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Background: Patients with advanced-stage ovarian cancer face a poor prognosis because of recurrent peritoneal cavity metastases following surgery and chemotherapy. Alpha-emitters may enable the efficient treatment of such disseminated diseases because of their short range and highly energetic radiation. Radium-224 is a candidate α-emitter due to its convenient 3.6-day half-life, with more than 90% of the decay energy originating from α-particles. However, its inherent skeletal accumulation must be overcome to facilitate intraperitoneal delivery of the radiation dose. Therefore, 224Ra-labeled CaCO3microparticles have been developed. Objective: The antitumor effect of CaCO3microparticles as a carrier for 224Ra was investigated, with an emphasis on the ratio of activity to mass dose of CaCO3, that is, specific activity. Methods: Nude athymic mice were inoculated intraperitoneally with human ovarian cancer cells (ES-2) and treated with a single intraperitoneal injection of 224Ra-labeled CaCO3microparticles with varying combinations of mass and activity dose, or cationic 224Ra in solution. Survival and ascites volume at sacrifice were evaluated. Results: Significant therapeutic effect was achieved for all tested specific activities ranging from 0.4 to 4.6 kBq/mg. Although treatment with a mean activity dose of 1305 kBq/kg of cationic 224Ra prolonged the survival compared with the control, equivalent median survival could be achieved with 224Ra-labeled microparticles with a mean dose of only 420 kBq/kg. The best outcome was achieved with the highest specific activities (2.6 and 4.6 kBq/mg). Conclusion: Radium-224-labeled CaCO3microparticles present a promising therapy against cancer dissemination in body cavities.

Purpose Cutaneous melanoma is among the fastest growing malignancies in Norway and ultraviolet radiation (UVR) exposure is the primary environmental risk factor. Immunomodulating drugs can increase skin photosensitivity and suppress immune responses, and by such mechanisms influence melanoma risk. We, therefore, aimed to examine the associations between use of immunomodulating drugs and melanoma risk, at a nationwide population level. Patients and methods In the Cancer Registry of Norway, we identified all cases aged 18-85 with a first primary cutaneous melanoma diagnosed in 2007-2015 (n=12,106). These were matched to population controls from the Norwegian National Registry 1:10 (n=118,564), on sex and year of birth using risk set sampling. Information on prescribed drugs (2004-2015) was obtained by linkage to the Norwegian Prescription Database (NorPD). Conditional logistic regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for associations between use of immunomodulating drugs (immunosuppressants and corticosteroids) and melanoma risk, adjusted for ambient UVR and other drug use. Results Compared with ≤1 prescription, use of ≥8 prescriptions of immunosuppressants was associated with increased risk of melanoma (RR 1.50, 95% CI 1.27, 1.77). Similar associations were found for subgroups of immunosuppressants: drugs typically prescribed to organ transplant recipients (OTRs) (RR 2.02, 95% CI 1.35, 3.03) and methotrexate (RR 1.27, 95% CI 1.04, 1.55). Similar results were found for high levels of cumulative doses and across all histological subtypes. Use of corticosteroids was not associated with melanoma risk. Conclusion We found a positive association between use of immunosuppressants and melanoma risk, with the highest risk seen for drugs prescribed to OTRs. Knowledge about this risk increase is important for physicians and users of these drugs, for intensified surveillance, awareness and cautious sun exposure.

This study aimed to determine the influence of cellular PSMA expression, radioligand binding and internalization, and repeated administrations on the therapeutic effects of the PSMA-targeting radioligand

Background Most antihypertensives can induce dermal photosensitivity, which may increase melanoma risk. However, corroborating evidence is limited. We examined the associations between use of antihypertensives and melanoma risk. Methods A nationwide nested case-control study was conducted using data from the Cancer Registry of Norway, the National Registry and the Norwegian Prescription Database in 2004–15. Ten controls were randomly selected for each melanoma case, matched on sex and birth year. The study included 12 048 cases and 117 895 controls. We estimated rate ratios (RRs) with 95% confidence intervals (CIs). All analyses were adjusted for ambient ultraviolet radiation (UVR). We additionally performed active comparator analyses, and sensitivity analyses by only including new users, distinguishing between exclusive and mixed users, allowing for different latency periods, and subgroup analyses by melanoma subtype and clinical stage. Results Compared with non-use, we observed a slightly increased melanoma risk in users of diuretics (RR 1.08, CI 1.01–1.15), calcium-channel blockers (RR 1.10, CI 1.04–1.18) and drugs affecting the renin-angiotensin system (RR 1.10, CI 1.04–1.16), but not for beta blockers (RR 0.97, CI 0.92–1.03). We found no heterogeneity of associations by melanoma subtype or clinical stage and no dose-response relationship between the cumulative defined daily doses (DDDs) and melanoma. No interaction was found between cumulative DDDs and ambient UVR. Conclusions Weak associations, with lack of a dose-response relationship and lack of interactions with ambient UVR, in the DDD analysis in this nationwide study do not support a causal relationship between antihypertensives and melanoma risk.

Prostate-specific membrane antigen (PSMA) is the most promising target for radioligand therapy of prostate cancer. The aim of this study was to prepare a small molecular ligand p-SCN-Bn-TCMC-PSMA (NG001) and compare it with the commonly used DOTA-based PSMA-617. The PSMA-targeting ability of the 212 Pb-labelled ligands was evaluated using PSMA-positive C4-2 human prostate cancer cells. Lead-212 is an in vivo generator of alpha particles by its daughter nuclides 212 Bi and 212 Po. NG001 was synthesized by conjugating the isothiocyanato group of p-SCN-Bn-TCMC to the amino group of a glutamate-urea-based PSMA-binding entity. Molecular size, chelator unit and chelator linking method are different in NG001 and PSMA-617. Both ligands were efficiently labelled with 212 Pb using a 224 Ra/212 Pb-solution generator in transient equilibrium with progeny. Lead-212-labelled NG001 was purified with a yield of 85.9±4.7% and with 0.7±0.2% of 224 Ra. Compared with [212 Pb]Pb-PSMA-617, [212 Pb]Pb-NG001 displayed a similar binding and internalization in C4-2 cells, with comparable tumour uptake in mice bearing C4-2 tumours, but almost a 2.5-fold lower kidney uptake. Due to the rapid normal tissue clearance and tumour cell internalization, any significant translocalization of 212 Bi was not detected in mice. In conclusion, the obtained results warrant further preclinical studies to evaluate the therapeutic efficacy of [212 Pb]Pb-NG001.

Radium-224-labeled CaCO3 microparticles have been developed to treat peritoneal carcinomatosis. The microparticles function as carriers of 224Ra, facilitating intraperitoneal retention of the alpha-emitting radionuclide. It was necessary to control the size of microparticles in suspension over time and introduce a sterilization process for the clinical use of the radiopharmaceutical. Ethylenediamine tetra(methylene phosphonic acid) (EDTMP) was investigated as a stabilizing additive. The possibility of encapsulating the radiolabeled microparticles with an outer surface layer of CaCO3 for the improved retention of radioactivity by the carrier was studied. This work evaluated these steps of optimization and their effect on radiochemical purity, the biodistribution of radionuclides, and therapeutic efficacy. An EDTMP concentration of &gt, 1% (w/w) relative to CaCO3 stabilized the particle size for at least one week. Without EDTMP, the median particle size increased from ~5 µm to ~25 µm immediately after sterilization by autoclaving, and the larger microparticles sedimented rapidly in suspension. The percentage of adsorbed 224Ra progeny 212Pb increased from 56% to 94% at 2.4–2.5% (w/w) EDTMP when the 224Ra-labeled microparticles were layer-encapsulated. The improved formulation also resulted in a suitable biodistribution of radionuclides in mice, as well as a survival benefit for mice with intraperitoneal ovarian or colorectal tumors.

Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with 212Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of 212Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of 212Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of 212Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of 212Pb-NG001.

Simple Summary Currently, there is no treatment that can cure patients with late stage metastatic prostate cancer. Prostate-specific membrane antigen is a type of protein overexpressed on the membrane surface of most prostate cancer cells. The preclinical and clinical experiences in the rapidly evolving field of targeted alpha-particle radiation therapy for metastatic prostate cancer overexpressing prostate-specific membrane antigen are reviewed. Targeted alpha therapy employs radionuclides emitting highly energetic alpha-particles (cytotoxic payload) chelated to small molecules or monoclonal antibodies designed to target prostate-specific membrane antigen. In this review, we summarize the availability of therapeutic alpha-emitting radionuclides (terbium-149, astatine-211, bismuth-212 (lead-212), bismuth-213, radium-223, actinium-225, thorium-227), and the development of small molecules and antibodies targeting prostate-specific membrane antigen. The limitations in studies using animal models of human prostate cancer to accurately predict efficacy and toxicity in patients are addressed. We have attempted to also critically discuss hurdles related to logistical and supply aspects between different alpha-emitting prostate-specific membrane antigen-targeting radiopharmaceuticals. Lastly, we discuss the potentials, limitations, and future perspectives of prostate-specific membrane antigen-targeted alpha therapy. Abstract Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β− therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT.

CAR T cells targeting the B-lymphocyte antigen CD19 have led to remarkable clinical results in B-cell leukemia and lymphoma, but eliminate all B-lineage cells, leading to increased susceptibility to severe infections. As malignant B cells will express either immunoglobulin (Ig) light chain κ or λ, we designed a second-generation CAR targeting Igκ, IGK CAR. This construct demonstrated high target specificity, but displayed reduced efficacy in the presence of serum IgG. Since CD19 CAR is insensitive to serum IgG, we designed various combinatorial CAR constructs in order to maintain the CD19 CAR T cell efficacy, but with IGK CAR target selectivity. The Kz-19BB design, combining CD19 CAR containing a 4-1BB co-stimulatory domain with an IGK CAR containing a CD3zeta stimulatory domain, maintained the target specificity of IgK CAR and was resistant to the presence of soluble IgG. Our results demonstrate that a combinatorial CAR approach can improve target selectivity and efficacy.

CAR T cells targeting the B lymphocyte antigen CD19 have led to remarkable clinical results in B cell leukemia and lymphoma but eliminate all B lineage cells, leading to increased susceptibility to severe infections. As malignant B cells will express either immunoglobulin (Ig) light chain κ or λ, we designed a second-generation CAR targeting Igκ, IGK CAR. This construct demonstrated high target specificity but displayed reduced efficacy in the presence of serum IgG. Since CD19 CAR is insensitive to serum IgG, we designed various combinatorial CAR constructs in order to maintain the CD19 CAR T cell efficacy, but with IGK CAR target selectivity. The Kz-19BB design, combining CD19 CAR containing a 4-1BB costimulatory domain with an IGK CAR containing a CD3zeta stimulatory domain, maintained the target specificity of IgK CAR and was resistant to the presence of soluble IgG. Our results demonstrate that a combinatorial CAR approach can improve target selectivity and efficacy.

Purpose Cutaneous melanoma is among the fastest growing malignancies in Norway and ultraviolet radiation (UVR) exposure is the primary environmental risk factor. Immunomodulating drugs can increase skin photosensitivity and suppress immune responses, and by such mechanisms influence melanoma risk. We, therefore, aimed to examine the associations between use of immunomodulating drugs and melanoma risk, at a nationwide population level. Patients and Methods In the Cancer Registry of Norway, we identified all cases aged 18–85 with a first primary cutaneous melanoma diagnosed in 2007–2015 (n=12,106). These were matched to population controls from the Norwegian National Registry 1:10 (n=118,564), on sex and year of birth using risk set sampling. Information on prescribed drugs (2004–2015) was obtained by linkage to the Norwegian Prescription Database (NorPD). Conditional logistic regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for associations between use of immunomodulating drugs (immunosuppressants and corticosteroids) and melanoma risk, adjusted for ambient UVR and other drug use. Results Compared with ≤1 prescription, use of ≥8 prescriptions of immunosuppressants was associated with increased risk of melanoma (RR 1.50, 95% CI 1.27, 1.77). Similar associations were found for subgroups of immunosuppressants: drugs typically prescribed to organ transplant recipients (OTRs) (RR 2.02, 95% CI 1.35, 3.03) and methotrexate (RR 1.27, 95% CI 1.04, 1.55). Similar results were found for high levels of cumulative doses and across all histological subtypes. Use of corticosteroids was not associated with melanoma risk. Conclusion We found a positive association between use of immunosuppressants and melanoma risk, with the highest risk seen for drugs prescribed to OTRs. Knowledge about this risk increase is important for physicians and users of these drugs, for intensified surveillance, awareness and cautious sun exposure.

Patients with advanced-stage ovarian cancer face a poor prognosis because of recurrent peritoneal cavity metastases following surgery and chemotherapy. Alpha-emitters may enable the efficient treatment of such disseminated diseases because of their short range and highly energetic radiation. Radium-224 is a candidate α-emitter due to its convenient 3.6-day half-life, with more than 90% of the decay energy originating from α-particles. However, its inherent skeletal accumulation must be overcome to facilitate intraperitoneal delivery of the radiation dose. Therefore,The antitumor effect of CaCONude athymic mice were inoculated intraperitoneally with human ovarian cancer cells (ES-2) and treated with a single intraperitoneal injection ofSignificant therapeutic effect was achieved for all tested specific activities ranging from 0.4 to 4.6 kBq/mg. Although treatment with a mean activity dose of 1305 kBq/kg of cationicRadium-224-labeled CaCO

Lead-212 is a promising radionuclide for cancer therapy, but no primary

In the present work, we study the photodynamic action of cercosporin (cerco), a naturally occurring photosensitizer, on human cancer multicellular spheroids. U87 spheroids exhibit double the uptake of cerco than T47D and T98G spheroids as shown by flow cytometry on the single cell level. Moreover, cerco is efficiently internalized by cells throughout the spheroid as shown by confocal microscopy, for all three cell lines. Despite their higher cerco uptake, U87 spheroids show the least vulnerability to cerco-PDT, in contrast to the other two cell lines (T47D and T98G). While 300 μm diameter spheroids consistently shrink and become necrotic after cerco PDT, bigger spheroids (>500 μm) start to regrow following blue-light PDT and exhibit high viability. Cerco-PDT was found to be effective on bigger spheroids reaching 1mm in diameter especially under longer exposure to yellow light (~590 nm). In terms of metabolism, T47D and T98G undergo a complete bioenergetic collapse (respiration and glycolysis) as a result of cerco-PDT. U87 spheroids also experienced a respiratory collapse following cerco-PDT, but retained half their glycolytic activity.

Purpose Melanoma is the cancer with the most rapidly rising incidence rate in Norway. Although exposure to ultraviolet radiation (UVR) is the major environmental risk factor, other factors may also contribute. Antidepressants have cancer inhibiting and promoting side effects, and their prescription rates have increased in parallel with melanoma incidence. Thus, we aimed to prospectively examine the association between use of antidepressants and melanoma by using nation-wide data from the Cancer Registry of Norway, the National Registry, the Norwegian Prescription Database and the Medical Birth Registry of Norway. Patient and Methods All cases aged 18–85 with a primary cutaneous invasive melanoma diagnosed during 2007–2015 (n=12,099) were matched to population controls 1:10 (n=118,467) by sex and year of birth using risk-set sampling. We obtained information on prescribed antidepressants and other potentially confounding drug use (2004–2015). Conditional logistic regression was used to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) for the association between overall and class-specific use of antidepressants and incident melanoma. Results Compared with ≤1 prescription, ≥8 prescriptions of antidepressants overall were negatively associated with melanoma (RR 0.81 CI 0.75–0.87). Class-specific analyses showed decreased RRs for selective serotonin reuptake inhibitors (RR 0.82 CI 0.73–0.93) and mixed antidepressants (RR 0.77 CI 0.69–0.86). The negative association was found for both sexes, age ≥50 years, residential regions with medium and highest ambient UVR exposure, all histological subtypes, trunk, upper and lower limb sites and local disease. Conclusion Use of antidepressants was associated with decreased risk of melanoma. There are at least two possible explanations for our results; cancer-inhibiting actions induced by the drug and less UVR exposure among the most frequent users of antidepressants.

Prostate-specific membrane antigen (PSMA) is the most promising target for radioligand therapy of prostate cancer. The aim of this study was to prepare a small molecular ligand p-SCN-Bn-TCMC-PSMA (NG001) and compare it with the commonly used DOTA-based PSMA-617. The PSMA-targeting ability of the

IntroductionThe incidence of cutaneous melanoma (hereafter melanoma) has increased dramatically among fair-skinned populations worldwide. In Norway, melanoma is the most rapidly growing type of cancer, with a 47% increase among women and 57% among men in 2000–2016. Intermittent ultraviolet exposure early in life and phenotypic characteristics like a fair complexion, freckles and nevi are established risk factors, yet the aetiology of melanoma is multifactorial. Certain prescription drugs may have carcinogenic side effects on the risk of melanoma. Some cardiovascular, antidepressant and immunosuppressive drugs can influence certain biological processes that modulate photosensitivity and immunoregulation. We aim to study whether these drugs are related to melanoma risk.Methods and analysisA population-based matched case–control study will be conducted using nation-wide registry data. Cases will consist of all first primary, histologically verified melanoma cases diagnosed between 2007 and 2015 identified in the Cancer Registry of Norway (14 000 cases). Ten melanoma-free controls per case (on date of case melanoma diagnosis) will be matched based on sex and year of birth from the National Registry of Norway. For the period 2004—2015, and by using the unique personal identification numbers assigned to all Norwegian citizens, the case–control data set will be linked to the Norwegian Prescription Database for information on drugs dispensed prior to the melanoma diagnosis, and to the Medical Birth Registry of Norway for data regarding the number of child births. Conditional logistic regression will be used to estimate associations between drug use and melanoma risk, taking potential confounding factors into account.Ethics and disseminationThe project is approved by the Regional Committee for Medical Research Ethics in Norway and by the Norwegian Data Protection Authority. The study is funded by the Southeastern Norway Regional Health Authority. Results will be published in peer-reviewed journals and disseminated further through scientific conferences, news media and relevant patient interest groups.

Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with 212Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of 212Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of 212Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of 212Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of 212Pb-NG001.

Cutaneous melanoma is a deadly skin cancer, resulting from malignant transformation of melanocytes. Long-wave ultraviolet radiation (315-400 nm) is able to damage DNA, cause mutations, and induce melanoma. However, the exact mechanisms of UVA-induced cutaneous melanoma remain a matter of debate. In this review, we give a brief characterization of the most important elements in the photobiology of UVA in melanomagenesis.

The skin is the site for the photosynthesis of vitamin D and is a target tissue for the active metabolite of vitamin D. An increasing body of evidence indicates that vitamin D produced during phototherapy may be responsible for the positive effects observed during treatment of some skin diseases. Topical or oral application of vitamin D derivatives are used alone or with phototherapy. This paper reviews what is known about the use of phototherapy to enhance vitamin D levels, the use of vitamin D analogues with phototherapy, the efficacy of combination therapies, and controversies regarding some of the outcomes. Vitamin D can play a beneficial role in treating psoriasis, even though the exact role of vitamin D in the pathogenesis and severity of psoriasis remains unclear. The role of vitamin D in vitiligo, atopic dermatitis, polymorphic light eruption, and mycosis fungoides must be further investigated.

Lead-212 is a promising radionuclide for cancer therapy, but no primary 212Pb activity standardization has been published. A need therefore exists for accurate estimation of injected doses of 212Pb activity in equilibrium with progeny, when it comes to preclinical and clinical trials. In this study, 212Pb activity was determined using a high purity germanium (HPGe) detector, which allowed the determination of geometry-specific calibration factors for commercially available reentrant ionization chambers (ICs) and sodium iodide (NaI) detectors.

BACKGROUND/AIM Bone metastases are associated with increased morbidity and poor prognosis in a variety of cancers. The present study investigated the effects of targeted radionuclide therapy with α-emitting, bone-seeking radium-224 (224Ra) on osteolytic bone metastasis of MDA-MB-231(SA)-GFP human breast cancer cells injected intracardially into nude mice. MATERIALS AND METHODS Vehicle, ethylenediamine tetra (methylene phosphonic acid) (EDTMP) and 224Ra-solution (45, 91 or 179 kBq/kg) with EDTMP were intravenously administered to mice two days after cell injection. The bone-seeking EDTMP was added to the 224Ra-solution to improve bone targeting of 212Pb, which is a progeny of 224Ra. RESULTS Radium-224 solution treatment decreased in a dose-dependent manner the areas of osteolytic lesions in the hind limbs and the number of tumor foci in the whole skeleton, and extended survival. Paraplegia was not observed in 179 kBq/kg 224Ra-solution group. CONCLUSION Radium-224-solution containing chelated 212Pb is a promising candidate for the treatment of breast cancer patients with bone metastases.

Background Solar ultraviolet (UV) radiation varies with latitude, time of day, and season. Both spectral UV composition and ambient UV dose lead to different health outcomes at different latitudes. Finding the optimal time for sun exposure, whereby the positive effects of UV exposure (vitamin D) are facilitated and the negative effects (skin cancer, photoimmunosuppression) avoided are the most important consideration in modern skin cancer prevention programs. Objectives This paper focuses on the latitude dependency of UVB, UVA, vitamin D production, and skin cancer risk in Caucasians. Methods Biologically effective UVB (280–315 nm) and UVA (315–400 nm) doses were calculated using radiative transfer models with appropriate climatologic data for selected locations. Incidences of squamous cell carcinoma (SCC) and cutaneous melanoma (CM) were retrieved from cancer registries and published articles. Results Annual doses of UVA radiation decrease much less with increasing latitude than annual doses of UVB. Incidences of CM also decrease less steeply with increasing latitude than incidences of SCC. As SCC is caused mainly by UVB, these observations support the assumption that UVA plays an important role in the development of CM. The variations in UVA (relevant to CM) and UVB (relevant to vitamin D production) over 1 day differ: the UVB : UVA ratio is maximal at noon. Conclusions The best way to obtain a given dose of vitamin D with minimal carcinogenic risk is through a non-burning exposure in the middle of the day, rather than in the afternoon or morning.

Nanocarriers based on polymers, metals and lipids have been extensively developed for cancer therapy and diagnosis due to their ability to enhance drug accumulation in cancer cells and decrease undesired drug toxicity in healthy tissues. Overcoming multidrug resistance by designing proper drug nanocarriers will improve outcome of existing oncologic treatments such as chemotherapy and radiotherapy. In this article the relation between physicochemical properties and capacity of a nanosystem to deliver therapeutic agents into pathological sites is discussed. Most promising examples of drug delivery systems are reviewed, and, in particular, the design of a carbohydrate based matrix with entrapped gold nanoparticles is highlighted.

Ultraviolet B (UVB) radiation increases vitamin D level, but the influence of different UV sources (broadband and narrowband UVB lamps, solar simulators and sunbeds) and exposure durations have not been well characterized. In this study the influence of different UV sources on serum 25-hydroxyvitamin-D3 (25(OH)D3) levels in humans are reviewed. Serum 25(OH)D levels before and after UV exposure, and UV doses were extracted from 18 papers published in the past eight years. It was found that the UV dose-response curve for vitamin D generation in humans, as measured by the increments of serum 25(OH)D, is not linear with increasing UV doses and reaches a plateau at about 55 nmol/L after 4-5 weeks. About a half of this increase is equal to the difference between winter and summer 25(OH)D levels, and may be reached after 23 SEDs. The increments decrease with increasing baseline concentration of serum 25(OH)D, and the efficiency of only 0.7 nmol/L per SED is expected on the average when initial concentrations are higher than 50-60 nmol/L. A whole body exposure to 2 SEDs of UVB radiation 3 times per week is expected to rise serum 25(OH)D with an initial rate of 3.9 nmol/L per SED, bringing a winter level of serum 25(OH)D up to a summer level.

Bone metastases are associated with increased morbidity and poor prognosis in a variety of cancers. The present study investigated the effects of targeted radionuclide therapy with α-emitting, bone-seeking radium-224 (Vehicle, ethylenediamine tetra (methylene phosphonic acid) (EDTMP) andRadium-224 solution treatment decreased in a dose-dependent manner the areas of osteolytic lesions in the hind limbs and the number of tumor foci in the whole skeleton, and extended survival. Paraplegia was not observed in 179 kBq/kgRadium-224-solution containing chelated

Four amphiphilic covalently linked meso-tetraphenylchlorin–chitosan nanoconjugates were synthesized and evaluated for use in photochemical internalization (PCI) in vitro and in vivo. The synthetic protocol for the preparation of two different hydrophobic chlorin photosensitizers, 5-(4-aminophenyl)-10,15,20-triphenylchlorin and 5-(4-carboxyphenyl)-10,15,20-triphenylchlorin, was optimized. These monofunctional photosensitizers were covalently attached to carrier chitosan via silyl-protected 3,6-di-O-tert-butyldimethylsilyl-chitosan (Di-TBDMS-chitosan) with 0.10 degree of substitution per glucosamine (DS). Hydrophilic moieties such as trimethylamine and/or 1-methylpiperazine were incorporated with 0.9 DS to give fully water-soluble conjugates after removal of the TBDMS groups. A dynamic light scattering (DLS) study confirmed the formation of nanoparticles with a 140–200 nm diameter. These nanoconjugates could be activated at 650 nm (red region) light, with a fluorescence quantum yield (ΦF) of 0.43–0.45, and ...

Sigmoidal (S-shaped) dose-cancer incidence relationships are often observed in animal bioassays for carcinogenicity. Ultraviolet (UV) radiation is an established skin carcinogen. The aim of this study is to examine if S-shaped curves describe the relationship between solar UV doses and skin cancer incidences, and if such relationships can be used to estimate threshold levels of non-carcinogenic UV exposure, as well as maximal incidence rates.We studied the incidence rate-annual erythema-effective UV dose relationship for squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and cutaneous melanoma (CM) among different Caucasian populations in Europe, Australia and New Zealand.Our analysis indicates that S-shaped associations describe the data well (P0.0001). The age-adjusted incidence rates for cases expected to be due to other causes than solar UV exposure (at zero UV dose) were found to be around 0.6, 9.7 and 4.0 per 100,000 for women in 1997-2007 for SCC, BCC and CM, respectively, and around 1.2, 14.3 and 2.6 per 100,000 for men. The analysis indicates that SCC, BCC and CM have maximal incidence of 361 ± 24, 1544 ± 49 and 36 ± 4 per 100,000 for women, and 592 ± 35, 2204 ± 109 and 50 ± 4 per 100,000 for men.Between 89 and 95% of the annual CM cases, around 99.8% SCC and 99.4% BCC cases are caused by solar UV exposure. The analysis did not identify any "safe" UV dose below which the risk for skin cancer was absent. Avoidance of UV radiation has a potential to reduce the incidence of skin cancer in fair-skinned population.

Summary 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.

Folate is essential for cell division and growth. Deficiency is linked to birth defects, magaloblastic anaemia, cardiovascular disease, etc. Folic acid is a synthetic form of folate and is used to fortify food and in supplements. In aqueous solutions, in blood and even in human skin, folic acid may be degraded by ultraviolet radiation. Consequently, photodegradation of folic acid in human blood may lead to folate deficiency. However, the degree and the health consequences of such photodegradation are unknown. It is not clear which spectral region plays the most important role in the photodegradation of folic acid. In this study the photodegradation of folic acid in aqueous solution under different wavelengths of ultraviolet radiation (260–400 nm) was investigated by fluorescence spectroscopy. The photodegradation rate of folic acid was dependent on wavelength. Action spectrum for 1 μM folic acid photodegradation was determined. Its action spectrum is not identical to its absorption or fluorescence excitation spectra. The action spectrum demonstrated that UVB and UVA degrade folic acid. Protecting skin against UVB and UVA radiation by sunscreens may help to protect folic acid in human blood under intense solar radiation.

Vitamin B12 (cobalamin) is required for proper red blood cell formation, neurologic function, and DNA synthesis. Cobalamins in solutions are light sensitive, but no comprehensive study has been performed to compare the photostability of different cobalamins under UVA exposure. Their indirect photodegradation due to their antioxidant properties and their photostability in vivo have also not been studied so far. The photodegradation of four cobalamins (methylcobalamin (MeCbl), adenosylcobalamin (AdCbl), hydroxocobalamin (OHCbl) and cyanocobalamin (CNCbl)) under UVA exposure in aqueous solutions (pH=7.4) have been investigated by absorption spectroscopy. The photodegradation of OHCbl in the absence and presence of the endogenous photosensitizer riboflavin was studied. Serum vitamin B12 concentrations before and after summer were measured in four patients with psoriasis. All studied cobalamins are photolabile. The biologically active forms of cobalamin, AdCbl and MeCbl, are converted to OHCbl within seconds during UVA exposure. OHCbl is the most stable cobalamin. However, reactive oxygen species increases the degradation rate of OHCbl. Our pilot study on humans demonstrates that serum vitamin B12 concentrations are not significantly affected during summertime in Norway. Further work is needed to determine vitamin B12 photostability in humans living at lower latitudes or using sunbeds.

Background Senescent cells, which are resistant to apoptosis, accumulate with age and after ultraviolet (UV) radiation, chemotherapy and radiation therapy. Preventing or eliminating senescent cells may be crucial for protection against skin cancer development and improving tumour treatment. The aim of the present study was to investigate the potential of photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) to induce senescence in skin cancer cells and to eliminate senescent cells induced by chemotherapy (bleomycin) or UVA (315–400 nm) exposure. Methods WM115 and A431 cells were incubated with 1 mM ALA for 2 and 4 h, respectively, before exposure to blue light (10 mW/cm 2 , 0–80 s, 0-0.8 J/cm 2 ). WM115 cells were treated once with 106 J/cm 2 (58.4 mW/cm 2 , 30.25 min) UVA 6 days before ALA-PDT or with 0.24 IU/ml bleomycin for 7 days to induce senescence before ALA-PDT. Cell viability was monitored by the MTT colorimetric assay. Senescent cells were detected using senescence-associated-beta-galactosidase (SA-β-Gal) staining and morphological changes (enlarged, flat cells). Results ALA-PDT caused a light dose dependent increase in senescence. ALA-PDT induced senescence very effectively only in WM115 cells but not in A431 cells, while similar cytotoxic effects were observed in both cell lines. After ALA-PDT with 0.4 J/cm 2 around 70% of survived WM115 cells were senescent, while only around 5% of A431 cells were senescent after ALA-PDT with 0.8 J/cm 2 . Conclusion ALA-PDT can induce premature senescence and kill senescent cells induced by ALA-PDT itself, UVA and chemotherapy (bleomycin). Light doses must be properly chosen to photoinactivate ALA-PDT-induced senescent cells.

Incidence rates of skin cancer increase with decreasing latitude in Norway, as in many other countries with white populations. The latitudinal trends of the incidence rates of skin cancer were studied and compared with data for vitamin D-induced by UV and for vitamin D intake. The north-south gradient for CMM incidence rates on sun exposed skin is much smaller than those for BCC and SCC, and that for BCC is smaller than that for SCC. This indicates that SCC and BCC are mainly due to solar UVB, while UVA may play a significant role for CMM and a smaller role for BCC, since the north-south gradient of annual UVB fluences is larger than that of UVA fluences. However, there is an inverse latitudinal gradient of skin cancer in central Europe. This is probably due to a gradient of skin color, since white skin is an important determinant of increased risk of skin cancer. The role of vitamin D for skin cancer risk is difficult to evaluate, since serum levels of 25-hydroxyvitamin D, as well as vitamin D intakes, are widely different from country to country. Still, epidemiological evidence indicates a role: for melanomas arising on non-sun exposed body localizations (uveal melanomas, melanomas arising in the vulva and perianal/anorectal regions) there appears to be no latitudinal gradient, or, a negative gradient, i.e., increasing rates with decreasing latitude as would be expected if UV-generated vitamin D plays a protective role. Both skin cancer risk and vitamin D photosynthesis decrease with increasing skin darkness.

International audience; Several reports describe U-shaped 25-hydroxyvitamin D [25(OH)D] concentration–health outcomes, including musculo-skeletal disorders such as falls and fractures, several cancers, cardiovascular disease (CVD), cognitive function, all-cause mortality rates, birth outcomes, allergic reactions, frailty, and some other disorders. This paper reviews reports of U-shaped outcome associations with vitamin D status for evidence of underlying pathophysiological processes, or of confounding, finding that some U-shaped associations appear to be biologically meaningful, but that many could well reflect confounding by factors such as lifestyle, or hypovitaminosis D-related disease onset being masked by self-supplementation that was begun too late to correct developing health problems but before baseline vitamin D status assessment. However, the various U-shaped associations for allergic reactions may be due to vitamin D modulation of the phenotype of the immune response, shifting the Th1-Th2 balance toward Th2 formation. For prostate cancer, there seems to be little effect of 25(OH)D concentration on incidence; however, there is an inverse correlation between 25(OH)D concentration and mortality rates. Future observational studies, and randomized controlled trial data analyses, should include adjustment for data collected on prior long-term vitamin D supplementation and solar UVB exposure, as well as other potential confounders.

Most studies have demonstrated that sunscreens with lower sun protection factor (SPF) do not prevent the production of vitamin D because much lower amount of sunscreen (SPF30) is applied than recommended (2 mg/cm(2)) indicating that a significant amount of UV radiation can penetrate the skin. Since less sunscreen is applied, higher SPF sunscreens may be used to achieve the desired protection. However, there is little information regarding the application of high-SPF sunscreen and vitamin D formation. The aim of this study was to measure the influence of the amount of two SPF 30 sunscreens on pre-vitamin D formation in a cuvette with 7-dehydrocholesterol.Sunscreen with physical (reflecting) or chemical (absorbing) UV filters exhibits different levels of protection in vitro even if the SPF is the same. The level of photoprotection is differentially reduced when less sunscreen than the recommended application thickness is applied.The usual application of 0.8-1 mg/cm(2) is below the recommended value of 2 mg/cm(2), and pre-vitamin D may be formed when lower amounts of SPF ≤30 sunscreen are applied, showing that a significant amount of UV radiation may enter the skin.

Superficial-spreading melanoma (SSM) and nodular melanoma (NM) are the most common histological types of melanoma. These are seemingly distinct entities, on the basis of epidemiology, clinical behavior, tumor biological, and histological aspects as well as molecular characteristics. Intermittent sun exposure seems to play a major role in SSM, which has an increasing incidence rate during the last decades. However, relationship with sun exposure is more complex in the case of NM, as the latter may arise on any body part and has a more stable incidence rate. To obtain more information on the role of sun exposure in these two types of melanoma, we have compared body site distributions and latitude gradients for a period of 30 years in Norway. The study was based on official reports from the Cancer Registry of Norway, using melanoma incidence rates for a period of 30 years (1978-2007), by age, sex, anatomic site, and region of Norway. Our results show that in Norway, SSM is more strongly related to intermittent sun exposure than NM, as it arises mostly on the trunk as compared with the head and neck. Moreover, SSM has a higher incidence in the Southern regions of Norway, whereas for NM, the north-south gradient is not statistically significant. Differences in sun exposure at northern latitudes have a major impact on different types of melanoma. It seems that NM is less sun-induced than SSM, for which other etiological and pathogenetic factors may play important roles.

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.

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.

Background Cutaneous malignant melanoma (CMM) incidence continues to increase in many parts of the world. Solar ultraviolet (UV) radiation is the main environmental risk factor for CMM. Different body locations are subjected to different doses and exposure patterns of solar UV. Time and latitudinal trends of CMMs on shielded and exposed skin give valuable information about the aetiology of these cancers. In this study, we have compared the time and latitudinal trends of CMM incidence on skin areas which are chronically (head and neck) and rarely (foot) exposed to UV radiation, to gain more information about the relationship between sun doses, exposure patterns and melanomagenesis. Methods We have analysed epidemiological data from the Cancer Registry of Norway, for foot and head and neck CMM for two time periods: 1966–1986 and 1987–2007. Results Cutaneous malignant melanoma incidence rate on head and neck has increased with time, while incidence rates of foot CMM have remained almost constant with time in Norway. There is a large north–south gradient in incidence rates of CMM on head and neck in Norway, while there is almost no north–south gradient for CMM incidence on foot. Conclusions Comparisons of time trends and latitudinal trends of the incidence rates of CMM on head/neck and on foot indicate that solar radiation plays a role in the induction of the former CMM but probably not for the latter.