Opposing effects of cannabidiol in patient-derived neuroendocrine tumor, pheochromocytoma/paraganglioma primary cultures.

CONTEXT: Treatment options for advanced neuroendocrine tumors (NETs), pheochromocytomas and paragangliomas (together PPGLs) are still limited. In recent years, anti-tumor effects of cannabinoids have been reported; however, there are only very limited data available in NETs or PPGLs. OBJECTIVE: Investigation of the effects of cannabidiol (CBD) on patient-derived human NET/PPGL primary cultures and on NET/PPGL cell lines. METHODS: We established primary cultures derived from 46 different patients with PPGLs (n = 35) or NETs (n = 11) who underwent tumor resection at two centers. Treatment of patient primary cultures with clinically relevant doses (5 µM) and slightly higher doses (10 µM) of CBD was performed. RESULTS: We found opposing effects of 5 µM CBD: significant anti-tumor effects in 5/35 (14%) and significant tumor-promoting effects in 6/35 (17%) of PPGL primary cultures. In terms of anti-tumor effects, cluster 2-related PPGLs showed significantly stronger responsivity to CBD compared to cluster 1-related PPGLs (p = 0.042). Of the cluster 2-related tumors, NF1 PPGLs showed strongest responsivity (4/5 PPGL primary cultures with a significant decrease in cell viability were NF1-mutated). We also found opposing effects of 10 µM CBD in PPGLs and NETs: significant anti-tumor effects in 9/33 of PPGL (27%) and 3/11 of NET (27%) primary cultures, significant tumor-promoting effects in 6/33 of PPGL (18%) and 2/11 of NET (18%) primary cultures. CONCLUSIONS: We suggest a potential novel treatment option for some NETs/PPGLs, but also provide evidence for caution when applying cannabinoids as supportive therapy for pain or appetite management to cancer patients, and possibly as health supplements.

[Conspicuous Conditions of the Tongue: Normal Variants vs. Pathological Findings].

INTRODUCTION: With its sensitivity, taste buds and complex anatomical structure of various muscles, the tongue is a central organ for speaking, tasting and food intake, especially oral food transport, chewing and swallowing. Changes in the tongue 's condition are frequent and often lead to uncertainty among patients and eventually to a visit to the family doctor, to the ear, nose and throat specialist, dentist or maxillofacial surgeon. The question whether the condition of the tongue is a lesion requiring treatment or just a variant can quite often prove a major challenge. The differential diagnoses are wide-ranging from harmless changes to alarming signs of disease. The time and duration of occurrence, the accompanying symptoms such as a burning sensation or taste disorders as well as risk factors such as nicotine and alcohol consumption are important anamnestic elements. Possible causes can be malnutrition, systemic diseases, inflammatory processes or malignancies. Accordingly, a blood test and a smear or a biopsy may be necessary as the first diagnostic step. The aim of this review is to explain the different types and causes of tongue problems and to explain in which cases further clarifications are necessary.

Need for adjuvant radiotherapy in oral cancer: depth of invasion rather than tumor diameter.

PURPOSE: The 8th edition of the TNM Cancer Staging Manual incorporates depth of invasion (DOI) into the pathologic tumor classification for oral squamous cell carcinoma (OSSC). While deep invading tumors with small tumor diameters (TD) have been categorized as early stage tumors in the 7th edition, they are now upstaged, potentially influencing the decision to initiate adjuvant radiotherapy (RT). METHODS: OSCC patients surgically treated with curative intent between 2010 and 2019 were consecutively included. Tumors were staged based on TD only (according to the 7th edition TNM Cancer Staging Manual), then restaged based solely on DOI. RESULTS: Of the 133 included patients, 58 patients (43.6%) had a different pT-stage when using DOI instead of TD for staging (upstaging in 23.3%). Overall survival (OS) was significantly worse in patients who were upstaged with DOI. In addition, stratification by adjuvant RT showed significant worse OS in upstaged patients without receiving adjuvant RT. CONCLUSIONS: DOI seems to be an import indicator for adjuvant RT in OSCC-patients.

Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures.

Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1-related (n = 10) and kinase signaling-associated cluster 2-related (n = 14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, and 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, and high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2a inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.

Histopathological Features of Parathyroid Adenoma and 18F-Choline Uptake in PET/MR of Primary Hyperparathyroidism.

BACKGROUND: The aim of this study was to assess the relationship between the histopathological properties of hyperfunctioning parathyroids and parathyroid 18F-choline uptake. PATIENTS AND METHODS: A total of 31 parathyroid adenomas were retrospectively analyzed in patients with primary hyperparathyroidism and preoperative 18F-choline PET/MR. PET/MR parameters of parathyroid glands (SUVmax and target-to-background ratio in early-phase [EP] and late-phase [LP]), MRI volume, preoperative parathyroid hormone (PTH) serum concentration, and postoperative histopathology (predominant cell type and growth pattern of adenoma cells, location and size of adenoma) were assessed. The relationship of PET/MR parameters, PTH, and histological parameters was determined using linear regression, Spearman correlation and Kruskal-Wallis test. RESULTS: The median volume of parathyroid adenoma was 421.78 ± 142.46 mm3 (46.39-4412.69). Adenomas were predominantly composed of chief, water-clear, and oncocytic/oxyphilic cells in 27/31, 2/31, and 2/31 cases, respectively. The growth pattern was predominantly solid, follicular, and trabecular in 18/31, 8/31, and 5/31, respectively. The SUVmax was 6.71 ± 3.39 in EP and 6.91 ± 3.97 in LP. Follicular growth pattern had slightly higher EP SUVmax (trabecular: 4.12 ± 0.56; solid: 6.62 ± 3.19; follicular: 8.56 ± 3.96; P = 0.046). Spearman correlation showed strong positive correlation between volume and both EP and LP SUVmax (0.626; P = 0.0001 and 0.576; P = 0.0001, respectively). Linear regression analysis revealed significant correlation between PTH level and EP and LP SUVmax (both P = 0.001); in contrast, no correlation was found between PTH level and both cell type and growth pattern. CONCLUSIONS: Our findings suggest that 18F-choline uptake of parathyroid adenomas might be associated both with the histological growth pattern and adenoma volume, but not with a specific cell type.

[Update for Diagnosis and Management of HPV-Driven Oropharyngeal Cancer]. / HPV-assoziierte Oropharynxkarzinome: Update zu Diagnose und Management.

Update for Diagnosis and Management of HPV-Driven Oropharyngeal Cancer Abstract. In the past decades, an increasing incidence of oropharyngeal squamous cell cancer could be observed. More than twenty years ago, a correlation between a pharyngeal Human papillomavirus high-risk type infection and the development of oropharyngeal cancer has been suspected. Especially younger patients without the former risk factors smoking and alcohol have a higher prevalence for this cancer type. HPV-associated cancer is developing in the lymphatic tissue of the tonsils and the base of the tongue. HPV-driven tumors can be defined as a clinical and morphologic distinct tumor entity with a significantly better prognosis compared to tumors based on smoking and alcohol consumption. They are demonstrating a clearly better treatment response irrespective of the treatment modality. The tumor development is assumed to be comparable to cervical cancer, probably through a step-wise process from dysplasia to invasive cancer. In the pharynx, no HPV-associated precursor lesions have been detected so far. Therefore, Screening program proven to be very successful in the cervix have not could not have been implemented so far. The reduction of HPV-associated tumor burden in the cervix is likely to be compensated by the rising number of HPV-driven oropharyngeal cancer. P16 as a surrogate marker for HPV has been implemented in the 8th edition of the TNM classification for oropharyngeal cancer. A worldwide accepted definition of an HPV-driven tumor is lacking so far. P16 immunhistochemistry or HPV-DNA detection by PCR as single markers have an insufficient sensitivity and specificity. A combination of both markers demonstrates a higher accuracy compared to the gold standard RNA. Antibodies to HPV oncoproteins are reliable diagnostic and prognostic markers that could in the future possibly serve for early tumor detection.

[Long-term sequelae after chemoradiation in head neck tumors]. / Langzeitfolgen der Radiochemotherapie bei Kopf-Hals-Tumoren.

The most common type of head and neck tumors are squamous cell cancer of the pharynx, the oral cavity and the larynx. These tumors can be treated by primary radio(chemo)therapy or surgery as well as a combination of both modalities depending on the site and extent of disease. This article will outline the recent developments in radiation therapy and give an overview of the potential long-term sequelae and their influencing factors.