High level of circulating vitamin D during neoadjuvant therapy may lower risk of metastatic progression in high-risk rectal cancer.

BACKGROUND: Following curative-intent neoadjuvant therapy in locally advanced rectal cancer, metastatic progression is still dominant. We investigated if patients' circulating 25-hydroxyvitamin D [25(OH)D] levels were associated with outcome. METHODS: Serum 25(OH)D concentration was assessed by liquid chromatography-mass spectrometry in samples collected from 84 patients at baseline, completion of the neoadjuvant therapy, and treatment evaluation before surgery, and analyzed with respect to season, disease presentation, and treatment effects. RESULTS: In the cohort of patients residing at latitude 58-62°N, baseline 25(OH)D differed significantly over the seasons, with highest measures (mean of 71.2 ± 5.6 nmol/L) in summer and lowest (48.7 ± 4.5 nmol/L) in spring, and changed over the three-month neoadjuvant period till response evaluation solely owing to season. The patient subgroup with slightly reduced performance status, anemia, and T4 disease that did not respond to the neoadjuvant therapy (ypT4 cases), had significantly lower baseline 25(OH)D (below 50 nmol/L) than T4 cases with response (ypT0-3) and T2-3 cases (above 60 nmol/L). Compared to the T4 patients with levels above 50 nmol/L, regarded as sufficient for a healthy bone status, those presenting levels below had significantly heightened risk of disease progression (mainly metastasis) and death, with hazard ratio of 3 and 17, respectively, on adjustment for age, sex, body mass index, and season. CONCLUSION: Rectal cancer T4 cases had high risk of metastatic progression and death if circulating 25(OH)D levels were insufficient but obtained short-term and long-term outcome to neoadjuvant treatment no worse than patients with T2-3 disease when 25(OH)D was sufficient. TRIAL REGISTRATION: ClinicalTrials.gov NCT00278694 ; registration date: 16 January 2006, retrospective to enrollment of the first 10 patients of the current report.

Photodynamic therapy of cancer: an update.

Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment.

The relationship between UV exposure and incidence of skin cancer.

BACKGROUND: The incidence rates of skin cancer increase with decreasing latitude in most western countries. Ultraviolet (UV) radiation is a main risk factor for skin cancer. METHODS: We have studied the relationship between UV exposure and skin cancer incidence rates of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and cutaneous melanoma (CM), and tried to fit different mathematical models to the experimental data. RESULTS: The incidence-UV exposure relationship for all three cancers is best described by the power law: ln(RTD) = Ab ·ln(annual UVEry dose), with relative tumor density (RTD) being age-adjusted incidence rate per unit area of skin, and the power parameter Ab being the biological amplification factor. For SCC, the RTD is a factor of 16-19 times larger on the head than on the trunk. For BCC, this factor is 7 and for CM it is 0.9-1.3. Ab for CM has remained almost unchanged from the 1960s until recently. CONCLUSIONS: The incidence-sun exposure relationship for all three cancers is well described by the power law. SCC is dependent on total UV exposures, while BCC, and even more CM, is dependent also on exposure patterns, with intermittent exposures being most carcinogenic.

Influence of multiple UV exposures on serum cobalamin and vitamin D levels in healthy females.

AIMS: Ultraviolet (UV) radiation is a major source for vitamin D production. Furthermore, UV destroys cobalamins (also called vitamin B12) in solution. However, data from humans are scarce. The aim of the present study was to clarify if UV exposure has any effect on serum cobalamins, as compared to vitamin D levels, in healthy volunteers. METHODS: This single-center, open observational study was conducted in a research institute: 23 non-pregnant, non-lactating, healthy, fair-skinned female subjects had their serum cobalamin and 25-hydroxyvitamin D (25(OH)D, the marker for vitamin D status) levels measured before and after exposure to UV. RESULTS: UV exposure increased serum 25(OH)D levels from 61.6 nmol/L to 88.5 nmol/L (44%; p < 0.001). A statistically insignificant decay in serum cobalamin levels from 300 pmol/L to 260 pmol/L (13%; p = 0.142) was observed in the volunteers after the first UV exposure; however, no additional decline of statistical significance was seen after subsequent exposures. CONCLUSIONS: Multiple exposure to UV radiation give a significant increase in 25(OH)D levels, but has no detrimental effect on cobalamin concentrations.

Sun exposure and melanomas on sun-shielded and sun-exposed body areas.

Malignant melanoma is a tumor that arises from melanocytes and accounts for around 4% of all malignancies in Europe and Northern America and for about 11% in Australia and New Zealand. About 10% of primary melanomas arise from sites not exposed to sun. Acral lentiginous melanoma, mucosal melanoma (in the oral cavities, nasal sinuses, genital tract and rectum) and uveal melanoma are all on non-sun-exposed tissues. Epidemiologic aspects ofmelanomas on non-sun-exposed areas in comparison with melanomas in sun-exposed areas have been reviewed. We focus on the relationship between melanoma incidence, geographic latitude of residence, race/ethnicity and host factors as well as time trends.

Ultraviolet radiation and cutaneous malignant melanoma.

Essential features of the epidemiology and photobiology of cutaneous malignant melanoma (CMM) in Norway were studied in comparison with data from countries at lower latitudes. Arguments for and against a relationship between ultraviolet radiation (UV) from sun and artificial light and CMM are discussed. Our data indicate that UV is a carcinogen for CMM and that intermittent exposures are notably melanomagenic. This hypothesis was supported both by latitude gradients, by time trends and by changing patterns of tumor density on different body localizations. However, even though UV radiation generates CMM, it may also have a protective action and/or an action that improves prognosis. There appears to be no, or even an inverse latitude gradient for CMM arising on non-UV exposed body localizations (uveal melanoma, CMMs arising in the vulva, perianal/anorectal regions, etc.). Furthermore, CMM prognosis was gradually improved over all years of increasing incidence (up to 1990), but during the past 20 years, incidence rates stabilized and prognosis was not improved significantly. Comparisons of skin cancer data from Norway, Australia and New Zealand indicate that squamous cell carcinoma and basal cell carcinoma are mainly related to annual solar UVB fluences, while UVA fluences play a larger role of CMM.

Ultraviolet-radiation and health: optimal time for sun exposure.

Positive as well as negative health effects of exposure of human skin to UV radiation depend on spectra and fluence rates, both of which being dependent on latitude, time of the day and several other factors. The major positive effects are related to vitamin D photosynthesis and the major negative effect is skin cancer development. The action spectra for these effects are different. This lead us to conclude that for optimal vitamin D synthesis at minimal risk of cutaneous malignant melanoma (CMM), the best time for sun exposure is between 10 a.m. and 1 p.m. Thus, the common health recommendation (that sun exposure should be avoided between the hours of 10 a.m. and 4 p.m. and postponed to the afternoon) may be wrong.

Dynamics of signaling, cytoskeleton and cell cycle regulation proteins in glioblastoma cells after sub-lethal photodynamic treatment: antibody microarray study.

BACKGROUND: Photodynamic therapy (PDT) that induces oxidative stress and cell death is used for tumor destruction in oncology. To characterize early molecular events in photosensitized glioblastoma cells, we studied expression of 224 proteins after sublethal PDT that doesn't kill but wounds cells. METHODS: Cultured glioblastoma D54Mg cells were photosensitized with 5-aminolevulinic acid so that cell survival was 95-100%. At following 0.5-5.5h protein expression and phosphorylation was assayed using proteomic antibody microarrays. RESULTS: Within the first post-treatment hour we observed phosphorylation of protein kinase Raf, adhesion-related kinases FAK and Pyk2, and microtubule-associated protein tau. Protein kinase Cγ and microtubule-associated protein MAP-1B were overexpressed. Dystrophin, calponin, and vinculin, components of the actin cytoskeleton scaffold, microtubule-associated proteins MAP2 and CNP, cytokeratins 4 and 7 were down-regulated that indicated changes in adhesion and cell shape. Down-regulation of cyclins A, D1 and D3, c-Myc, checkpoint proteins chk1/2 and up-regulation of Smad4 could arrest the cell cycle. Overexpression of Bcl-xL and down-regulation of caspase 9 demonstrated anti-apoptotic response. At 2h post-treatment protein expression changed lesser but at 5.5h levels of PKCγ and ß-synuclein and phosphorylation of Raf, FAK, Pyk2, and tau increased again. CONCLUSIONS: Sub-lethal PDT induces complex response of glioblastoma cells including changes in activity and expression of proteins involved in adhesion-mediated signaling, signal transduction, cytoskeleton remodeling, cell cycle regulation and anti-apoptotic processes. GENERAL SIGNIFICANCE: Multiple reactions of various cellular subsystems including adhesion, cytoskeleton, signal transduction, cell cycle, and apoptosis are integrated into the general cell response to a sublethal impact.

Immediate pigment darkening: its evolutionary roles may include protection against folate photosensitization.

The evolution of dark human skin colors in tropical areas is possibly related to photoprotection of folates. However, natural folates absorb mainly UVB radiation, and too little UVB can penetrate down to folates in dermal vessels to cause serious damage. However, endogenous photosensitizers, like riboflavin and uroporphyrin, absorbing UVA and visible light, can cause photosensitization of folates. Immediate pigment darkening (IPD), generated by UVA, has an absorption spectrum covering those of the endogenous photosensitizers. IPD is most prominent for darker skin types, which were typical for populations living under tropical solar fluences. We here propose that the biological role of IPD is protection of folates against photodegradation, which would be of large evolutionary importance for early hominids.

Cutaneous malignant melanoma incidence rates in Norway.

AIMS: The incidence rates of cutaneous malignant melanoma (CMM) increase throughout the world, in spite of introduction of strategies for prevention. However, a decrease in incidence rates is observed in some countries. If the reason for this could be found, it might be useful to transfer the knowledge to other fields of medicine. METHODS: CMM age-standardized incidence rates in different age groups in Norway were obtained from NORDCAN for the years 1970-1989 and 1990-2009. RESULTS: Until 1990, the CMM rates increased, but after that time a stabilization or a decrease was observed for young age groups (15-54 years old), while in older generations (>55 years old) the rates continued to increase. CONCLUSIONS: The decreasing CMM pattern in young age groups may be due to changing patterns to sunlight in sunbathing and use of sunbeds.

Sunbed use and cutaneous melanoma in Norway.

AIMS: Incidence rates of cutaneous melanoma (CM) in light skinned people in Norway are among the highest in the world. Sunbed use has increased in Norway since 1980. We will try to elucidate whether there is any correlation between the increase in sunbed use and the CM incidence rates, whether the increase in CM risk is similar for all age groups, and whether the possible difference between young and old persons can inform future healthcare strategies. METHODS: The frequency of sunbed use by different age groups in the time period 1980-2011 and incidence rates (1980-2009) of CM at different age groups in Norway were studied. Time in minutes per day spent in front of screen of computers or TVs for boys and girls was also analysed. RESULTS: The number of sunbed sessions per year in Norway increased throughout the entire period. The number of men and women diagnosed with CM per year, all ages combined, also increased. Sunbed use increased at a similar rate for three age groups (0-19, 20-50, and >50 years old), while the age-adjusted CM incidence rate increased only for the oldest group. Time spent in front of the screen of computers or TVs increased from 1985 to 2005 and is still increasing. CONCLUSIONS: CM incidence is decreasing while sunbed use is increasing in younger age groups. The present data indicate that more work needs to be done before one can know whether the overall health effects of sunbed exposure are positive or negative.

UVA, UVB and incidence of cutaneous malignant melanoma in Norway and Sweden.

Latitudinal dependencies of UVA and UVB were studied together with relevant epidemiological data for squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM) in Norway and Sweden. Our data support the hypothesis that solar UVA radiation may play a role for CMM induction. The etiologies of SCC and CMM are different according to a latitudinal dependency and differences in age curves. Sun exposure patterns, age-related decay rates of repair of UV damage and sex hormones may play different roles for the two skin cancers. Also, UVB induction of vitamin D may be involved. CMM incidence rates among young people have decreased or been constant since about 1990 in Norway and Sweden. All reasons for UVA contributing to CMM will be discussed.

Vitamin D, sun, sunbeds and health.

OBJECTIVE: To review the health effects of solar radiation, sunbeds and vitamin D. DESIGN: The literature was searched in the electronic database MEDLINE to indentify published data between 1981 and 2011. Studies were included if they reported relative risk for cutaneous malignant melanoma (CMM) associated with sunbed use, vitamin D and UV effects on human health. SETTING: Data from different time periods for populations at different latitudes. SUBJECTS: Persons of different ages and ethnic groups. RESULTS: UV from sun and sunbeds is the main vitamin D source. Young people with white or pigmented skin in northern Europe have a low vitamin D status. A number of health benefits from sufficient levels of vitamin D have been identified. However, UV exposure has been suspected of causing skin cancer, notably CMM, and authorities warn against it. CONCLUSIONS: The overall health benefit of an improved vitamin D status may be more important than the possibly increased CMM risk resulting from carefully increasing UV exposure. Important scientific facts behind this judgement are given.

Vitamin D status in healthy Romanian caregivers and risk of respiratory infections.

OBJECTIVES: To investigate the vitamin D status during winter of a healthy population of hospital employees and to assess the correlation between vitamin D status and risk of infections in the upper respiratory tract. DESIGN: One hundred and ten healthy volunteers answered a questionnaire on their solar exposure habits and vitamin D intake and delivered one blood sample for quantification of vitamin D level (serum 25-hydroxyvitamin D (25(OH)D) concentration) during December 2007-January 2008. At the end of the winter we screened for the occurrence of respiratory infections and sought associations with vitamin D status. SETTING: Bucharest, Romania, 45°N. SUBJECTS: One hundred and ten healthy hospital employees. RESULTS: Eighty per cent of participants were vitamin D deficient (25(OH)D level below 50 nmol/l). The main determinant of serum 25(OH)D was sun exposure during the summer previous to the study (P = 0·02 in multivariate analysis). Intake of vitamin D, BMI and age played no significant role for the level of 25(OH)D. Overall we found a non-significant negative correlation between 25(OH)D level and new cases of infection (Spearman correlation coefficient of -0·12, P = 0·2). CONCLUSIONS: Vitamin D status is alarmingly poor in active, relatively young women residing in Romania. If our results are reproduced by other investigations, action to improve vitamin D status at the population level is necessary. We were not able to show a statistically significant relationship between vitamin D status and infection risk in our material.

Serum 25-hydroxyvitamin D is a predictor of serum 1,25-dihydroxyvitamin D in overweight and obese patients.

Recent research suggests that 1,25-dihydroxyvitamin D [1,25(OH)(2)D], a steroid hormone that regulates calcium homeostasis, may also play a role in the development and progression of cancer, multiple sclerosis, cardiovascular, and other diseases. Decreased serum 1,25(OH)(2)D concentrations are often observed in overweight and obese patients. However, little is known about the factors that may influence 1,25(OH)(2)D renal synthesis, because it is generally accepted that serum 1,25(OH)(2)D concentration is strictly regulated by parathyroid hormone and serum concentrations of calcium and phosphorus. In this study, the associations among serum 1,25(OH)(2)D, serum 25-hydroxyvitamin D [25(OH)D], and body composition were analyzed in 1779 patients with excess body weight registered in a Metabolic and Medical Lifestyle Management Clinic in Oslo, Norway. According to our results, serum 25(OH)D, adiposity, age, season of blood sampling, and gender directly influence serum 1,25(OH)(2)D (r = 0.33; P < 0.001), with serum 25(OH)D being the strongest predictor for serum 1,25(OH)(2)D. The 1,25(OH)(2)D concentrations were 25.4 pmol/L (95% Cl: 19.3-31.5; P < 0.001) lower in the lowest 25(OH)D quartile to compared with highest quartile. A seasonal variation was observed for both vitamin D metabolites. Thus, our results suggest that in patients with excess body weight, serum 1,25(OH)(2)D concentrations were associated with 25(OH)D and varied during the year. Therefore, it may also be valuable to measure both serum 25(OH)D and 1,25(OH)(2)D for the evaluation of vitamin D status in overweight and obese persons.

Metabolic-targeted therapy with dichloroacetate (DCA): a novel treatment strategy to improve the outcome of photodynamic therapy.

For the first time we present data showing that metabolic targeted therapy with dichloroacetate (DCA) may improve the outcome of photodynamic therapy. This treatment modality can be easily introduced into clinical practice guidelines.

Vitamin D status in Norwegian children and adolescents with excess body weight.

OBJECTIVES: The prevalence of childhood and adolescent obesity has increased during the past decades. A high body mass index (BMI) is associated with a low vitamin D status. The purpose of this study was to determine the prevalence of vitamin D deficiency and insufficiency in Norwegian children and adolescents with excess body weight. METHODS: Vitamin D status and seasonal variations of 25(OH)D and 1,25(OH)(2)D were analyzed in 102 children and adolescents (70 girls and 32 boys), 8-19 yr of age, with overweight and obesity. RESULTS: Overall, 50% of the children and adolescents included in the study had a low vitamin D status (25(OH)D <75 nmol/L) and 19% had vitamin D deficiency (25(OH)D <50 nmol/L). This was most prevalent in adolescents. Only 42% of teenagers had 25(OH)D levels ≥75 nmol/L vs. 72% of preteens. Both 25(OH)D and 1,25(OH)(2)D showed seasonal variations. A peak in serum 25(OH)D concentrations was observed during the summer while the lowest values were seen during the spring. In contrast, serum 1,25(OH)(2)D had a peak during the spring and the lowest concentrations during the winter. CONCLUSIONS: The prevalence of vitamin D deficiency and insufficiency is higher in obese and overweight adolescents than in overweight children. This might be related to low outdoor activities and low vitamin D intake in teenagers. Seasonal variations of both the vitamin D metabolites were observed.

Review Article: Health benefit of increased serum 25(OH)D levels from oral intake and ultraviolet-B irradiance in the Nordic countries.

AIMS: A low serum 25-hydroxyvitamin D [25(OH)D] level is a risk factor for many diseases, including musculoskeletal diseases, many types of cancer, cardiovascular diseases, diabetes mellitus, infectious diseases, autoimmune diseases, and brain diseases. This report estimates the reduction in mortality rates for the five Nordic countries for an increase in population mean serum 25-hydroxyvitamin D level to 105 nmol/L. METHODS: Serum vitamin D dose-incidence/prognosis relationships can be developed with significant levels of reliability for most vitamin D-sensitive diseases on the basis of ecological, cross-sectional, and observational studies, randomized controlled trials, and meta-analysis of such studies. These dose-response relations are used to estimate the population-wide benefit of raising mean serum 25(OH)D concentration to 105 nmol/L for the five Nordic countries. RESULTS: From this study, the reductions in mortality rates possible by raising population mean serum 25(OH)D levels to 105 nmol/L are: Denmark, 17% (estimated range,11%-24%); Finland, 24% (17%-32%); Iceland, 24% (17%-32%); Norway, 18% (11%-26%); and Sweden, 18% (8%-25%). CONCLUSIONS: Reaching these levels would require changes in health policies with respect to solar ultraviolet-B (UVB) irradiance, vitamin D fortification of food, availability of vitamin D and calcium supplements, and attitude toward use of UVB lamps. Adverse effects of oral vitamin D intake are limited, and those from UVB irradiance are minor compared with the benefits.

Addressing the health benefits and risks, involving vitamin D or skin cancer, of increased sun exposure.

Solar radiation is the main cause of skin cancers. However, it also is a main source of vitamin D for humans. Because the optimal status of vitamin D protects against internal cancers and a number of other diseases, a controversy exists: Will increased sun exposure lead to net health benefits or risks? We calculated the relative yield of vitamin D photosynthesis as a function of latitude with a radiative transfer model and cylinder geometry for the human skin surface. The annual yield of vitamin D is 3.4 and 4.8 times larger below the equator than in the U.K. and Scandinavia, respectively. In populations with similar skin types, there are clear latitude gradients of all major forms of skin cancer, indicating a north-south gradient in real sun exposure. Surprisingly, the incidence rates of major internal cancers also increase from north to south. However, the survival prognosis also improves significantly from north to south. Reasons for these findings are discussed in view of the role of vitamin D. In Norway, melanoma rates increased by a factor of 6 from 1960 to 1990, while the prognosis improved in the same period. After 1990, melanoma rates have remained constant or even decreased in age groups <50 years, whereas the prognosis has not improved further. These data, together with those for internal cancers and the beneficial effects of an optimal vitamin D status, indicate that increased sun exposure may lead to improved cancer prognosis and, possibly, give more positive than adverse health effects.

Influence of narrowband UVB phototherapy on vitamin D and folate status.

BACKGROUND: A variety of studies have shown beneficial effects of different types of phototherapy in skin disorders. Such therapy leads to enhanced cutaneous vitamin D synthesis, which may be one of the mechanisms of action. Furthermore, another nutrient, folate, can probably also be influenced by UV radiation. OBJECTIVE: The aim of our study was to investigate the influence of low-dose narrowband UVB (nUVB) phototherapy of patients with psoriasis, atopic eczema and other skin disorders on serum levels of 25(OH) vitamin D (the serum marker for vitamin D status) and on serum and erythrocyte-folate. METHODS: 25(OH) vitamin D (25(OH)D), serum and erythrocyte-folate levels were measured before and after low-dose nUVB (TL-01 tubes) phototherapy of these patients. The spectrum of the TL-01 tube was compared with the solar spectrum, and the efficiency spectra of vitamin D photosynthesis were calculated. RESULTS: For patients with a high initial 25(OH)D serum level (> 80 nmol/l), no significant (P = 0.36) increase in 25(OH)D levels was seen, in contrast to patients with a low initial level (< 80 nmol/l) where a significant increase (P < 0.001) was observed. The increase was 30-60%, depending on the UVB dose (2.35-13.4 J/cm(2)). No significant nUVB-effect was found on the erythrocyte and serum-folate level. CONCLUSION: Low-dose nUVB treatment gives a significant increase (P < 0.001) of the vitamin D status in persons with low initial levels of 25(OH)D, but no effect on the folate level.