Swiss clinical practice guidelines on field cancerization of the skin.

Actinic keratosis (AK) affects millions of people worldwide, and its prevalence continues to increase. AK lesions are caused by chronic ultraviolet radiation exposure, and the presence of two or more AK lesions along with photodamage should raise the consideration of a diagnosis of field cancerization. Effective treatment of individual lesions as well as field cancerization is essential for good long-term outcomes. The Swiss Registry of Actinic Keratosis Treatment (REAKT) Working Group has developed clinical practice guidelines for the treatment of field cancerization in patients who present with AK. These guidelines are intended to serve as a resource for physicians as to the most appropriate treatment and management of AK and field cancerization based on current evidence and the combined practical experience of the authors. Treatment of AK and field cancerization should be driven by consideration of relevant patient, disease, and treatment factors, and appropriate treatment decisions will differ from patient to patient. Prevention measures and screening recommendations are discussed, and special considerations related to management of immunocompromised patients are provided.

Protective immunity of single and multi-antigen DNA vaccines against schistosomiasis

We evaluated the usefulness of the combination of three plasmids encoding tegumental (pECL and pSM14) and muscular (pIRV5) antigens of the Schistosoma mansoni on improving the protective immunity over the use of a single antigen as DNA vaccines. Female BALB/c mice were inoculated twice with 25 µg DNA plasmid within two weeks interval. The challenge was performed with 80 cercarias of a regional isolate of S. mansoni (SLM) one week after the last immunization. Six weeks after challenge, all mice were perfused for worm load determination. The following groups were analyzed: saline; empty vector; monovalent formulations of pECL; pSM14 and pIRV5 and also double combinations of pECL/pIRV5 and pIRV5/pSM14 and a triple combination of pECL/pIRV5/pSM14. The protection was expressed as a percentage of worm loads in each group compared with the saline group. The results obtained were 41% (p < 0.05); 52% (p < 0.05); 51% (p < 0.05); 48% (p < 0.05); 55% (p < 0.05); 45% (p < 0.05); 65% (p < 0.05) for each group respectively.

Effect of gamma radiation on the activity of hemocytes and on the course of Schistosoma mansoni infection in resistant Biomphalaria tenagophila snails

High doses of gamma radiation (10 Krad) in Biomphalaria tenagophila snails (Taim strain), which have been found to be resistant to Schistosoma mansoni, were not sufficient to impair their resistance to the parasite. The number of hemocytes, as well as their phagocytic activity, were not affected by irradiation, thus showing resemblance with mammal macrophages, which are resistant to gamma irradiation also.

Neurotensin is a regulator of insulin secretion in pancreatic beta-cells.

Neurotensin (NT) is secreted from neurons and gastrointestinal endocrine cells. We previously reported that the three NT receptors (NTSRs) are expressed in pancreatic islets and beta cell lines on which we observed a protective effect of NT against cytotoxic agents. In this study, we explored the role of NT on insulin secretion in the endocrine pancreatic beta cells. We observed that NT stimulates insulin secretion at low glucose level and has a small inhibiting effect on stimulated insulin secretion from isolated islets or INS-1E cells. We studied the mechanisms by which NT elicited calcium concentration changes using fura-2 loaded islets or INS-1E cells. NT increases calcium influx through the opening of cationic channels. Similar calcium influxes were observed after treatment with NTSR selective ligands. NT-evoked calcium regulation involves PKC and the translocation of PKCalpha and PKCepsilon to the plasma membrane. Part of NT effects appears to be also mediated by PKA but not via the Erk pathway. Taken together, these data provide evidence for an important endocrine role of NT in the regulation of the secretory function of beta cells.

Coexistence of antibodies to tick-borne agents of babesiosis and Lyme borreliosis in patients from Cotia county, State of São Paulo, Brazil

This paper reports a case of coinfection caused by pathogens of Lyme disease and babesiosis in brothers. This was the first case of borreliosis in Brazil, acquired in Cotia County, State of São Paulo, Brazil. Both children had tick bite history, presented erythema migrans, fever, arthralgia, mialgia, and developed positive serology (ELISA and Western-blotting) directed to Borrelia burgdorferi G 39/40 and Babesia bovis antigens, mainly of IgM class antibodies, suggestive of acute disease. Also, high frequencies of antibodies to B. bovis was observed in a group of 59 Brazilian patients with Lyme borreliosis (25.4%), when compared with that obtained in a normal control group (10.2%) (chi-square = 5.6; p < 0.05). Interestingly, both children presented the highest titers for IgM antibodies directed to both infective diseases, among all patients with Lyme borreliosis.

Phenotypic divergence but not genetic distance predicts assortative mating among species of a cichlid fish radiation.

The hypothesis of ecological divergence giving rise to premating isolation in the face of gene flow is controversial. However, this may be an important mechanism to explain the rapid multiplication of species during adaptive radiation following the colonization of a new environment when geographical barriers to gene flow are largely absent but underutilized niche space is abundant. Using cichlid fish, we tested the prediction of ecological speciation that the strength of premating isolation among species is predicted by phenotypic rather than genetic distance. We conducted mate choice experiments between three closely related, sympatric species of a recent radiation in Lake Mweru (Zambia/DRC) that differ in habitat use and phenotype, and a distantly related population from Lake Bangweulu that resembles one of the species in Lake Mweru. We found significant assortative mating among all closely related, sympatric species that differed phenotypically, but none between the distantly related allopatric populations of more similar phenotype. Phenotypic distance between species was a good predictor of the strength of premating isolation, suggesting that assortative mating can evolve rapidly in association with ecological divergence during adaptive radiation. Our data also reveals that distantly related allopatric populations that have not diverged phenotypically, may hybridize when coming into secondary contact, e.g. upon river capture because of diversion of drainage systems.

Decreased local control following radiation therapy alone in early-stage glottic carcinoma with anterior commissure extension.

PURPOSE: To assess the patterns of failure in the treatment of early-stage squamous cell carcinoma of the glottic larynx. PATIENTS AND METHODS: Between 1983-2000, 122 consecutive patients treated for early laryngeal cancer (UICC T1N0 and T2N0) by radical radiation therapy (RT) were retrospectively studied. Male-to-female ratio was 106 : 16, and median age 62 years (35-92 years). There were 68 patients with T1a, 18 with T1b, and 36 with T2 tumors. Diagnosis was made by biopsy in 104 patients, and by laser vaporization or stripping in 18. Treatment planning consisted of three-dimensional (3-D) conformal RT in 49 (40%) patients including nine patients irradiated using arytenoid protection. A median dose of 70 Gy (60-74 Gy) was given (2 Gy/fraction) over a median period of 46 days (21-79 days). Median follow-up period was 85 months. RESULTS: The 5-year overall, cancer-specific, and disease-free survival amounted to 80%, 94%, and 70%, respectively. 5-year local control was 83%. Median time to local recurrence in 19 patients was 13 months (5-58 months). Salvage treatment consisted of surgery in 17 patients (one patient refused salvage and one was inoperable; total laryngectomy in eleven, and partial laryngectomy or cordectomy in six patients). Six patients died because of laryngeal cancer. Univariate analyses revealed that prognostic factors negatively influencing local control were anterior commissure extension, arytenoid protection, and total RT dose < 66 Gy. Among the factors analyzed, multivariate analysis (Cox model) demonstrated that anterior commissure extension, arytenoid protection, and male gender were the worst independent prognostic factors in terms of local control. CONCLUSION: For early-stage laryngeal cancer, outcome after RT is excellent. In case of anterior commissure extension, surgery or higher RT doses are warranted. Because of a high relapse risk, arytenoid protection should not be attempted.

Staff eye lens and extremity exposure in interventional cardiology: Results of the ORAMED project

Within the ORAMED project a coordinated measurement program for occupationally exposed medical staff was performed in different hospitals in Europe. The main objectives of ORAMED were to obtain a set of standardized data on doses for staff in interventional cardiology and radiology and to optimize staff protection. Doses were measured with thermoluminescent dosemeters on the ring finger and wrist of both hands, on legs and at the level of the eyes of the main operator performing interventional procedures. In this paper an overview of the doses per procedure measured during 646 interventional cardiology procedures is given for cardiac angiographies and angioplasties (CA/PTCA), radiofrequency ablations (RFA) and pacemaker and defibrillator implantations (PM/ICD). 31% of the monitored procedures were associated with no collective protective equipment, whereas 44% involved a ceiling screen and a table curtain. Although associated with the smallest air kerma - area product (KAP), PM/ICD procedures led to the highest doses. As expected, KAP and doses values exhibited a very large variability. The left side of the operator, most frequently the closest to the X-ray scattering region, was more exposed than his right side. An analysis of the effect of parameters influencing the doses, namely collective protective equipment, X-ray tube configuration and catheter access route, was performed on the doses normalized to KAP. Ceiling screen and table curtain were observed to reduce normalized doses by atmost a factor 4, much smaller than theoretical attenuation factors typical for such protections, i.e. from 10 to 100. This observation was understood as their inappropriate use by the operators and their non-optimized design. Configurations with tube above the patient led to higher normalized doses to the operator than tube below, but the effect of using a biplane X-ray suite was more complex to analyze. For CA/PTCA procedures, the upper part of the operator's body received higher normalized doses for radial than for femoral catheter access, by atmost a factor 5. This could be seen for cases with no collective protection. The eyes were observed to receive the maximum fraction of the annual dose limit almost as frequently as legs and hands, and clearly the most frequently, if the former 150 mSv and new 20 mSv recommended limits for the lens of the eye are considered, respectively.

Second cranio-facial malignancies in hereditary retinoblastoma survivors previously treated with radiation therapy: clinic and radiologic characteristics and survival outcomes.

INTRODUCTION: Hereditary retinoblastoma survivors have an increased risk for cranio-facial second primary tumours (SPT), especially after treatment with external beam radiotherapy (EBRT). This multicentre study evaluates the clinical and imaging characteristics and outcomes of cranio-facial SPTs in irradiated retinoblastoma survivors. PATIENTS AND METHODS: Clinical and radiological data of 42 hereditary retinoblastoma patients with 44 second and third malignancies were reviewed. Radiological data included anatomic location and computed tomography (CT) and magnetic resonance (MR) characteristics. Cox regression and likelihood ratio chi-square test were used to evaluate differences in patients' survival rates. RESULTS: Cranio-facial SPTs were diagnosed at a median age of 13 years. Histological types included osteosarcomas (43%), rhabdomyosarcomas (20%) (57% embryonal, 43% alveolar) and a variety of other types of SPT (37%). Predilection sites were: temporal fossa (39%), ethmoid sinus (23%), orbit (18%), maxillary sinus (16%) and intracranial dura mater (4%). Most of the osteosarcomas (78%) and rhabdomyosarcomas (80%) occurred in patients treated with EBRT in the first year-of-life. Treatment of SPTs with a microscopically complete surgical resection led to a significantly better 5-year overall survival (OS) (P=0.017) and event-free survival (EFS) (P=0.012) compared to patients treated without surgery or incomplete resection (OS: 83% versus 52%; EFS: 80% versus 47%). CONCLUSIONS: Osteosarcomas and rhabdomyosarcomas are the most common cranio-facial SPTs in irradiated hereditary retinoblastoma survivors, which develop in specific locations and occur predominantly in patients irradiated in their first year-of-life. Microscopically complete surgical resection of SPTs is a major prognostic factor, suggesting the potential benefit of early detection by imaging.

Traitement non chirurgical des rectites postactiniques ou radiques chroniques [Non-surgical treatment of acute and late radiation proctitis]

Pelvic external radiotherapy with or without brachytherapy plays an important role in the management of pelvic cancers. Despite recent technical innovations including conformal three-dimensional (3D) external beam radiotherapy and more recently intensity modulated radiotherapy (IMRT), local side effects can occur secondary to normal tissue damage caused by ionising radiation. Morbidity depends on the anatomic position of the rectum within the pelvis and the fast turnover rate of the mucosa, as well as the characteristics of the radiation treatment and patient co-morbidities. Medical management is sometimes complex and merits herein a short review.

Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry.

The treatment of some cancer patients has shifted from traditional, non-specific cytotoxic chemotherapy to chronic treatment with molecular targeted therapies. Imatinib mesylate, a selective inhibitor of tyrosine kinases (TKIs) is the most prominent example of this new era and has opened the way to the development of several additional TKIs, including sunitinib, nilotinib, dasatinib, sorafenib and lapatinib, in the treatment of various hematological malignancies and solid tumors. All these agents are characterized by an important inter-individual pharmacokinetic variability, are at risk for drug interactions, and are not devoid of toxicity. Additionally, they are administered for prolonged periods, anticipating the careful monitoring of their plasma exposure via Therapeutic Drug Monitoring (TDM) to be an important component of patients' follow-up. We have developed a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) requiring 100 microL of plasma for the simultaneous determination of the six major TKIs currently in use. Plasma is purified by protein precipitation and the supernatant is diluted in ammonium formate 20 mM (pH 4.0) 1:2. Reverse-phase chromatographic separation of TKIs is obtained using a gradient elution of 20 mM ammonium formate pH 2.2 and acetonitrile containing 1% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 20 min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (<9.6%), overall process efficiency (87.1-104.2%), as well as TKIs short- and long-term stability in plasma. The method is precise (inter-day CV%: 1.3-9.4%), accurate (-9.2 to +9.9%) and sensitive (lower limits of quantification comprised between 1 and 10 ng/mL). This is the first broad-range LC-MS/MS assay covering the major currently in-use TKIs. It is an improvement over previous methods in terms of convenience (a single extraction procedure for six major TKIs, reducing significantly the analytical time), sensitivity, selectivity and throughput. It may contribute to filling the current knowledge gaps in the pharmacokinetics/pharmacodynamics relationships of the latest TKIs developed after imatinib and better define their therapeutic ranges in different patient populations in order to evaluate whether a systematic TDM-guided dose adjustment of these anticancer drugs could contribute to minimize the risk of major adverse reactions and to increase the probability of efficient, long lasting, therapeutic response.

Water-filtered infrared-A radiation (wIRA) is not implicated in cellular degeneration of human skin

Rapport de synthèse : Introduction : le vieillissement cutané est un processus biologique complexe auquel participe une exposition excessive au rayonnement ultraviolet du soleil. En particulier, les longueurs d'onde des rayons ultraviolets A et B (UV-A et UV-B) peuvent induire une augmentation de la synthèse de protéases, comme la métalloprotéinase matricielle 1 (MMP-1), qui est impliquée dans le processus de vieillissement. La thermothérapie par infrarouges, dont les longueurs d'onde sont plus longues que celles des UV, est largement utilisée à des fins thérapeutiques ou cosmétiques. Or, il a été démontré que les infrarouges en filtration aqueuse (IRFA) pouvaient induire une augmentation de la production de MMP-1 et par conséquent être nocifs. Il serait donc intéressant d'évaluer les effets des IRFA au niveau cellulaire et moléculaire. But Expérimental : étudier les effets des lampes à infrarouges en filtration aqueuse utilisées en clinique sur des fibroblastes cutanés humains en culture, afin d'analyser l'expression du gène codant pour la protéine MMP-1. Méthode : des fibroblastes cutanés humain ont été irradiés d'une part avec approximativement 88% d'IRFA (780-1400 nm) et 12% de lumière rouge (LR, 665-780 nm) avec 380 mW/cm2 IRFA(+LR) (333 mW/cm2 IRFA) et d'autre part avec des UV-A comme contrôle. Des courbes de survie cellulaire ont été établies après une exposition allant de 15 minutes à 8 heures au IRFA(+LR) (340-10880 J/cm2 wIRA(+RL), 300-9600 J/cm2 wIRA) ou de 15 à 45 minutes aux UV-A(+BL) (25-75 J/cm2 UV-A(+BL). L'induction de l'ARNm du gène de la MMP-1 a été analysé dans les fibroblastes cutanés humain à deux températures physiologiques (30°C et 37°C) lors d'expositions uniques de 15 à 60 minutes aux IRFA(+LR) (340-1360 J/cm2 IRFA(+LR), 300-1200 J/cm2 IRFA) ou de 30 minutes aux UV-A(+BL) (50 J/cm2 UVA(+BL)). De plus, nous avons effectué des irradiations répétées, une a chaque passage cellulaire jusqu'au passage. 10 de 15 minutes d'IRFA(+LR) 340 J/cm2 IRFA(+LR), 300 J/cm2 IRFA) . Résultats : une exposition unique aux UV-A (+BL) entraîne chez des fibroblastes cutanés humains une augmentation de la mort cellulaire, ainsi qu'une forte augmentation de l'expression du gène codant pour la MMP-1. L'augmentation mise en évidence pour cet ARNm varie en fonction de la technique utilisée : elle est de 11 ± 1 fois par RT-PCR classique, de 76 ± 2 fois par RT-PCR quantitative à 30°C, et de 75 ± 1 fois par RT-PCR quantitative à 37°C. Par contre, une exposition unique ou répétée aux IRFA (+LR) n'induit aucune augmentation de la mort cellulaire, ni de l'expression de l'ARNm de la MMP-1 chez ces fibroblastes. Conclusions : les résultats de cette étude montrent que, contrairement aux rayons ultraviolets, les IRFA (+LR) ne semblent impliqués ni dans le vieillissement, ni dans la mort cellulaire, même utilisés à des doses très élevées. Ces résultats sont en accord avec certaines investigations in vivo montrant une induction de MMP-1 par des UV et non des infrarouges. Ces dernières études suggèrent d'ailleurs plutôt un rôle protecteur des IRFA (+LR).

Evaluation of organ-specific peripheral doses after 2-dimensional, 3-dimensional and hybrid intensity modulated radiation therapy for breast cancer based on Monte Carlo and convolution/superposition algorithms: implications for secondary cancer risk assessment.

To make a comprehensive evaluation of organ-specific out-of-field doses using Monte Carlo (MC) simulations for different breast cancer irradiation techniques and to compare results with a commercial treatment planning system (TPS). Three breast radiotherapy techniques using 6MV tangential photon beams were compared: (a) 2DRT (open rectangular fields), (b) 3DCRT (conformal wedged fields), and (c) hybrid IMRT (open conformal+modulated fields). Over 35 organs were contoured in a whole-body CT scan and organ-specific dose distributions were determined with MC and the TPS. Large differences in out-of-field doses were observed between MC and TPS calculations, even for organs close to the target volume such as the heart, the lungs and the contralateral breast (up to 70% difference). MC simulations showed that a large fraction of the out-of-field dose comes from the out-of-field head scatter fluence (>40%) which is not adequately modeled by the TPS. Based on MC simulations, the 3DCRT technique using external wedges yielded significantly higher doses (up to a factor 4-5 in the pelvis) than the 2DRT and the hybrid IMRT techniques which yielded similar out-of-field doses. In sharp contrast to popular belief, the IMRT technique investigated here does not increase the out-of-field dose compared to conventional techniques and may offer the most optimal plan. The 3DCRT technique with external wedges yields the largest out-of-field doses. For accurate out-of-field dose assessment, a commercial TPS should not be used, even for organs near the target volume (contralateral breast, lungs, heart).

A New Twist on Radiation Oncology: Low-Dose Irradiation Elicits Immunostimulatory Macrophages that Unlock Barriers to Tumor Immunotherapy.

Tumor-infiltrating macrophages typically promote angiogenesis while suppressing antitumoral T cell responses. In this issue of Cancer Cell, Klug and colleagues report that clinically-feasible, low-dose irradiation redirects macrophage differentiation from a tumor-promoting/immunosuppressive state to one that enables cytotoxic T cells to infiltrate tumors and kill cancer cells, rendering immunotherapy successful in mice.

Protection from radiation-induced colitis requires MHC class II antigen expression by cells of hemopoietic origin.

Ulcerative colitis, an inflammatory bowel disease, is believed to result from a breakdown of dominant tolerance mechanisms that normally control intestinal immunity. Although CD4+ T lymphocyte subpopulations and expression of MHC class II molecules have been shown to play a role in the pathogenesis of the disease, the nature of the responsible mechanisms remains unclear. In this paper we describe a novel mouse model for inflammatory bowel disease, radiation-induced colitis, that occurs with complete penetrance 6-8 wk postinduction. A combination of high dose gamma-irradiation and lack of MHC class II expression on cells of hemopoietic origin results in development of colitis in C57BL/6 mice. Because of its versatility (due to susceptibility of mice of the widely genetically manipulated C57BL/6 background), high reproducibility, and 100% penetrance, radiation-induced colitis will be a useful mouse model for colitis and a significant tool to study dominant immunological tolerance mechanisms. Moreover, our data imply that tolerization to enteric Ags requires MHC class II mediated presentation by APC of hemopoietic origin.