Renal Cancer Stem Cells: Characterization and Targeted Therapies

Renal cell carcinoma (RCC) is a major neoplasm with high incidence in western countries. Tumors are heterogeneous and are composed of differentiated cancer cells, stromal cells, and cancer stem cells (CSCs). CSCs possess two main properties: self-renewal and proliferation. Additionally, they can generate new tumors once transplanted into immunodeficient mice. Several approaches have been described to identify them, through the expression of cell markers, functional assays, or a combination of both. As CSCs are involved in the resistance mechanisms to radio- and chemotherapies, several new strategies have been proposed to directly target CSCs in RCC. One approach drives CSCs to differentiate into cancer cells sensitive to conventional treatments, while the other proposes to eradicate them selectively. A series of innovative therapies aiming at eliminating CSCs have been designed to treat other types of cancer and have not been experimented with on RCC yet, but they reveal themselves to be promising. In conclusion, CSCs are an important player in carcinogenesis and represent a valid target for therapy in RCC patients.

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An Uncemented Spreading Stem for the Fixation in the Metaphyseal Femur: A Preliminary Report

Surgical treatment to restore full range of motion and full weight bearing after extensive femoral bone resection in patients with primary or metastatic femoral tumours is individually challenging. Especially when the remaining distal or proximal bone is very short, a rigid fixation of an implant is difficult to achieve due to the reverse funnel shape of the metaphysis. Herein, we present a novel implant design using a spreading mechanism in the distal part of the prosthesis for rigid, uncemented fixation in the remaining femoral bone after extensive tumour resection of the femur. We present the outcome of 5 female patients who underwent implantation of this spreading stem after extensive proximal or distal femoral bone resection. There was no radiological or clinical loosening or implant-related revision surgery in our follow-up (mean 21.46 months, range 3.5–46 months). This uncemented spreading stem may therefore represent an alternative option for fixation of a prosthetic device in the remaining metaphyseal femur.

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Diagnostic Performance of McMonnies Questionnaire as a Screening Survey for Dry Eye: A Multicenter Analysis

Purpose. To evaluate the diagnostic performance of the McMonnies questionnaire as a screening survey for dry eye in Chinese outpatients. Methods. The questionnaire was self-administered by 27,999 patients with dry eye symptoms. A thorough ophthalmic examination including tear break-up time (TBUT), fluorescein staining, and Schirmer I test was completed to make a clinical diagnosis of dry eye. Reliability, validity, and accuracy of the McMonnies questionnaire were assessed. Results. The McMonnies questionnaire showed poor internal consistency (Cronbach ), but excellent validity as the scores correlated with TBUT (Spearman test, , ) and Schirmer I test (Spearman’s test, , ), and significantly differed between the dry eye and control groups (2-sample t-test, , ). The area under the receiver-operating characteristics (ROC) curve (AUC) was 0.729, suggesting moderate accuracy in identifying dry eye and non-dry eye patients. However, the AUCs varied significantly in different gender and age subgroups (z test, ), as the discriminating ability declined with age. Analysis of the ROC curves also revealed that different cut-off points should be employed for each subgroup to achieve the same level of accuracy. Conclusions. The McMonnies questionnaire demonstrates moderate diagnostic value, and different cut-off points should be selected for various study populations.

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(Collage: Tablet Magazine) - Tablet Magazine

Tablet Magazine

(Collage: Tablet Magazine) Tablet Magazine Sometime after age 50, depending on personal genetics and life history, our gums withdraw, we lose our hair, our saliva glands falter, and our teeth grow brittle and break off or fall out. ... Irving Weissman M.D., Ludwig professor for Clinical ...

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Human papillomavirus promotes Epstein-Barr virus maintenance and lytic reactivation in immortalized oral keratinocytes.

Human papillomavirus promotes Epstein-Barr virus maintenance and lytic reactivation in immortalized oral keratinocytes.

Virology. 2016 May 11;495:52-62

Authors: Makielski KR, Lee D, Lorenz LD, Nawandar DM, Chiu YF, Kenney SC, Lambert PF

Abstract
Epstein-Barr virus and human papillomaviruses are human tumor viruses that infect and replicate in upper aerodigestive tract epithelia and cause head and neck cancers. The productive phases of both viruses are tied to stratified epithelia highlighting the possibility that these viruses may affect each other's life cycles. Our lab has established an in vitro model system to test the effects of EBV and HPV co-infection in stratified squamous oral epithelial cells. Our results indicate that HPV increases maintenance of the EBV genome in the co-infected cells and promotes lytic reactivation of EBV in upper layers of stratified epithelium. Expression of the HPV oncogenes E6 and E7 were found to be necessary and sufficient to account for HPV-mediated lytic reactivation of EBV. Our findings indicate that HPV increases the capacity of epithelial cells to support the EBV life cycle, which could in turn increase EBV-mediated pathogenesis in the oral cavity.

PMID: 27179345 [PubMed - as supplied by publisher]

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Renal clear cell carcinoma metastasis to salivary glands - a series of 9 cases: clinico-pathological study.

Renal clear cell carcinoma metastasis to salivary glands - a series of 9 cases: clinico-pathological study.

Pol J Pathol. 2016;67(1):39-45

Authors: Majewska H, Skálová A, Radecka K, Stodulski D, Hyrcza M, Stankiewicz C, Biernat W

Abstract
Metastatic tumors involving salivary glands arising from the non-head and neck area are very rare. Renal cell carcinoma (RCC) is known for its high propensity for metastasis to unusual localizations. RCC metastasis to the maxillofacial area is an uncommon event (16%), but metastasis to salivary glands is extremely rare. We report a series of 9 such cases retrieved from two institutions. The group included 6 females and 3 males. The age at diagnosis ranged from 60 to 97 years (mean 72.6 years). The tumors involved the parotid gland in 7 cases, and the submandibular and small salivary gland of the oral cavity in 1 case each. The size of tumors ranged from 0.4 to 5 cm. Total parotidectomy with selective neck dissection was performed in 4 cases, while superficial parotidectomy was performed in 1 case and simple resection in 3 cases. Histologically, all the tumors were clear cell renal cell carcinomas, and therefore the differential diagnosis mainly included clear cell variants of salivary gland carcinomas. The parotid gland was the initial manifestation of renal malignancy in 4 of the cases, while in the remaining 5 cases a history of RCC had been known. The salivary gland involvement developed from 11 months to 13 years after the time of diagnosis of the primary tumor. In 2 cases it was the first site of dissemination. Pathologists need to maintain a high index of suspicion for the possibility of metastasis when confronted with oncocytic or clear cell neoplasms developing in salivary glands. RCC, although rare, should be included in this differential diagnosis.

PMID: 27179273 [PubMed - as supplied by publisher]

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2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells.

2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells.

Oncol Res. 2016;24(1):55-64

Authors: Sobhakumari A, Orcutt KP, Love-Homan L, Kowalski CE, Parsons AD, Knudson CM, Simons AL

Abstract
Poor tumor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a significant challenge for effective treatment of head and neck squamous cell carcinoma (HNSCC). Therefore, strategies that may increase tumor response to EGFR TKIs are warranted in order to improve HNSCC patient treatment and overall survival. HNSCC tumors are highly glycolytic, and increased EGFR signaling has been found to promote glucose metabolism through various mechanisms. We have previously shown that inhibition of glycolysis with 2-deoxy-d-glucose (2DG) significantly enhanced the antitumor effects of cisplatin and radiation, which are commonly used to treat HNSCC. The goal of the current studies is to determine if 2DG will enhance the antitumor activity of the EGFR TKI erlotinib in HNSCC. Erlotinib transiently suppressed glucose consumption accompanied by alterations in pyruvate kinase M2 (PKM2) expression. 2DG enhanced the cytotoxic effect of erlotinib in vitro but reversed the antitumor effect of erlotinib in vivo. 2DG altered the N-glycosylation status of EGFR and induced the endoplasmic reticulum (ER) stress markers CHOP and BiP in vitro. Additionally, the effects of 2DG + erlotinib on cytotoxicity and ER stress in vitro were reversed by mannose but not glucose or antioxidant enzymes. Lastly, the protective effect of 2DG on erlotinib-induced cytotoxicity in vivo was reversed by chloroquine. Altogether, 2DG suppressed the antitumor efficacy of erlotinib in a HNSCC xenograft mouse model, which may be due to increased cytoprotective autophagy mediated by ER stress activation.

PMID: 27178822 [PubMed - in process]

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