Adverse outcome pathway (AOP): α2u-globulin nephropathy and kidney tumors in male rats.

The National Research Council's vision of using adverse outcome pathways (AOPs) as a framework to assist with toxicity assessment for regulatory requirements of chemical assessment has continued to gain traction since its release in 2007. The need to expand the AOP knowledge base has gained urgency, with the U.S. Environmental Protection Agency's directive to eliminate reliance on animal toxicity testing by 2035. To meet these needs, our goal was to elucidate the AOP for male-rat-specific kidney cancer. Male-rat-specific kidney tumors occur through the ability of structurally diverse substances to induce α2u-globulin nephropathy (α2u-N), a well-studied mode of action (MoA) not relevant in humans that results in kidney tumor formation in male rats. An accepted AOP may help facilitate the differentiation from other kidney tumors MoAs. Following identification and review of relevant in vitro and in vivo literature, both the MIE and subsequent KEs were identified. Based on the weight of evidence from the various resources, the confidence in this AOP is high. Uses of this AOP include hazard identification, development of in vitro assays to determine if the MoA is through α2u-N and not relevant to humans resulting in decreased use of animals, and regulatory applications.

[Surgical therapy of oropharyngeal cancer-state of the art]. / Operative Behandlung des Oropharynxkarzinoms ­ Stand der Technik.

Surgical therapy, regardless of the procedure, remains of great importance for today's treatment of oropharyngeal carcinomas, despite advances in radiation and immunotherapy. The individual treatment plan should be defined in discussion with the patient and in an interdisciplinary tumor conference, taking into account the likelihood of achieving of tumor-free resection margins and an acceptable postoperative quality of life. With regard to conventional and possibly also open surgical procedures, a good overview of the surgical site-particularly in the case of more extensive carcinomas and challenging patient anatomy-and simplified reconstructability of the defect region are decisive aspects. Endoscopically, microsurgically, or even robot-assisted minimally invasive procedures have the advantage of precise and gentle removal of tumor tissue with improved maintenance of function. Overall, selection of the appropriate surgical procedure remains an individual decision based on tumor size, the facilities at the tumor center, and the surgeon's experience. The extent of surgical intervention, also with regard to simultaneous neck dissection, depends on tumor stage. In the case of oropharyngeal carcinomas, there will be an increasing distinction between human papillomavirus (HPV)-negative and HPV-positive tumors in the future; however, the therapeutic strategy is currently identical. Upcoming clinical trials will show whether treatment de-escalation is appropriate depending on HPV infection status.

[Prognostic and predictive methylation biomarkers in HNSCC : Epigenomic diagnostics for head and neck squamous cell carcinoma (HNSCC)]. / Prognostische und prädiktive Methylierungsbiomarker für HNSCC : Epigenomische Diagnostika für Plattenepithelkarzinome des Kopf- und Halsbereichs (HNSCC).

BACKGROUND: Prognostic and predictive biomarkers for personalized treatment management in head and neck squamous cell carcinoma (HNSCC) are of great clinical interest. OBJECTIVE: DNA methylation is an epigenetic process involved in gene regulation and could be a source of potential prognostic and predictive biomarkers. METHODS: This study comprises literature research in PubMed and own studies. RESULTS: Gene methylation, e.g. of PITX2, is a strong, human papillomavirus (HPV)-independent prognostic biomarker. SHOX2 and SEPT9 methylation in circulating cell-free DNA within blood plasma correlates with tumor stage and prognosis. Methylation of diverse immune checkpoints, e.g., PD­1, PD-L1, and CTLA4, is also prognostic and correlates with gene expression. CONCLUSION: DNA methylation is a source of efficient prognostic blood plasma- and tissue-based biomarkers. However, prior to clinical implementation, studies must prove that biomarker-guided treatment selection can lead to better outcomes or reduced toxicity. The applicability of DNA methylation as a predictive biomarker for targeted drug-based cancer therapy seems promising, although further validation is needed.

[Tonsil surgery in Brandenburg-trends between 2013 and 2017]. / Operationen an den Gaumenmandeln im Land Brandenburg ­ Entwicklungen von 2013 bis 2017.

BACKGROUND: The frequency of tonsil surgery in Brandenburg (BB) during the period from 2013 to 2017 is analyzed. Causes and possible consequences of the trends are discussed. MATERIALS AND METHODS: An OPS code-based survey is carried out in the 10 ENT hospitals in BB and using the data from the federal states (Federal Statistical Office). In addition, the respective heads of ENT departments are interviewed concerning the indication for tonsillectomy (TE). The average number of operations in 2013/2014 is compared to that in 2017 (BB) and 2016 (federal states). RESULTS: In 9/10 participating hospitals in BB, 10,302 operations were performed, thereof 58.4% as TE, 19.0% as tonsillotomy (TT), 13.7% as abscess tonsillectomy (abscess TE), and 8.9% other. In BB in 2017 in comparison to 2013/2014, because of the decrease in TE by 45.6%, a total of 21.1% less operations were performed, while TT and abscess TE increased by 32% and 18%, respectively. The average age at surgery was 28.1, 38.1, and 5.9 years for TE, abscess TE, and TT, respectively. The entire trend for Germany until 2016 on the basis of 395,674 cases reflects a decrease in TE (30.7%) and abscess TE (14%), while TT was performed 27.5% more often, resulting in a total decrease of 21.3%. The interviewed persons follow the "justifiable operation indications" of the German guideline from 2015 and adapted their previous practice. CONCLUSION: Our survey and results indicate that the massive decrease of TE in BB is associated with the "justifiable operation indications" of the 2015 German guidelines on inflammatory diseases of the tonsils. TE is mainly performed in adults. Therefore, research concerning conservative versus surgical treatment for recurrent tonsillitis is urgently needed for this age profile.

[Significance of Secondary Mucosal Primaries in Patients with a Cervical CUP-Syndrome]. / Bedeutung des sekundär auftretenden Primärtumors bei einem zervikalen CUP-Syndrom.

BACKGROUND: We discuss the significance of an occult primary in the prognosis of cervical carcinoma with unknown primary (CUP) after completion of diagnostic and treatment. PATIENTS/METHODS: A series of 36 patients diagnosed between 2001 and 2009 underwent staging including panendoscopy, mapping and tonsillectomy, ultrasound and CT/MRI of the neck, thorax and abdomen. The patients recieved neck surgery followed by adjuvant radio-(chemo-)therapy of cervical fields as well as limited mucosal irradiation (IMRT, GHD 50 Gy). The results of tumor control and therapy-related toxicity were ascertained. RESULTS: A secondary primary of the cervical metastases was not detected during follow-up. 6 patients died from distant metastases and 1 from chemotherapy; 4 patients died from a different secondary tumour, 2 patients died intercurrently. We did not observe late toxicity but 8% of patients had Grade 3 dysphagia. DISCUSSION: Efficacy of diagnostic procedure and therapy are important in treating occult primary tumours in CUP. Our results show that omitting PET-CT, which was not available in diagnostic workup of the study-patients, did not impact negatively on the manifestation rate of mucosal primaries and/or was compensated for by intensive therapy. Distant metastases and infraclavicular secondary primaries had a negative impact for the survival. Elective therapy of a presumed occult primary tumour in CUP should be included into the therapeutic discussion considering its efficacy and toxicity.

[Extranodal Metastases of Renal Cell Carcinoma to the Head and Neck: A Diagnostic Challenge]. / Extranodale Metastasen von Nierenzellkarzinomen in der Kopf-Hals-Region.

BACKGROUND: Single case reports about extranodal renal cell carcinoma (RCC) metastasis to the head and neck (HN) often implicating unusual clinical follow-ups are well known. Subject of our investigation is to ascertain the true meaning of RCC for differential diagnostic of the head and neck surgion. METHODS: We retrospectively review the reports of 612 patients with RCC treated in a 13-years period in the department of urology. RESULTS: Of the 612 RCC 191 (31%) were metastatic, 3 female and 4 male (mean 66.8a, 56a-78a) presented with extranodal metastases within the HN. Extranodal locations were parotid and thyroid glands (2 ×), tongue, forehead scin, bone and paranasal sinus. Occurrence of metastases were observed in mean 40.8 months (5-87) after the primary. In one patient metastasis to the parotid gland was the only manifestation of RCC 78 month treated before, the others presented with further metastases to infraclavicular organs. DISCUSSION: According to our results extranodal metastases of RCC to the HN are uncommon (1.1%). Therefore and because of the unusual location extranodal metastases of RCC remain a diagnostic challenge for the ENT specialist and the pathologist with peculiar knowledge of the oncological history of the patient remaining an essential condition. We found exclusive metastasis to the HN in only one of 7 cases. Nevertheless surgical treatment has to be considered in curative and symptomatic treatment strategies.

[Acute dyspnea in malignant melanoma]. / Akute Dyspnoe bei malignem Melanom der Haut.

Metastases to the larynx are rare. The current article presents the case of a 75-year-old patient with a history of shortness of breath due to a supraglottic exophytic lesion that was identified as a metastasis of a cutaneous melanoma treated 2.5 years previously. As a result of our medline analysis we found approximately 30 cases of metastatic melanoma to the larynx published to date. Primary tumors are always cutaneous in origin and spread over the whole integument of trunk and extremities. The time interval between diagnosis of the primary and the laryngeal metastasis is often several years. In most reports a supraglottic exophytic, red coloured lesion is described. Diagnosis can only be proven by histological examination. Laryngeal metastasis is usually an indication of tumor dissemination and always has a fatal prognosis.

[Neck tumor following tracheotomy]. / Raumforderung des Halses nach Tracheotomie.

The patient presented here suffered from a tumor of the frontal part of the neck and from position-dependent dyspnea. He had a history of tracheostomy following vascular surgery; the tracheostomy did not close spontaneously, so it needed to be sutured. The tracheostomy channel seemed to have developed spontaneous epithelization. After its closure, an epidermoid cyst developed from the epithelium. This cyst was the cause of the patient's symptoms, and it was surgically removed.

Health-related quality of life in oropharyngeal cancer survivors - a population-based study.

OBJECTIVE: The aim of this study was to compare QoL of oropharyngeal cancer survivors who had received different treatments. SUBJECTS AND METHODS: We contacted 954 survivors. Each survivor received the QoL questionnaires EORTC QLQ-C30 and EORTC QLQ-H&N35. RESULTS: A total of 263 survivors completed the questionnaires (28% responses). Forty-five of them had undergone surgery, 20 had received definitive radiotherapy or chemo-radiotherapy, 85 surgery plus adjuvant radiotherapy, and 111 surgery plus adjuvant chemo-radiotherapy. Survivors who had received adjuvant radiotherapy and surgery reported significantly more problems with swallowing (B=13.43 [95% Confidence Interval (CI) 1.83-25.03]), senses (B=24,91 [CI 11.86-37.97]), eating (B=16.91 [CI 3.46-30.36]), dry mouth (B=26.42 [CI 12.17-40.67]), sticky saliva (B=22.37 [CI 6.23-38.50]) and nutritional supplements (B=18.59 [CI 0.62-36.56]) than those who had received surgery only. Survivors who had received adjuvant chemo-radiotherapy and surgery reported significantly many more problems with dry mouth (B=34.15 [CI 18.91-49.39]) and sticky saliva (B=22.90 [CI 5.65-40.16]), and fewer problems with physical functioning (B=-12.07 [CI 0.49-23-64]). CONCLUSION: Survivors who participated in this survey and who had undergone surgery alone reported in some head- and neck-specific domains a better health-related quality of life than patients who had undergone multi-modal treatment or adjuvant radiotherapy.

The rising incidence of parotid metastases: our experience from four decades of parotid gland surgery.

Secondary neoplasia in the parotid gland is increasingly frequent. We examined outcomes from 40 years of parotid surgery to analyse patterns for metastasis, review the staging procedure and discuss management. We retrospectively examined 772 consecutive cases of parotid surgery in a university hospital between 1975 and 2015 and assessed changes in incidence and management over four decades. In all, 71% percent of patients were male and 29% were female, with a mean age of 68 years, aged between 23 and 93 years. We diagnosed 683 parotid tumours of which 15.8% (n = 108) were malignant; 44% (n = 48) of all malignant lesions were metastases. The incidence of malignant tumours rose from 8% in the first decade, 14% in the second, 17% in the third to 21% in the fourth. The incidence increased even further from 10% in the first to 57% in the final decade. Most frequent tumours were metastases of squamous cell carcinoma (79%), and the majority of these lesions (87%) arose from above the clavicle, with 30 primary tumours in the skin. In most cases, the skin tumour had been excised between 6 and 24 months prior to parotid metastasis. Management consisted of surgery with neck dissection. 48 patients (67%) received adjuvant therapy, but despite aggressive multimodal treatment, disease progressed in the majority of cases, in 57% squamous cell carcinoma of the skin primaries, 67% of mucosal primaries above the clavicle and 83% of infraclavicular primaries. Parotid malignant tumours are increasing in incidence, mostly due to a rise in metastatic malignant tumours within the parotid gland, most of which are metastases of skin tumours, commonly squamous cell carcinoma. Despite multimodal therapy, their recurrence and progression rate remains high. We propose inclusion in head and neck follow-up in all cases of head and neck skin cancers.

Expression of transforming growth factor-beta1, activin A, and their receptors in thyroid follicle cells: negative regulation of thyrocyte growth and function.

Thyroid growth and function are intricately regulated by both positive and negative factors. In the present study, we have investigated the expression of transforming growth factor-beta (TGF-beta) super-family members and their receptors in normal porcine thyroid follicle cells. In tissue sections of porcine thyroids, we observed an expression of TGF-beta1, activin A, and bone morphogenetic protein (BMP)-7 proteins. The staining was localized to the follicular epithelium. In affinity cross-linking experiments, TGF-beta1 was found to bind to heteromeric complexes of TGF-beta type I and type II receptors, and activin A bound most efficiently to heteromeric complexes of activin type IB and type II receptors. We were unable to detect any BMP receptors (BMPRs) in attempts to perform affinity cross-linking with BMP-7. However, expression of BMPR-IA and BMPR-II messenger RNA (mRNA) was detected by Northern blot analysis. Both TGF-beta1 and activin A, but not BMP-7, increased the phosphorylation of Smad2, induced nuclear translocation of Smad2, Smad3, and Smad4, and inhibited thyrocyte cell growth as well as TSH-stimulated cAMP response. TGF-beta1 was more potent, compared with activin A, to induce these cellular responses. Taken together, our findings indicate a role for several members of the TGF-beta family in regulation of thyroid growth and function.

Usefulness of tilt test-induced patterns of heart rate and blood pressure using a two-stage protocol with glyceryl trinitrate provocation in patients with syncope of unknown origin.

This study assesses the vasovagal collapse pattern changes, i.e, heart rate (HR) and arterial blood pressure (BP) with a 2-stage tilt-test protocol using glyceryl trinitrate (GTN) provocation. With use of the 45-minute 60 degrees head-up Westminster protocol, 102 consecutive patients were studied. Sublingual GTN 300 microg was given to those with a negative passive tilt. Heart rate and BP patterns were classified according to the Vasovagal International Study classification (VASIS) and then compared between those with a positive passive tilt and those with a positive tilt after having been given GTN. Twelve patients did not tolerate tilt testing, and 16 had a negative response despite taking GTN. Thirty-five patients (20 women and 15 men, mean age 45 +/- 21 years [mean +/- SD]) did not take GTN and 38 (26 women and 12 men, mean age 53 +/- 22 years) had positive passive test results. When comparing the VASIS classification between the 2 groups, results showed: type 1, mixed BP and HR decreased without severe bradycardia (31% [passive] vs 54% [with GTN], p = NS); type 2A, BP decreased before HR decreased (20% vs 22%, p = NS); type 2B, HR decreased before or coincident with BP (34% vs 8%, p = 0.003); type 3, BP decreased without HR decrease (9% vs 0%, p = NS); exception 1, chronotropic incompetence (0% vs 13%, p = 0.026); and exception 2, excessive HR increase (6% vs 3%, p = NS). Thus, GTN use increases frequency of positive results from 34% to 73%. Older people with chronotropic incompetence, who may benefit from pacing, were identified. In younger people there was an increase in those with cardioinhibition.

Extracellular matrix components in atherosclerotic arteries of Apo E/LDL receptor deficient mice: an immunohistochemical study.

During accelerated vascular remodeling such as in atherosclerosis, the composition of the extracellular matrix becomes altered. The matrix components of the diseased artery influence cellular processes such as adhesion, migration and proliferation. Furthermore, in atherosclerosis, the inability of the cells within the lesion to produce a mechanically stable matrix may lead to plaque rupture. In this immunohistochemical study of atherosclerotic mice aorta, we have reviewed the presence of ECM components with roles in maintaining tissue structure and function. These components include osteopontin and COMP as well as the leucine rich repeats proteins decorin, PRELP, and fibromodulin. Immunohistochemistry demonstrated presence of osteopontin, COMP, decorin, PRELP and fibromodulin in lesion areas of ApoE/LDLr deficient mice. Some advanced lesions exhibited areas of cartilage-like morphology and were shown to represent cartilage by their content of the cartilage specific proteins collagen II and aggrecan. The results suggest that cartilage-associated cell/collagen binding ECM proteins may be involved in the pathogenesis of atherosclerosis.

Alkylaminopropenones and alkylamino-propenoates as efficient and versatile synthons in microwave-assisted combinatorial synthesis.

A simple and fast one-pot method using microwave irradiation for the synthesis of a number of small libraries of diverse heterocycles is described in this paper. The two-step one-pot method includes the formation of alkylaminopropenones or alkylaminopropenoates in 5 min at 180 degrees C and a subsequent treatment with dinucleophiles for 3 to 5 min at 150 degrees C to 180 degrees C to form a variety of biologically interesting heterocycles in a cascade-type reaction. The combination of combinatorial chemistry and microwave-assisted synthesis was found to be very efficient.

Morphometric and densitometric study of the biogenesis of electron-dense granules in Fonsecaea pedrosoi.

Fonsecaea pedrosoi is a polymorphic pathogenic fungus, etiological agent of chromoblastomycosis, that synthesizes a melanin-like pigment. Although this pigment has been described as a component of the outer layers of the cell wall, electron-dense cytoplasmic bodies have also been visualized. In this work, we have correlated the appearance of intracellular electron-dense granules with the melanization process in F. pedrosoi. For this, conidial forms were grown under conditions where melanin was not synthesized. Afterwards, cells were incubated in Hank's medium supplemented with bovine fetal serum, at 37 degrees C, to stimulate the pigment production. The genesis of cytoplasmic bodies, with different stages of electron density, was demonstrated by transmission electron microscopy. The appearance of fungal acidic compartments, visualized by confocal laser scanning microscopy in cells stained with acridine orange, was time coincident with the formation of electron-dense granules observed by transmission electron microscopy. The quantification of granule numbers as well as morphometric and densitometric studies were performed.

Expression of stanniocalcin in the epithelium of human choroid plexus.

Stanniocalcin (STC) is a 28 kD glycoprotein hormone originally found in bony fish in which it regulates calcium/phosphate homeostasis and protects against hypercalcemia. The recently characterized mammalian STC shows about 70% homology with fish STC. The epithelial cells of proximal tubuli in human and rat kidney and brain neurons have been found to express STC. Here we show that the epithelium of the choroid plexus, already at 16 weeks of fetal age, and of plexus papillomas, synthesize and express STC. Our findings suggest that STC may be of importance for the distribution of calcium and phosphate between the cerebrospinal fluid and blood.