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Several in vitro and in vivo models have revealed the key role of CXCR4/CXCL12 axis in tumor-stroma interactions. Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein, directly stimulating proliferation and migration of CXCR4-expressing cancer cells. This specific prosurvival influence of stromal cells on tumor cells is thought to protect them from cytotoxic chemotherapy and is postulated as a possible explanation for the minimal residual disease in hematological and solid cancers. Therefore, CXCR4/CXCL12 signaling is an attractive therapeutic target in cancer, as proven in preclinical leukemia mouse models, where CXCR4 inhibition sensitized cancer cells to conventional chemotherapy. This study investigates whether inhibition of CXCR4 with the specific inhibitor AMD3100 sensitizes human prostate cancer cells to docetaxel. We showed that both mouse and human stromal cell lines have a protective effect on PC3-luc cells by promoting their survival after chemotherapy. Furthermore, we demonstrated that AMD3100 sensitizes PC3-luc cells to docetaxel. In a subcutaneous xenograft mouse model of human prostate carcinoma, we showed that a combination of docetaxel and AMD3100 exerts increased antitumor effect compared with docetaxel alone. We concluded that CXCR4 inhibition chemosensitizes prostate cancer cells, both in vitro and in vivo. To explore the relevance of these findings, we analyzed CXCR4 expression levels in human prostate cancer samples. We found that cancer cells present in bone metastatic lesions express higher CXCR4 levels relative to the cells present in primary tumors and lymph node metastatic lesions. These findings underscore the potential of CXCR4 inhibitors as chemosensitizing agents.

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BackgroundMalnutrition, low muscle strength and muscle mass are highly prevalent in older hospitalized patients and associated with adverse outcomes. Malnutrition may be a risk factor for developing low muscle mass. We aimed to investigate the association between the risk of malnutrition and 1) muscle strength and muscle mass at admission and 2) the change of muscle strength and muscle mass during hospitalization in older patients.MethodsThe EMPOWER study included 378 patients aged seventy years or older who were acutely or electively admitted to four different wards of an academic teaching hospital in Amsterdam. Patients were grouped into low risk of malnutrition and high risk of malnutrition based on the Short Nutritional Assessment Questionnaire (SNAQ) score and were assessed for hand grip strength and muscle mass using hand held dynamometry respectively bioelectrical impedance analysis (BIA) within 48 h after admission and at day seven, or earlier at the day of discharge. Muscle mass was expressed as skeletal muscle mass, appendicular lean mass, fat free mass and the skeletal muscle index.ResultsThe mean age of the patients was 79.7 years (SD 6.39), 48.9% were female. At admission, being at high risk of malnutrition was significantly associated with lower muscle mass (Odds Ratio, 95% CI, 0.90, 0.85–0.96), but not with muscle strength. Muscle strength and muscle mass did not change significantly during hospitalization in both groups.ConclusionIn older hospitalized patients, a high risk of malnutrition is associated with lower muscle mass at admission, but not with muscle strength nor with change of either muscle strength or muscle mass during hospitalization.

Metastases are the cause of 90% of human cancer deaths. The current treatment of cancer with chemo,- and/or radiotherapy is based on cell death by DNA damage neglecting the fact that cancer cell invasion into surrounding tissues and metastasizing are fundamental features of neoplasms and the major reason for treatment failure. Metastasis is the result of several sequential steps and represents a highly organized, non-random, and organ-selective process. A number of in vitro and in vivo models show that tumor cells use chemokine-mediated mechanisms during this metastasizing process, comparable to those observed in the regulation of leukocyte trafficking. Furthermore, chemokines modulate tumor behavior such as the regulation of tumor-associated angiogenesis, activation of host tumor-specific immunological responses, and direct stimulation of tumor cell proliferation in an autocrine fashion. These findings may lead to new drugs that target chemokines or their receptors and will likely be of great additional value for treatment of cancer patients.

Pregnancy in patients with VHL disease induces cerebellar hemangioblastoma progression and causes a high VHL disease-related pregnancy complication rate. We recommend intensified surveillance of patients with VHL disease, especially of cerebellar hemangioblastomas during preconception care and pregnancy.

Abstractvon Hippel-Lindau (VHL) mutation carriers develop benign and malignant tumors, requiring regular surveillance. The aim of this study was to calculate the optimal organ-specific age to initiate surveillance and optimal intervals to detect initial and subsequent VHL-related manifestations. In this study, we compare these results with the current VHL surveillance guidelines. We collected data from 82 VHL mutation carriers in the Dutch VHL surveillance program. The cumulative proportion of carriers diagnosed with a first VHL-related manifestation was estimated by the Kaplan-Meier method. The Poisson distribution model was used to calculate average time to detection of the first VHL-related manifestation and subsequent manifestations. We used this to calculate the optimal organ-specific age to initiate surveillance and the surveillance interval that results in a detection probability of 5%. The calculated organ-specific ages to initiate surveillance were 0 years (birth) for adrenal glands, 7 years for the retina, 14 years for the cerebellum, 15 years for the spinal cord, 16 years for pancreas, and 18 years for the kidneys. The calculated surveillance intervals were 4 years for the adrenal glands, biennially for the retina and pancreas, and annually for the cerebellum, spinal cord, and kidneys. Compared with current VHL guidelines, the calculated starting age of surveillance was 6 years later for the retina and 5 years earlier for adrenal glands. The surveillance intervals were two times longer for the retina and four times longer for the adrenal glands. To attain a 5% detection probability rate per organ, our mathematical model indicates that several modifications of current VHL surveillance guidelines should be considered.

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