Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel ...running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth.
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•Exercise reduces tumor incidence and growth in several mouse models•Exercise increases NK cell infiltration, thereby controlling tumor growth•Epinephrine mobilizes NK cells and β-blockade blunts the tumor suppression•Exercise-induced muscle-derived IL-6 is involved in NK cell redistribution
The beneficial effects of exercise are countless. Pedersen et al. now link exercise, cancer, and immunity and reveal that exercise decreases tumor incidence and growth by over 60% across several mouse tumor models through a direct regulation of NK cell mobilization and trafficking in an epinephrine- and IL-6-dependent manner.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
The aim of this article was to provide worldwide, population-based incidence rates for Merkel cell carcinoma (MCC).
We included 11,576 cases from 20 countries for time trend analyses (1990–2007) and ...11,028 cases (2.5 billion person-years) from 21 countries for the period 2003–2007 extracted from Cancer Incidence in Five Continents. We computed age-standardised incidence rates (World Standard population) per million person years and sex ratios of these rates. We estimated annual percentage changes (EAPCs) of the incidence and studied the association between geographic latitude and MCC incidence. We examined the body site distribution of MCC.
In the majority of populations, the incidence has increased over time (EAPC, men 2.0–21.0%; women 1.6–27.2%). Rate differences between 1995 and 2007 were typically small (men: 0.8–2.2; women: 0.2–1.7). The incidence was relatively stable in some populations (men: U.S. blacks, Japan, Norway, Denmark; women: Denmark, Norway, Sweden). Incidences from 2003 to 2007 were highest in Australia, New Zealand, the United States and Israel among men and in New Zealand, Australia, Ireland and the Netherlands among women. The incidence of MCC and melanoma among white non-Hispanic males in North America was positively associated with living closer to the equator. The proportion of MCC on the head was higher with advanced age. The head was a less likely primary site among blacks as compared with any other ethnicity.
Several countries showed increases in MCC incidence among white non-Hispanics over time. Latitude closer to the equator was associated with the MCC incidence in North American men, but barely in women, possibly due to occupational sunlight exposure patterns.
•Currently, the highest incidence rates have been observed in Australia, New Zealand and the United States.•Latitude closer to the equator in North America is associated with the Merkel cell carcinoma (MCC) incidence in men.•Body site distribution of MCC was associated with sex, age, and ethnicity.•Blacks have a substantially higher proportion of anogenital MCC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Merkel cell carcinoma (MCC) is a relatively uncommon but highly lethal form of skin cancer. A majority of MCC tumors carry DNA sequences derived from a newly identified virus called Merkel cell ...polyomavirus (MCV or MCPyV), a candidate etiologic agent underlying the development of MCC. To further investigate the role of MCV infection in the development of MCC, we developed a reporter vector-based neutralization assay to quantitate MCV-specific serum antibody responses in human subjects. Our results showed that 21 MCC patients whose tumors harbored MCV DNA all displayed vigorous MCV-specific antibody responses. Although 88% (42/48) of adult subjects without MCC were MCV seropositive, the geometric mean titer of the control group was 59-fold lower than the MCC patient group (p<0.0001). Only 4% (2/48) of control subjects displayed neutralizing titers greater than the mean titer of the MCV-positive MCC patient population. MCC tumors were found not to express detectable amounts of MCV VP1 capsid protein, suggesting that the strong humoral responses observed in MCC patients were primed by an unusually immunogenic MCV infection, and not by viral antigen expressed by the MCC tumor itself. The occurrence of highly immunogenic MCV infection in MCC patients is unlikely to reflect a failure to control polyomavirus infections in general, as seroreactivity to BK polyomavirus was similar among MCC patients and control subjects. The results support the concept that MCV infection is a causative factor in the development of most cases of MCC. Although MCC tumorigenesis can evidently proceed in the face of effective MCV-specific antibody responses, a small pilot animal immunization study revealed that a candidate vaccine based on MCV virus-like particles (VLPs) elicits antibody responses that robustly neutralize MCV reporter vectors in vitro. This suggests that a VLP-based vaccine could be effective for preventing the initial establishment of MCV infection.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Common acquired melanocytic nevi are benign neoplasms that are composed of small, uniform melanocytes and are typically present as flat or slightly elevated pigmented lesions on the skin. We describe ...two families with a new autosomal dominant syndrome characterized by multiple, skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected individuals developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of BAP1, which encodes a ubiquitin carboxy-terminal hydrolase. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histological similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in Caucasian populations, accounting for 20% of all cutaneous malignancies. A unique collaboration of ...multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cSCC diagnosis and management, based on a critical review of the literature, existing guidelines and the expert’s experience. The diagnosis of cSCC is primarily based on clinical features. A biopsy or excision and histologic confirmation should be performed in all clinically suspicious lesions in order to facilitate the prognostic classification and correct management of cSCC. The first line treatment of cutaneous SCC is complete surgical excision with histopathological control of excision margins. The EDF–EADO–EORTC consensus group recommends a standardised minimal margin of 5 mm even for low-risk tumours. For tumours, with histological thickness of >6 mm or in tumours with high risk pathological features, e.g. high histological grade, subcutaneous invasion, perineural invasion, recurrent tumours and/or tumours at high risk locations an extended margin of 10 mm is recommended. As lymph node involvement by cSCC increases the risk of recurrence and mortality, a lymph node ultrasound is highly recommended, particularly in tumours with high-risk characteristics. In the case of clinical suspicion or positive findings upon imaging, a histologic confirmation should be sought either by fine needle aspiration or by open lymph node biopsy. In large infiltrating tumours with signs of involvement of underlying structures, additional imaging tests, such as CT or MRI imaging may be required to accurately assess the extent of the tumour and the presence of metastatic spread. Current staging systems for cSCC are not optimal, as they have been developed for head and neck tumours and lack extensive validation or adequate prognostic discrimination in certain stages with heterogeneous outcome measures. Sentinel lymph node biopsy has been used in patients with cSCC, but there is no conclusive evidence of its prognostic or therapeutic value. In the case of lymph node involvement by cSCC, the preferred treatment is a regional lymph node dissection. Radiation therapy represents a fair alternative to surgery in the non-surgical treatment of small cSCCs in low risk areas. It generally should be discussed either as a primary treatment for inoperable cSCC or in the adjuvant setting. Stage IV cSCC can be responsive to various chemotherapeutic agents; however, there is no standard regimen. EGFR inhibitors such as cetuximab or erlotinib, should be discussed as second line treatments after mono- or polychemotherapy failure and disease progression or within the framework of clinical trials. There is no standardised follow-up schedule for patients with cSCC. A close follow-up plan is recommended based on risk assessment of locoregional recurrences, metastatic spread or development of new lesions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Abstract Merkel cell carcinoma (MCC) is a rare skin cancer that is associated with Merkel cell polyomavirus infection in most cases. Incidence rates of MCC have increased in past decades. Risk ...factors for MCC include ultraviolet light exposure, immunosuppression and advanced age. MCC is an aggressive malignancy with frequent recurrences and a high mortality rate, although patient outcomes are generally more favourable if the patient is referred for treatment at an early stage. Although advances have been made recently in the MCC field, large gaps remain with regard to definitive biomarkers and prognostic indicators. Although MCC is chemosensitive, responses in advanced stages are mostly of short duration, and the associated clinical benefit on overall survival is unclear. Recent nonrandomised phase 2 clinical trials with anti–PD-L1/PD-1 antibodies have demonstrated safety and efficacy; however, there are still no approved treatments for patients with metastatic MCC. Patients with advanced disease are encouraged to participate in clinical trials for treatment, indicating the largely unmet need for durable, safe treatment within this population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
Survivin is expressed in most human neoplasms, but is absent in normal, differentiated tissues. Survivin is a bifunctional
inhibitor of apoptosis protein that has been implicated in protection from ...apoptosis and regulation of mitosis. Several clinical
trials targeting survivin with a collection of different approaches from small molecule antagonists to immunotherapy are currently
under way. With regard to the latter, spontaneous anti-survivin T-cell reactivity has been described in cancer patients suffering
from a huge range of cancers of different origin, e.g., breast and colon cancer, lymphoma, leukemia, and melanoma. Thus, survivin
may serve as a universal target antigen for anticancer immunotherapy. Accordingly, down-regulation of survivin as a means
of immune escape would severely inflict the survival capacity of tumor cells, which highlights this protein as a prime target
candidate for therapeutic vaccinations against cancer. Data from several ongoing phase I/II trials targeting survivin for
patients with advanced cancer will provide further information about this idea.
Merkel cell carcinoma Becker, Jürgen C; Stang, Andreas; DeCaprio, James A ...
Nature reviews. Disease primers,
10/2017, Volume:
3
Journal Article
Peer reviewed
Open access
Merkel cell carcinoma (MCC) is a rare but highly aggressive skin cancer with neuroendocrine features. MCC pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic ...exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. The two aetiologies share similar clinical, histopathological and prognostic characteristics. MCC presents with a solitary cutaneous or subcutaneous nodule, most frequently in sun-exposed areas. In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. Confirmation of diagnosis relies on analyses of histological features and immunological marker expression profiles of the lesion. At primary diagnosis, loco-regional metastases are already present in ∼30% of patients. Excision of the tumour is the first-line therapy; if not feasible, radiotherapy can often effectively control the disease. Chemotherapy was the only alternative in advanced-stage or refractory MCC until several clinical trials demonstrated the efficacy of immune-checkpoint inhibitors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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