. In contrast, emergency treatment remained unchanged or even increased in 80 % of the facilities and surgical treatment of emergency patients remained unchanged or even increased in more than 90 %. Emergency outpatient and surgical treatment of patients was provided throughout the pandemic in all facilities. In total, about 35 000 outpatients and about 12 000 surgical cases were postponed. As a result of the acute structural changes, the potential danger of falling below current treatment standards was seen in individual areas of patient care. DISCUSSION: The assessment of the impact of the SARS-CoV-2 pandemic is heterogeneous. The majority of the chairmen are critically aware of the risk of falling below current medical treatment standards or guidelines. In the phase of an exponential increase in the number of infections, significant changes in treatment processes had to be accepted for understandable reasons. However, with the currently significantly reduced number of infections, falling below treatment standards and guidelines should not be allowed to remain constant and tolerated. SUMMARY: This study shows a differentiated picture with regard to the effects of the SARS-CoV-2 pandemic on outpatient, inpatient and operative patient care at the ORL university hospitals in Germany and illustrates the importance of these institutions for ensuring patient care during this critical phase.

Development of a smartphone app for neuromuscular facial training.

BACKGROUND: Several studies have demonstrated a significant benefit of neuromuscular facial training in the rehabilitation of patients with facial palsy. However, printed instructions for home training are often not of optimum quality and associated with low adherence to therapy. Professional guidance, e.g., by occupational therapists, is regarded as being of high quality, but is associated with a high cost burden, particularly in chronic forms of disease. OBJECTIVE: The idea to develop a smartphone app for facial training arose from the above-described situation. The aim was to provide structured exercises for the mimic muscles in the sense of neuromuscular training with visual feedback via the front camera of the device. MATERIALS AND METHODS: A native app architecture in iOS was chosen to implement the graphical and content-related concept. In the Apple Xcode (Apple, Cupertino, CA, US) development environment, the app's code was written in the Swift programming language (Apple) and the graphical user interface was created. RESULTS: An app prototype was implemented that provides step-by-step instructions on selected mimic exercises via animated smileys. The duration and speed of the exercise can be varied within a limited range. In the development environment, the correct functionality of both physical and virtual devices was successfully tested. CONCLUSION: App-based facial training offers attractive opportunities to motivate patients for improved adherence to treatment, which could hypothetically lead to a better outcome. Evaluation of this question is planned in a clinical trial after completion of the development.

[Development of a smartphone app for neuromuscular facial training. German Version]. / Entwicklung einer Smartphone-App für neuromuskuläres Fazialistraining.

BACKGROUND: Several studies have demonstrated a significant benefit of neuromuscular facial training in the rehabilitation of patients with facial palsy. However, printed instructions for home training are often not of optimum quality and associated with low adherence to therapy. Professional guidance, e.g., by occupational therapists, is regarded as being of high quality, but is associated with a high cost burden, particularly in chronic forms of disease. OBJECTIVE: The idea to develop a smartphone app for facial training arose from the above-described situation. The aim was to provide structured exercises for the mimic muscles in the sense of neuromuscular training with visual feedback via the front camera of the device. MATERIALS AND METHODS: A native app architecture in iOS was chosen to implement the graphical and content-related concept. In the Apple Xcode (Apple, Cupertino, California, US) development environment, the app's code was written in the Swift programming language (Apple) and the graphical user interface was created. RESULTS: An app prototype was implemented that provides step-by-step instructions on selected mimic exercises via animated smileys. The duration and speed of the exercise can be varied within a limited range. In the development environment, the correct functionality of both physical and virtual devices was successfully tested. CONCLUSION: App-based facial training offers attractive opportunities to motivate patients for improved adherence to treatment, which could hypothetically lead to a better outcome. Evaluation of this question is planned in a clinical trial after completion of the development.

Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging in Pancreatic Cancer is Associated with Tumor Hypoxia.

Hypoxia is a hallmark of pancreatic cancer (PDAC) due to its compact and extensive fibrotic tumor stroma. Hypoxia contributes to high lethality of this disease, by inducing a more malignant phenotype and resistance to radiation and chemotherapy. Thus, non-invasive methods to quantify hypoxia could be helpful for treatment decisions, for monitoring, especially in non-resectable tumors, or to optimize personalized therapy. In the present study, we investigated whether tumor hypoxia in PDAC is reflected by diffusion-weighted magnetic resonance imaging (DW-MRI), a functional imaging technique, frequently used in clinical practice for identification and characterization of pancreatic lesions. DW-MRI assesses the tissue microarchitecture by measuring the diffusion of water molecules, which is more restricted in highly compact tissues. As reliable surrogate markers for hypoxia, we determined Blimp-1 (B-lymphocyte induced maturation protein), a transcription factor, as well as vascular endothelial growth factor (VEGF), which are up-regulated in response to hypoxia. In 42 PDAC patients, we observed a close association between restricted water diffusion in DW-MRI and tumor hypoxia in matched samples, as expressed by high levels of Blimp-1 and VEGF in tissue samples of the respective patients. In summary, our data show that DW-MRI is well suited for the evaluation of tumor hypoxia in PDAC and could potentially be used for the identification of lesions with a high hypoxic fraction, which are at high risk for failure of radiochemotherapy.

Risk factors for children requiring adenotonsillectomy and their impact on postoperative complications: a retrospective analysis of 2000 patients.

Adenotonsillectomies are commonly performed procedures and sleep-disordered breathing is becoming increasingly important as an indication for surgery. Because of the higher risks in patients with obstructive sleep apnoea, the required level of postoperative care for these patients is currently under discussion, and better identification of patients at risk may reduce unnecessary postoperative monitoring. To evaluate the influence of obstructive sleep apnoea, and other risk factors, on peri-operative complications in children requiring adenotonsillectomy, we performed a retrospective case-control study that included 1995 patients treated between January 2009 and June 2017. In our analysis, young age (OR 3.8, 95%CI 2.1-7.1), low body weight (OR 2.6, 95%CI 1.5-4.4), obstructive sleep apnoea (OR 2.4, 95%CI 1.5-3.8), pre-existing craniofacial or syndromal disorders (OR 2.3, 95%CI 1.4-3.8) and adenotonsillectomy, compared with adenoidectomy alone, (OR 7.9, 95%CI 4.7-13.1) were identified as risk factors for complications during or after surgery, p < 0.001. All 13 patients suffering from complications more than 3 h postoperatively had obstructive sleep apnoea plus at least one more of these risk factors. Patients at risk of postoperative complications can therefore be identified by several criteria pre-operatively, and should be monitored postoperatively using pulse oximetry overnight. For all other patients, postoperative observation on a surgical ward without extra monitoring is sufficient. Admission to paediatric intensive care should be reserved for patients suffering serious intra-operative complications.

Perilipin 1 Expression Differentiates Liposarcoma from Other Types of Soft Tissue Sarcoma.

Lipid droplets, a morphologic feature of adipocytic tumors, are strongly regulated by associated proteins of the perilipin/PAT (perilipin, adipophilin, and tail-interacting protein of 47 kD) family. So far, the use of perilipins as markers for differential diagnosis of soft tissue tumors has only been studied in a few cases. The aim of this study was to investigate the expression of perilipins in 478 human soft tissue tumors and 60 respective normal tissues. Perilipin 1 was immunohistochemically positive in all studied cases of well-differentiated liposarcomas, >90% of myxoid round cell liposarcomas, and >70% of pleomorphic liposarcomas, whereas only the differentiated components of dedifferentiated liposarcomas were immunohistochemically positive for perilipin 1. All other types of soft tissue sarcomas were negative for perilipin 1. Perilipin 2 was more prominent in dedifferentiated and pleomorphic liposarcomas and nearly all other high-grade sarcomas. In well-differentiated liposarcomas, lipomas, or normal adipose tissue, perilipin 2 was virtually absent. In addition, long-term stimulation of adipogenesis in the liposarcoma cell line LiSa-2 restored perilipin 1 expression, as exhibited in the source tumor. Furthermore, knockdown of perilipin 2 or perilipin 3 in LiSa-2 cells influenced lipid droplet number and size as well as cell vitality. In summary, perilipin 1 is a promising marker for the differential diagnosis of liposarcomas from other soft tissue sarcomas, whereas perilipin 2 correlates negatively with tumor grade and may be therapeutically useful.

[Recurrent infections of the upper aerodigestive tract in patients with primary immunodeficiency]. / Rezidivierende Infektionen bei Patienten mit primären Immundefekten im oberen Aerodigestivtrakt.

BACKGROUND: Primary immunodeficiency is a rare disease of humoral and cellular immune defense, which can lead to severe and recurrent infections of different organs. The diagnosis of this disease is often difficult, and its early identification is necessary for adequate treatment and control. OBJECTIVE: This study aimed to analyze ear, nose, and throat (ENT) infections in adults and children with a primary immunodeficiency. We attempted to characterize possible warning signs that should trigger an immunologic diagnostic workup. MATERIALS AND METHODS: The current study comprised a retrospective case series of patients with primary immunodeficiencies. The type of immunodeficiency and the number of ENT infections were recorded. RESULTS: A total of 85 Patients were included in the study. 56 patients (66%) had an acute exacerbation of chronic rhinosinusitis (n = 28), cervical lymphadenitis (n = 16), acute tonsillitis (n = 14), and acute otitis media (n = 6). Reporting detailed information about the frequencies and dates of infections was not possible, due to the retrospective nature of the analysis. CONCLUSION: The prevalence of ENT infections in patients with a primary immunodeficiency is increased compared to the normal population. For the ENT specialist, these findings underline the necessity of including primary immunodeficiency in the differential diagnosis and initiating targeted diagnostic methods where indicated. Interdisciplinary collaboration with rheumatologists and immunologists is highly recommended, particularly for pediatric patients.

Loop-mediated isothermal amplification for paratyphoid fever - a proof-of-principle analysis.

In-house loop-mediated isothermal amplification (LAMP) procedures for the detection of paratyphoid fever-associated bacteria on serovar level were evaluated. Therefore, LAMP primers for Salmonella genus, for two LAMP schemes for S. Paratyphi A, for S. Paratyphi B and for S. Paratyphi C were tested with DNA from culture isolates from strain collections and spiked blood cultures against published PCR protocols targeting the same micro-organisms. Sensitivity and specificity for DNA from culture isolates verified by LAMP ranged from 80·0 to 100·0% and 96·1 to 100·0% vs 65 to 100% and 98·7 to 100% for the PCR approaches. For the spiked blood culture materials, sensitivity and specificity for LAMP ranged from 87·5 to 100·0% and 96·7 to 100·0% vs from 60 to 100% and 98·2 to 100% for PCR. In conclusion, LAMP for paratyphoid fever shows comparable performance characteristics as PCR. Due to its easy application, the procedure is well suited for surveillance purposes in resource-limited settings. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of easy-to-apply, point-of-care-testing-like loop-mediated isothermal amplification (LAMP) for the diagnosis of paratyphoid fever is evaluated. This approach can contribute to low-threshold availability of surveillance options for resource limited settings. Easy-to-teach and easy-to-apply LAMP schemes with similar performance characteristics as PCR are provided. The described test evaluation is of particular use for surveillance and public health experts.

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.