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.

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.

[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.

Pegylated liposomal doxorubicin as first-line monotherapy in elderly women with locally advanced or metastatic breast cancer: novel treatment predictive factors identified.

We investigated the efficacy and safety of single-agent pegylated liposomal doxorubicin (PLD) as first-line treatment for elderly women with advanced breast cancer and evaluated predictive markers for response and toxicity. Twenty-five women ≥ 65 years received 40 mg/m(2) PLD every 28 days. Time to treatment failure (TTF), response rate, time to progression (TTP) and overall survival (OS) was calculated. The ABCB1 single nucleotide polymorphisms (SNP), tumor MRN complex, and TOPOIIα were analyzed. A mean of 7.4 cycles PLD were administered and TTF was 5.5 months and OS 20.6 months. ABCB1 SNPs were found to correlate to both efficacy and toxicity, while tumor expression of the MRN complex and TOPOIIα correlated to TTP. PLD is a safe and effective treatment for elderly breast cancer patients. Also potential predictive markers were identified.

[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.

[Small cell carcinoma of parotid gland--a case report]. / Kleinzelliges Karzinom der Glandula parotis--ein Fallbeispiel.

BACKGROUND: Small cell carcinoma of the major salivary glands are very seldom. If there is such a tumor always have in mind that it can be a metastatic process of another small cell carcinoma in other locations of the body. That's why first of all a primary in the bronchial system has to be excluded with special diagnostics. CASE REPORT: We present the case of a 72-year-old woman suffering from a small cell carcinoma of Parotid gland. Because a surgical therapy was impossible she underwent a radiotherapy. CONCLUSION: First choice for therapy of tumors of the major salivary glands is surgical therapy in combination with radiation/chemotherapy. If this is not possible a primary radiotherapy sometimes in combination with chemotherapy seems to be another therapeutic option.

[Carcinosarcoma of the larynx and hypopharynx]. / Karzinosarkome des Larynx und Hypopharynx.

INTRODUCTION: A carcinosarcoma is an uncommon neoplasm with both malignant epithelial and malignant mesenchymal components. The tumor entity has been described in many epithelial organs. Manifestation in the larynx and the hypopharynx is rare. PATIENTS: This report recounts two patients, one with a carcinosarcoma of the vocal cords and the other with a hypopharynx tumour. On the background of the literature we discuss the peculiarities of histology, pathogenesis, clinical features and therapy. DISCUSSION: Carcinosarcomas of the larynx and hypopharynx are typically described in elderly men. Smoking, alcohol and previous irradiation of the head and neck are predisposing etiologic factors. Clinical symptoms correspond to other neoplasms of the area--a short anamnesis is typical. In most cases the endoscopy reveals the presence of an exophytic lesion with intact epithelial surface. Crucial for the diagnosis is the revelation of a carcinoma together with sarcoma in the histology and immunohistochemistry both in the primary and secondary side. The histogenesis of carcinosarcoma is not yet clear--it seems that a pluripotent cell produces both tumour components. Most authors recommend complete surgical excision of the primary, regional lymphadenectomy and postoperative irradiation. Despite of an often large tumor volume the preservation of the larynx seems to be possible in many cases, because exophytic tumours are pre-potent. Survival rates are similar to those of patients with squamous cell carcinoma.

Oncogene-blocking therapies: new insights from conditional mouse tumor models.

Identification of oncogene dependent signaling pathways controlling aggressive tumor growth has led to the emergence of a new era of oncogene-blocking therapies, including Herceptin and Gleevec. In the recent years conditional mouse tumor models have been established that allow switching-off the expression of specific oncogenes controlling tumor growth. The results may have two important implications for oncogene-blocking therapies: (i) downregulation of oncogenes, for instance HER2, MYC, RAS, RAF, BCR-ABL or WNT1, usually leads to a rapid tumor remission. However, it was observed that the initial remission was followed by recurrent tumor growth in most studies. Interestingly, different oncogenes controlled tumor growth in the recurrent than in the primary tumors. This could explain the astonishing clinical observation that inhibitors of a broader spectrum of protein kinases (so-called: "dirty inhibitors") may be superior over highly specific substances. Due to their additional "unspecific" inhibition of a broader spectrum of kinases, they may hamper the escape mechanisms by antagonizing also the pathways controlling recurrent tumor growth. (ii) Experiments with cell systems that allow switching-on oncogene expression point to a so far possibly underestimated cancer drug target: the dormant tumor cell. Oncogene expression (for instance: NeuT or RAS) led to a phenomenon named oncogene-induced senescence or dormancy. Dormant cells are unresponsive to mitogenic stimuli. Importantly, such cells are not at all ready to die, but can remain viable for extended periods of time. Recently, dormant tumor cells have been shown to be more resistant to stresses such as hypoxia or exposure to cytostatic drugs. It still is a matter of debate if and under which conditions dormant tumor cells can be "kissed to life". If these cells contribute to carcinogenesis, it will be important to identify substances specifically killing senescent cells. This review will focus on the possible relevance of senescence both as a pre-oncogenic condition and also for therapy.

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.