Acute toxicity of hypofractionated intensity-modulated radiotherapy for prostate cancer.

BACKGROUND: Dose-escalated hypofractionated radiotherapy (hfrt) using intensity-modulated radiotherapy (imrt), with inclusion of the pelvic lymph nodes (plns), plus androgen suppression therapy (ast) in high-risk prostate cancer patients should improve patient outcomes, but acute toxicity could limit its feasibility. METHODS: Our single-centre phase ii prospective study enrolled 40 high-risk prostate cancer patients. All patients received hfrt using imrt with daily mega-voltage computed tomography imaging guidance, with 95% of planning target volumes (ptv68 and ptv50) receiving 68 Gy and 50 Gy (respectively) in 25 daily fractions. The boost volume was targeted to the involved plns and the prostate (minus the urethra plus 3 mm and minus 3 mm from adjacent rectal wall) and totalled up to 75 Gy in 25 fractions. Acute toxicity scores were recorded weekly during and 3 months after radiotherapy (rt) administration. RESULTS: For the 37 patients who completed rt and the 3-month follow-up, median age was 65.5 years (range: 50-76 years). Disease was organ-confined (T1c-T2c) in 23 patients (62.1%), and node-positive in 5 patients (13.5%). All patients received long-term ast. Maximum acute genitourinary (gu) and gastrointestinal (gi) toxicity peaked at grade 2 in 6 of 36 evaluated patients (16.6%) and in 4 of 31 evaluated patients (12.9%) respectively. Diarrhea and urinary frequency were the chief complaints. Dose-volume parameters demonstrated no correlation with toxicity. The ptv treatment objectives were met in 36 of the 37 patients. CONCLUSIONS: This hfrt dose-escalation trial in high-risk prostate cancer has demonstrated the feasibility of administering 75 Gy in 25 fractions with minimal acute gi and gu toxicities. Further follow-up will report late toxicities and outcomes.

Analysis of intraprostatic therapeutic effects in prostate cancer patients using [(11)C]-choline pet/ct after external-beam radiation therapy.

PURPOSE: The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. METHODS: The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. RESULTS: Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. CONCLUSIONS: Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.

Prostate brachytherapy postimplant dosimetry: automatic plan reconstruction of stranded implants.

PURPOSE: Plan reconstruction for permanent implant prostate brachytherapy is the process of determining the correspondence between planned and implanted seeds in postimplant analysis. Plan reconstruction informs many areas of brachytherapy quality assurance, including the verification of seed segmentation, misplacement and migration assessment, implant simulations, and the dosimetry of mixed-activity or mixed-species implants. METHODS: An algorithm has been developed for stranded implants which uses the interseed spacing constraints imposed by the suture to improve the accuracy of reconstruction. Seventy randomly selected clinical cases with a mean of 23.6 (range 18-30) needles and mean density of 2.0 (range 1.6-2.6) 2.0 (range 1.6-2.6) seeds/cm3 were automatically reconstructed and the accuracy compared to manual reconstructions performed using a custom 3D graphical interface. RESULTS: Using the automatic algorithm, the mean accuracy of the assignment relative to manual reconstruction was found to be 97.7 +/- 0.5%. Fifty-two of the 70 cases (74%) were error-free; of seeds in the remaining cases, 96.7 +/- 0.3% were found to be attributed to the correct strand and 97.0 +/-0.3% were correctly connected to their neighbors. Any necessary manual correction using the interface is usually straightforward. For the clinical data set tested, neither the number of seeds or needles, average density, nor the presence of clusters was found to have an effect on reconstruction accuracy using this method. CONCLUSIONS: Routine plan reconstruction of stranded implants can be performed with a high degree of accuracy to support postimplant dosimetry and quality analyses.

Photochemotherapy for systemic sclerosis: effect on clinical and molecular markers.

BACKGROUND: The cutaneous changes seen in systemic sclerosis (SSc) can result in considerable patient morbidity. AIM: We previously reported on the beneficial effect of psoralen ultraviolet A (PUVA) phototherapy in 13 patients with morphoea. We now report the findings of a study in which patients with SSc were treated with PUVA. METHODS: Twelve patients with SSc were treated with PUVA phototherapy. The effect on cutaneous disease activity was assessed using the modified Rodnan score, and the effect on serological and immunohistochemical growth factors and adhesion molecules was also measured. RESULTS: The median Rodnan score at baseline was 24.5 [interquartile range (IQR) 18.5-26.0]. The median number of treatments with PUVA was 24 exposures (IQR 20-26) with a median cumulative exposure of 68.3 J/cm(2) (IQR 28.6-139.8). Of the 12 patients, 11 responded well to phototherapy with a mean change in Rodnan score of 6.58 (36.98%) (P < 0.01, Wilcoxon signed ranks test). After treatment with PUVA there was a significant increase in circulating tumour necrosis factor-alpha levels in 8/12 patients (P = 0.03). In 7/12 patients there was an increase in E-selectin and vascular cell adhesion molecule, although this was not significant. CONCLUSIONS: PUVA treatment is associated with a significant improvement in cutaneous symptoms in patients with SSc as measured by the Rodnan score (P < 0.01). Specific lymphocyte markers, adhesion molecules and cytokines are also affected by this treatment, helping to clarify further the mechanism of action of PUVA treatment and our understanding of the primary pathological process.

Determinants of the nuclear localization of the heterodimeric DNA fragmentation factor (ICAD/CAD).

Programmed cell death or apoptosis leads to the activation of the caspase-activated DNase (CAD), which degrades chromosomal DNA into nucleosomal fragments. Biochemical studies revealed that CAD forms an inactive heterodimer with the inhibitor of caspase-activated DNase (ICAD), or its alternatively spliced variant, ICAD-S, in the cytoplasm. It was initially proposed that proteolytic cleavage of ICAD by activated caspases causes the dissociation of the ICAD/CAD heterodimer and the translocation of active CAD into the nucleus in apoptotic cells. Here, we show that endogenous and heterologously expressed ICAD and CAD reside predominantly in the nucleus in nonapoptotic cells. Deletional mutagenesis and GFP fusion proteins identified a bipartite nuclear localization signal (NLS) in ICAD and verified the function of the NLS in CAD. The two NLSs have an additive effect on the nuclear targeting of the CAD-ICAD complex, whereas ICAD-S, lacking its NLS, appears to have a modulatory role in the nuclear localization of CAD. Staurosporine-induced apoptosis evoked the proteolysis and disappearance of endogenous and exogenous ICAD from the nuclei of HeLa cells, as monitored by immunoblotting and immunofluorescence microscopy. Similar phenomenon was observed in the caspase-3-deficient MCF7 cells upon expressing procaspase-3 transiently. We conclude that a complex mechanism, involving the recognition of the NLSs of both ICAD and CAD, accounts for the constitutive accumulation of CAD/ICAD in the nucleus, where caspase-3-dependent regulation of CAD activity takes place.

Photochemotherapy for localized morphoea: effect on clinical and molecular markers.

BACKGROUND: Effective treatment options for morphoea remain limited. As a result, there has been increasing interest in the role of phototherapy in the management of this condition. Aims. We report the findings of a study in which 13 patients with localized morphoea were treated with oral (n = 11) and topical (n = 2) psoralen ultraviolet (PUVA) phototherapy. METHODS: The clinical effect on disease activity was assessed using a skin score adapted from the modified Rodnan score. The effect on serological and immunohistochemical markers was also measured. RESULTS: In total, 11/13 patients showed an improvement in their skin score after phototherapy, with the mean reduction in score being 62.9% (P = 0.003, Wilcoxon signed rank test). After treatment with PUVA, there was a fall in circulating levels of vascular cell adhesion molecule in 10/13 patients (P = 0.059) and a significant increase in tumour necrosis factor-alpha in 9 of 13 patients (P = 0.036). In the five patients in whom CD3 and CD4 was measured, all showed a reduction in CD3 (P = 0.025), with a fall in CD4 (P = 0.046) seen in four of the five patients. CONCLUSIONS: PUVA is associated with clinical improvement in patients with morphoea, as shown by significant improvement in the skin score. However, in one patient who had been simultaneously started on ciclosporin, this improvement could not be attributed to the phototherapy alone. Although the sample size was small, we also found that certain lymphocyte markers, adhesion molecules and cytokines are affected by this treatment, helping to further clarify the mechanism of action of PUVA treatment.

Intraoperative factors associated with stranded source placement accuracy in low-dose-rate prostate brachytherapy.

PURPOSE: The quality of a low-dose rate prostate brachytherapy implant depends on the accurate placement of sources in their planned locations. This study investigates intraoperative factors that potentially contribute to stranded source placement inaccuracy in prostate brachytherapy. METHODS AND MATERIALS: Intraoperative video images of the brachytherapist's hand motions and needle insertions during the implant procedure were acquired for analysis. Using video analysis software, maximum and average needle insertion velocities were determined. The number of needle insertion attempts and the use of the brachytherapist's other hand to manipulate the needle direction were also recorded. Sources misplacements were analyzed using an ultrasound-based method described elsewhere. RESULTS: Fifteen patients agreed to undergo this study; 1619 125I seeds were inserted using 357 needles; 1197 seeds were confidently identified using ultrasound images and included in the analysis. The mean overall misplacement was 0.49 cm (0-2 cm, 95% CI = 0.47-0.51); 614 seeds were delivered with a single pass and 583 seeds with >1 passes (range 2-6). The mean maximum needle velocity was 12.34 cm s-1 (range 4-28 cm s-1) and mean average velocity was 4.76 cm s-1 (range 0.4-17.4 cm s-1); 747 seeds were delivered with manipulation of the needle. The generalized linear model test was used to analyze factors contributing to seed misplacement, and it was found that a maximum speed <12 cm s-1 was associated with a decrease in seed misplacement by 0.049 cm vs. a maximum speed >12 cm s-1, p = 0.0121). Other evaluated factors were found to have no statistically significant correlation with seed misplacement: average speed (p = 0.4947), manual manipulation of needle (p = 0.9264), and number of needle passes (p = 0.8907). CONCLUSIONS: This study identified that needles inserted with lower maximum velocity were associated with less seed misplacement. Manual manipulation of the needle, number of passes, and average speed did not show statistically significant correlation with seed misplacement.

Convexity subarachnoid hemorrhage in ischemic stroke.

OBJECTIVE: To report three cases of convexity subarachnoid hemorrhage (cSAH) after acute ischemic stroke and review the relevant literature. BACKGROUND: cSAH is an unusual presentation and the association with acute ischemic stroke has only infrequently been reported. DESIGN AND METHODS: Case series with retrospective review of the clinical presentation and neuroimaging features of patients who presented with cSAH and acute ischemic stroke. RESULTS: We describe three cases of cSAH who presented with ipsilateral acute ischemic stroke. Two patients had ipsilateral ICA stenosis, with one patient developing cSAH after ICA stenting. The third patient developed cSAH in setting of small distal cortical ischemic lesions with normal cranial vasculature. None of these patients had evidence for cerebral amyloid angiopathy on magnetic resonance imaging-gradient echo (MRI-GRE) sequence. All our patients remained clinically stable with limited neurological deficit at the time of discharge. CONCLUSION: We report three more cases linking cSAH with ischemic strokes. All of our patients had good outcome with minimal neurological deficit. cSAH should remain in differential diagnosis and early complication of acute ischemic stroke.

Impact of edema and seed movement on the dosimetry of prostate seed implants.

This article summarizes current knowledge concerning the characterization of prostatic edema and intra-prostatic seed movement as these relate to dosimetry of permanent prostate implants, and reports the initial application to clinical data of a new edema model used in calculating pre- and post-implant dose distributions. Published edema magnitude and half-life parameters span a broad range depending on implant technique and measurement uncertainty, hence clinically applicable values should be determined locally. Observed intra-prostatic seed movements appear to be associated with particular aspects of implant technique and could be minimized by technique modification. Using an extended AAPM TG-43 formalism incorporating the new edema model, relative dose error RE associated with neglecting edema was calculated for three I-125 seed implants (18.9 cc, 37.6 cc, 60.2 cc) performed at our center. Pre- and post-plan RE average values and ranges in a 50 × 50 × 50 mm(3) calculation volume were similar at ~2% and ~0-3.5%, respectively, for all three implants; however, the spatial distribution of RE varied for different seed configurations. Post-plan values of D90 and V100 for prostate were reduced by ~2% and ~1%, respectively. In cases where RE is not clinically negligible as a consequence of large edema magnitude and / or use of Pd-103 seeds, the dose calculation method demonstrated here can be applied to account for edema explicitly and there by improve the accuracy of clinical dose estimates.

Allergic skin disease: investigation of both immediate- and delayed-type hypersensitivity is essential.

BACKGROUND: In our clinic we routinely patch test patients referred from occupational health for the investigation of latex contact urticaria. We also undertake both patch and prick testing (where indicated) in patients referred with persistent dermatitis/eczema. If investigation of allergic skin disease is undertaken by a non-dermatologist, it is unlikely that patch testing will be performed. OBJECTIVE: To carry out a retrospective analysis of patients who had been prick tested to establish whether an incomplete diagnosis would have been reached if patch testing had been omitted. METHODS: Details of patients who had attended for patch testing between July 2004 and December 2005 were analysed. Patients who had had prick tests and patch testing were identified. The outcomes of prick tests and patch testing were documented together with the clinical relevance. RESULTS: Three hundred and thirty out of 1060 patients referred to the clinic were prick tested. 54.2% patients were referred from dermatologists. 26.6% were referred from occupational health, 68 patients had positive reactions on prick testing of whom 36 had positive patch tests (52.9%), which were of current relevance in 27 patients (39.7%). Nine out of 106 health workers referred to exclude latex contact urticaria had positive prick tests to latex. Fifty of these patients demonstrated delayed-type hypersensitivity with nickel, cobalt, rubber and its additives being the most common allergens found. Of the 262 patients who had negative prick tests, 121 had positive patch tests (46.1%) of current relevance to patient history in 92 subjects (35.1%). While none of the six patients referred for investigation of reaction to local anaesthetics had a positive prick test, one was allergic to local anaesthetic on patch testing. CONCLUSION: Omission of patch testing from the investigation of allergic skin disease, even when contact urticaria may be the sole suspected diagnosis, would result in the frequent missed diagnosis of contact allergy. We recommend that patients with suspected allergic skin disease are investigated in an environment where investigation of both immediate- and delayed-type hypersensitivity can be undertaken. In particular, patients with atopic eczema, suspected latex rubber allergy, hand dermatitis (particularly occupational) and drug reactions should be targeted to receive both investigations.

A case of sarcoidosis occurring within an extensive burns scar.

Scarring from burn injuries can result in cosmetic and functional deformities. In addition, late complications can also occur presenting as other pathology developing within the scarred tissue. We report a unique case of cutaneous sarcoidosis developing within a burns scar in an adult male who sustained a burns injury to his torso, right arm and thigh.