Diagnostic accuracy and interobserver concordance: teledermoscopy of 600 suspicious skin lesions in Southern Denmark.

BACKGROUND: Skin cancer incidences are increasing and early diagnosis, especially of malignant melanoma, is crucial. Teledermatology including teledermoscopy (TDS) can be used to triage referrals of suspicious skin lesions, however, this is not currently recommended in Denmark. OBJECTIVES: To evaluate diagnostic accuracy, sensitivity, specificity and interobserver concordance of TDS, and to evaluate the number of incidental lesions potentially missed by TDS. METHODS: Fifty general practices were invited to send images of suspicious skin lesions for evaluation using smartphone TDS. Simultaneously, the patient was referred for a face-to-face (FTF) consultation. Images for TDS were independently evaluated by two dermatologists; a third dermatologist performed the FTF consultation. Diagnosis, management plan and level of diagnostic confidence were noted. For TDS photo quality was rated, and for FTF any incidental findings were described. RESULTS: Six hundred lesions in 519 patients were included. The diagnostic accuracy was significantly higher on FTF evaluation than on TDS (P < 0.01). However, this was associated with a significant difference in specificity (P ≤ 0.012) whereas no significant difference was found in sensitivity. The concordance between FTF and TDS, and the interobserver concordance of two TDS evaluations was moderate to substantial (AC1 = 0.57-0.71). Incidental melanomas were found in 0.6% of patients on FTF evaluation, adding an extra 13% of melanomas. However, on TDS these patients' photographed lesions all warranted FTF follow-up, where these melanomas would have been identified. CONCLUSION: In this large prospective study, no significant difference in sensitivity was observed between FTF and TDS, but specificity was lower on TDS than FTF. Taking management plans into account, we would, however, potentially have dismissed 2 of 23 melanomas, if only TDS had been used for assessment. One of these was a melanoma located on the scalp, an anatomic region less suitable for TDS.

Histamine-release test in angioedema patients without urticaria - a retrospective cohort study of 404 patients.

Summary: A subset of patients with angioedema (AE) and urticaria has histamine releasing autoantibodies. The histamine release test (HR-test) has been used as a tool in chronic urticaria to define the autoimmune subgroup and may possibly guide the clinician to a more personalized therapy, like omalizumab and cyclosporine. The prevalence and value of positive histamine releasing autoantibodies in monosymptomatic AE is sparsely described in the literature. The purpose of this study was to report the prevalence of positive histamine releasing autoantibodies in a cohort of patients with recurrent AE and evaluate the usefulness of this test in AE patients. We performed a retrospective cohort study of 612 patients referred due to AE between 1995 and 2013. HR-test results were available in 404 patients. In the sub-group of patients with AE and urticaria, 17.3% had a positive HR-test but only 4.3% of patients with mono-symptomatic AE had a positive HR-test. No statistically significant treatment benefits of antihistamines, corticosteroids or adrenaline were found comparing patients with angioedema +/- urticaria based on the result of the HR-test (negative / positive). Thus, the HR-test result cannot be used as predictor of the efficacy of anti-allergic treatment.

Long term surgical and hearing outcomes in the management of tympanomastoid paragangliomas.

OBJECTIVE: To analyze the long term outcomes after surgery in tympanomastoid paragangliomas. STUDY DESIGN: Retrospective study. METHODS: The charts of 145 patients with tympanomastoid paragangliomas managed between 1988 and 2013 were reviewed. The clinical features, audiological data, pre- and postoperative notes were noted. The tumors were staged according to the modified Fish and Mattox classification. The surgical approaches for all patients were formulated according to the surgical algorithm developed at our center. RESULTS: 34 (23.5%), 46 (31.7%), 22 (15.2%), 18 (12.4%) and 25 (17.2%) patients were diagnosed to have TMP class A1, A2, B1, B2 and B3 tumors respectively. Gross tumor resection was achieved in 141 (97.2%) patients. The facial nerve was uncovered in four patients and infiltrated in three. The cochlea was found eroded in seven cases. The mean follow-up was 48.4 months. Recurrence was seen in one patient (0.7%). In the cases where the facial nerve was preserved (n=143), the nerve function was graded as HB grade 1 in 138 patients (97%). Postoperatively, the mean AC showed an improvement in all categories except in class B2 and B3, which corresponds to the classes that include patients who underwent subtotal petrosectomy. CONCLUSION: We report the long term surgical outcomes in tympanomastoid paragangliomas in the largest series published till date. It is possible to completely eradicate all types of tympanomastoid paragangliomas with minimum sequelae by choosing the correct surgical approach to achieve adequate exposure for individual tumor classes as described in our classification and algorithm. LEVEL OF EVIDENCE: IIb.

Vocal cord hemangioma.

Laryngeal hemangiomas are relatively rare. Laryngeal hemangiomas occur in two main forms--infantile and adult laryngeal hemangiomas. While infantile hemangiomas are usually found to occur in the subglottis, adult hemangiomas occur commonly in the supraglottic regions of the larynx. Laryngeal hemangioma with cavernous features isolated to the free edge of the vocal fold is a very rare clinical finding. We present a case of hemangioma of the right vocal cord in an adult, which was managed successfully in our center.

Enhanced poly(adenosine diphosphate ribose) polymerase activity and gene expression in Ewing's sarcoma cells.

Ewing's sarcoma (ES) is a highly malignant childhood bone tumor and is considered curable by moderate doses of radiotherapy. The addition of chemical inhibitors of the activity of the nuclear enzyme poly(adenosine diphosphate ribose) [poly(ADPR)] polymerase to ES cells in culture results in increased cell killing, a phenomenon called "inhibitor sensitization." Since poly(ADPR) polymerase is thought to be associated with DNA repair, it has been suggested that ES cells and other inhibitor-sensitized cells may have a reduced capacity for polymer synthesis resulting in deficient postirradiation recovery. We present here the unexpected observation that in comparison to other cell lines tested, ES cells exhibit a high enzyme activity, higher constitutive levels of the protein, and elevated levels of its mRNA transcript for poly(ADPR) polymerase. No gross amplifications or rearrangements of the gene were observed; however, regulation of poly(ADPR) polymerase in these tumor cells takes place at the level of the gene transcript.

Radiation-induced neoplastic transformation of human prostate epithelial cells.

We report the malignant transformation of human prostate epithelial cells (267B1) after multiple exposures to ionizing radiation. Carcinogenic progression of cells from immortal growth to anchorage-independent growth in soft agar to tumorigenicity in athymic mice resulted after a cumulative X-ray dose of 30 Gy. The tumors were characterized histologically as poorly differentiated adenocarcinomas, expressed prostate-specific antigen, and stained positive for keratin. No p53 or ras mutations were observed. Numerous chromosomal defects were noted on karyotypes after radiation exposure. However, chromosome 3 and 8 translocations were observed predominantly in the tumor outgrowths. These findings provide the first evidence of malignant transformation of human prostate epithelial cells exposed to ionizing radiation.

Computed tomography in definitive radiotherapy of prostatic carcinoma, part 2: definition of target volume.

Pretreatment computed tomography (CT) scanning of the pelvis was performed in 100 consecutive patients with carcinoma of the prostate treated with external irradiation (82 patients) or interstitial I125 (18 patients). Treatment plan modifications prompted by CT scan findings were most frequent in patients with (clinical) involvement of the seminal vesicles in whom the conventional treatment planning often resulted in an underestimate of tumor volume. Seventeen of 32 (53%) such patients required an enlargement of treatment fields to adequately encompass the target volume. Using skeletal landmarks as reference, the dimensions of the prostate, seminal vesicles and the detectable tumor and their topographic relationships were systematically tabulated. These measurements provide a basis for the definition of the target volume in patients with carcinoma of the prostate in whom CT scans might not be available.

Radiation protection considerations for endocavitary X ray units.

Application of a contact X ray therapy unit for endocavitary irradiation of selected rectal carcinomas is gaining acceptance as a treatment of choice. The patient is placed on a proctoscopic table in the surgical suite and the anus is anesthetized and dilated to allow insertion of a 3 cm diameter proctoscope designed to admit the X ray tube. The measured half-value layer for 50 kVp X rays filtered by 1.0 mm of aluminum was determined to be 0.65 mm of aluminium. The dose rate at the end of the 4.0 cm source-skin-distance (SSD) cone was measured to be on the order of 1000 rad/minute. Radiation surveys performed for several treatment geometries indicate that exposure rate levels in the environs immediately around the patient can be quite high. Radiation measurements were made for the following locations: where the radiotherapist stands holding the X ray tube; at the side of the patient where the technologist or any supporting personnel might stand; and at the patient's posterior surface in the direction where the anesthesiologist might stand. Radiation levels ranged from 0.001 to 1.0 roentgen (R) per hour and depend primarily on the depth and angle of the X ray tube inserted into the rectum.

Differential expression of stathmin during neoplastic conversion of human prostate epithelial cells is reversed by hypomethylating agent, 5-azacytidine.

In a variety of human tumor tissues, including those of prostate and breast, CpG hypermethylation represents one of the mechanisms downregulating the expression of specific proteins, including tumor suppressor proteins. Using 267B1-XR cells generated by ionizing radiation-induced transformation of epithelial cells, derived from neonatal human prostate and immortalized by SV40 (267B1), we now report markedly low levels of expression of the cytoplasmic phosphoprotein stathmin, in addition to several proteins of the actin microfilaments and intermediate filaments that characterize the altered phenotype. Stathmin is emerging as a relay protein integrating signals from diverse pathways during differentiation and neoplastic progression. In this in vitro prostate carcinogenesis model system, where loss of specific-protein expression is a major feature of the transformed 267B1-XR cells, we employed 5-azacytidine treatment followed by 2D-PAGE to reveal if experimental genomic hypomethylation reinstated the levels of any of the differentially expressed proteins. Our data suggest that stathmin represents one such example.

Quantitation of strand breaks in human DNA using 32P-Alu hybridization: application to exponential and plateau-phase cells.

A sensitive quantitation of DNA (0.2 to 10 ng) can be achieved using a 32P-labeled Alu probe to hybridize human DNA spotted onto nylon membrane. This allows the determination of radiation-induced single-strand breaks without the use of [3H]thymidine prelabeling of cells in culture. The sensitivity of this technique in HeLa cells is comparable to results obtained using the alkaline unwinding technique. The method is applicable to cells in both exponential and plateau phases of growth.

Constraints to DNA unwinding near radiation-induced strand breaks in Ewing's sarcoma cells.

Ewing's sarcoma cell lines were compared to other cell lines for induction of DNA strand breaks by ionizing radiation and their ability to repair those breaks. The alkali-unwinding assay and alkaline sucrose gradient analysis were used for these studies. The alkali-unwinding assay revealed that the amount of DNA unwound per strand break in Ewing's sarcoma cells was less than for other cells and was not influenced by high-salt denaturation conditions. Ewing's sarcoma cells had similar induction and repair rates for strand breaks compared with other cell lines. The kinetics of unwinding suggests there are constraints to DNA unwinding in the chromatin of Ewing's sarcoma cells, possibly related to high levels of poly(ADP-ribose) polymerase in these cells.

Two-dimensional gel electrophoresis analyses identify nucleophosmin as an estrogen regulated protein associated with acquired estrogen-independence in human breast cancer cells.

We have used two-dimensional gel electrophoresis to identify proteins associated with estrogen-induced proliferation in MCF-7 breast cancer cells and their progression to estrogen-independent proliferation. We compared the total cellular proteins from MCF-7 cells and an estrogen independent derivative of the MCF-7 cells MCF-7/LCC1 (Brünner et al. Cancer Research 1993, 53, 283-290), each grown with and without estradiol. These comparisons reveal seven estrogen-regulated proteins. Three of these proteins (HI-1: 36 kDa/pI 4.5, HI-10: 40 kDa/pI 5.5 and HI-19: 62 kDa/pI 5.0) exhibit a 'progression-like' pattern, being induced by estradiol in MCF-7 cells and constitutively present/upregulated in the MCF-7/LCC1 growing without estradiol. HI-11 (65 kDa/pI 5.5) is strongly induced by estradiol in MCF-7 cells but constitutively downregulated and unresponsive to estradiol in the MCF-7/LCC1 cells. Two proteins exhibit a suppressor pattern and are downregulated by estradiol in the estrogen-dependent MCF-7 cells (HI-3: 44 kDa/pI 4.4 and HI-4: 56 kDa/ pI 5.2) and present in MCF-7/LCC1 cells growing without estradiol at levels comparable to that seen in estrogen-treated MCF-7 cells. One protein (HI-9: 68 kDa/pI 5.5) exhibits a marked estrogen regulated pI shift, rather than changes in abundance. We purified and sequenced the HI-10 protein, which we identified as the nucleolar protein, nucleophosmin (NPM). One- and two-dimensional Western blot analyses of MCF-7/LCC1 cell lysates confirmed that HI-10 is immunoreactive with an antinucleophosmin antibody. Western blotting also confirmed the estrogenic regulation of NPM seen in the initial two-dimensional gel electrophoresis studies. Thus, NPM is induced by estradiol in the MCF-7 cells and upregulated in the MCF-7/LCC1 cells growing without estrogen, clearly associating its expression with an acquired estrogen-independent phenotype. NPM has several potentially important roles in regulating cell function and signaling. It is a substrate for phosphorylation by p34cdc2 kinase, protein kinase C and nuclear kinase II, and a repressor of the transcriptional regulating activities of both the IRF-1 tumor suppressor protein and the YY1 transcription factor. Studies are currently underway to determine which of these NPM functions may be involved in the hormonal progression of breast cancer.

Determination of dose enhancement in cortical bone substitute material for electron beams.

Dose measurements in Witt liquid, which simulates cortical bone, have been compared with dose in water for 6-, 9-, 12-, and 15-MeV electron beams. Measurements were made using a Farmer ionization chamber. The results of the study show dose enhancement in Witt liquid of 5%, 7%, 4%, and 0.4% for 6-, 9-, 12-, and 15 MeV electrons at shallow depths. The dose to a small mass of soft tissue in bone has also been estimated using ionization measurements. The results show a significantly higher dose in bone.

Relation between tolerance dose and treatment field size in radiotherapy.

A relation is developed between tolerance dose and field size from an analysis of available clinical data on skin-tolerance doses for various treatment field sizes in radiotherapy. It is shown that plots of log-dose against log-field-size for various fractionation schedules give isoeffect lines all having approximately the same slope. This suggests a power law relation between tolerance dose and field size. A generalized form of NSD equation, incorporating the field-size dependence of tolerance dose, is shown to follow naturally when this new relation is combined with Ellis' NSD relation. Certain discrepancies between the sets of data used in the present analysis are pointed out and it is suggested that more data are needed before the generalized NSD relation can be applied under varying conditions of dose, time, fractionation, and field size.

Effects of focal spot intensity distribution and collimator width in reconstructive x-ray tomography.

In computed tomography the finite width of the collimator aperture implies that the image is reconstructed from scans having finite strip width. This blurs the image and limits scanner resolution. Bracewell has discussed the nature of the blurring produced and suggested a method to partially restore the image under the assumption that the x-ray focal spot has a uniform intensity distribution. However, pinhole radiographs of x-ray focal spots reveal intensity distribution in the scanning plane which peaks at the edges of the focal spot with a reduced intensity in the center. A model is presented which simulates this intensity distribution as the sum of two point sources of x rays separated by a uniform line source. This results in a point absorber response function which is a superposition of two rectangular distributions and the one discussed by Bracewell. The corresponding tranfer function is derived which shows that the intensity distribution of the focal spot influences the high spatial frequency components of the reconstructed image more than the low frequency components.

Comparison of absorbed dose in bone substitute material and water using ionization measurements.

Absorbed dose in a liquid substitute for bone has been compared with absorbed dose in water for 9-, 12-, and 15-MeV electron beams using ionization chamber measurements. The ionization readings were converted to dose using collisional mass stopping power ratios. The collisional mass stopping powers for the liquid substitute of bone were calculated using the Monte Carlo Code PEGS4. The results of our study show that there is an increase in dose in the liquid bone substitute compared to water at shallow depths. The maximum increase in dose was 5%, 4%, and 2% at depths of 1.2, 1.5, and 2.0 cm, respectively, for 9-, 12-, and 15-MeV electrons. The density of the liquid bone substitute was 1360 kg/m3 and the effective atomic number was 11.

Corner transmission in several linear accelerator photon beams.

Maximum x-ray field sizes on many linear accelerators are obtained only with truncated corners. Transmissions through the corners of such fields has been measured utilizing film and ion chamber dosimetry for a number of accelerators. Transmissions are found to be significantly larger than for the movable jaws.

Effective size of the transverse dimension of x-ray-tube focal spots.

Corrections for nonuniform x-ray intensity distributions have been computed for the dimension perpendicular to the anode-cathode axis of x-ray-tube focal spots. These correction factors were developed from comparison of OTFs for focal spots with uniform intensity distributions to those for focal spots with symmetric double-peaked intensity distributions.

Calculation of dose in off-central axis planes using off-axis ratios.

Accuracy of dose calculation for regular fields in off-central axis planes was investigated on a RAD-8 treatment planning computer for 4- and 10-MV x-ray beams produced by Varian Clinac -4 and Clinac -18 linear accelerators. These calculations, which are based on central axis depth dose and off-axis ratios in the principal planes, can be in error by as much as 25%-30% at locations well within the irradiated volume for the 4-MV x-ray beam. These large errors for the Clinac -4 beam result from the falloff in dose beyond the peak dose along a diagonal of a large field at distances greater than 14 cm from the central axis due to the lead flattening filter. The profile data stored in the computer along the principal planes cannot be used to calculate the dose accurately in such a situation. Computed doses for the 10-MV x-ray beam agreed with the measured doses within 4%-6% at all locations.

Buildup factors and dose around a 137Cs source in the presence of inhomogeneities.

The effect of inhomogeneities on dose near a gamma-ray source has been investigated. Experimental measurements were made with a 137Cs source in a polystyrene phantom at a distance of 5 cm from the source. Inhomogeneities consisted of 2-cm-thick slabs interposed between the source and the plane of measurement. Dose correction factors (DCF) for 2-cm-thick aluminum, bone, lung, and air have been determined. Our results show that for 137Cs source the dose correction factors are of the order of 3% to 8%. A theoretical model for calculation of dose correction factor in brachytherapy in the presence of inhomogeneities has been developed. The model calculates DCF using buildup factors for the water-equivalent path between the source and the point of calculation. Good agreement was found between calculations and experimental measurements.