Transitional cell carcinoma of the renal pelvis and ureter: Outcome and patterns of relapse in patients treated with postoperative radiation

We assessed the records of 101 patients with locally advanced transitional cell carcinoma (TCC) of the renal pelvis and ureter treated with postoperative radiation therapy to determine outcome and patterns of failure. Locally advanced disease (i.e., T3–4N0 or N+ disease) was identified in 65 patients. Postoperative radiation was used to treat 86 patients, with a median dose of 35 Gy in 20 fractions over 4 weeks to the tumor bed and regional lymph nodes. There were 15 patients with no residual disease who were offered no further therapy. No patient received postoperative chemotherapy. Prognostic factors were examined using univariate and multivariate analysis, and the patterns of failure were identified after postoperative irradiation. Median follow-up was 9.3 years, during which 76 deaths occurred. The 5-year overall survival was 43% and 10-year survival was 23%. A multivariate analysis identified T3 category, lymph node involvement, and age at diagnosis as significant prognostic factors for survival. Tumor grade was a significant prognostic factor on univariate analysis but not on multivariate analysis. Failure analysis showed that only 36% of patients with locally advanced disease remained relapse free. For this group of patients, distant metastases developed in 53%, and locoregional failured occurred in 35% despite postoperative irradiation. Locoregional failure occurred in 95% of patients with nodal involvement who received postoperative radiation, and 77% of those developed distant relapse. This leads us to conclude that patients with resected locally advanced (T3, T4N0, N+) TCC of the upper urinary tracts have a high risk of relapse and death from disease despite postoperative radiotherapy. Because the main feature of the disease is early distant failure, post-operative chemotherapy is required to improve the outcome for this group of patients.     

Clonogenic survival and cytokinesis-blocked binucleation of skin fibroblasts and normal tissue complications in soft tissue sarcoma patients treated with preoperative radiotherapy.

BACKGROUND AND PURPOSE:To evaluate the clonogenic and cytokinesis-blocked assays in skin fibroblast cultures for their utility as tools for predicting normal tissue responses in soft tissue sarcoma (STS) patients treated with preoperative radiotherapy. PATIENTS AND METHODS:Dermal fibroblast strains were established from skin biopsies of 26 STS patients who received preoperative radiotherapy. Cultures were subjected to the colony forming and cytokinesis-blocked assays after low (approximately 0.02 Gy/min) dose-rate 60Co -irradiation. Fibroblast radiosensitivity was expressed as the dose for 1% clonogenic survival, D0.01, based on colonies/clusters with >or=10 cells. Fibroblast proliferative capability was represented by binucleation index (BNI) and genomic damage was expressed in terms of micronucleus frequency. Wound healing complications (WHC) and subcutaneous fibrosis were the clinical endpoints examined. The ability of each in vitro parameter to detect patients at high risk of a given normal tissue complication was assessed using receiver operating characteristic (ROC) analysis. RESULTS:While fibroblasts from patients without WHC were marginally more radiosensitive than fibroblasts from patients with WHC (P=0.08), the reduction in BNI following a dose of 2.4 Gy was significantly higher in strains from patients without WHC compared to those from patients with WHC (P=0.01). The area under the ROC curve (c-index) is indicative of the power of discrimination of D0.01 and BNI for WHC, and was found to be 0.68 and 0.79, respectively. Subcutaneous fibrosis was not associated with D0.01 (rs=0.09, P=0.66) and the percent reduction in BNI after 2.4 Gy (rs=-0.19, P=0.36). Micronucleus frequency did not reflect differences in normal tissue responses. CONCLUSION:These data suggest that it is the ability of fibroblasts to undergo one-three divisions in vitro following radiation treatment that may reflect the development of wound healing morbidity or subcutaneous fibrosis in this population of patients.     

Magnetic resonance imaging in the radiation treatment planning of localized prostate cancer using intra-prostatic fiducial markers for computed tomography co-registration.

PURPOSE: To assess the feasibility, and potential implications, of using intra-prostatic fiducial markers, rather than bony landmarks, for the co-registration of computed tomography (CT) and magnetic resonance (MR) images in the radiation treatment planning of localized prostate cancer. METHODS: All men treated with conformal therapy for localized prostate cancer underwent routine pre-treatment insertion of prostatic fiducial markers to assist with gross target volume (GTV) delineation and to identify prostate positioning during therapy. Six of these men were selected for investigation. Phantom MRI measurements were obtained to quantify image distortion, to determine the most suitable gold alloy marker composition, and to identify the spin-echo sequences that optimized both marker identification and the contrast between the prostate and the surrounding tissues. The GTV for each patient was contoured independently by three radiation oncologists on axial planning CT slices, and on axial MRI slices fused to the CT slices by matching the implanted fiducial markers. From each set of contours the scan common volume (SCV), and the scan encompassing volume (SEV), were obtained. The ratio SEV/SCV for a given scan is a measure of inter-observer variation in contouring. For each of the 18 patient-observer combinations the observer common volume (OCV) and the observer encompassing volume (OEV) was obtained. The ratio OEV/OCV for a given patient-observer combination is a measure of the inter-modality variation in contouring. The distance from the treatment planning isocenter to the prostate contours was measured and the discrepancy between the CT- and the MR-defined contour recorded. The discrepancies between the CT- and MR-defined contours of the posterior prostate were recorded in the sagittal plane at 1-cm intervals above and below the isocenter. RESULTS: Phantom measurements demonstrated trivial image distortion within the required field of view, and an 18K Au/Cu alloy to be the marker composition most suitable for CT-MRI image fusion purposes. Inter-observer variation in prostate contouring was significantly less for MR compared to CT. The mean SEV/SCV ratio was 1.58 (confidence interval (CI): 1.47-1.69) for CT scans and 1.37 (CI: 1.33-1.41) for MR scans (paired t-test; P=0.036). The overall magnitude of contoured GTV was similar for MR and CT; however, there were spatial discrepancies in contouring between the two modalities. The greatest systematic discrepancy was at the posterior apical prostate border, which was defined 3.6 mm (SD 3.5 mm) more posterior on MR- than CT-defined contouring. CONCLUSIONS: Prostate contouring on MR is associated with less inter-observer variation than on CT. In addition, we have demonstrated the feasibility of using intra-prostatic fiducial markers, rather than bony landmarks, for the co-registration of CT and MR images in the radiation treatment planning of localized prostate cancer. This technique, together with on-line correction of treatment set-up according to the fiducial marker position on electronic portal imaging, may enable a reduction in the planning target volume (PTV) margin needed to account for inter-observer error in target delineation, and for prostate motion.     

Immune deficiencies in chronic intestinal pseudo-obstruction

Aim: Chronic intestinal pseudo-obstruction has been associated with urinary disorders, myopathy, and ophthalmoplegia in adults and cholelithiasis in children. We observed a high percentage of total-parenteral-nutrition-dependent patients with pseudo-obstruction and recurrent infections requiring gammaglobulin infusions. Methods: AH records for 23 children with chronic intestinal pseudo-obstruction (10 females and 13 males, mean age 9.8 y ± 4.9 y, range 4–24 y) referred for a nutritional evaluation from 1992 to 1995 were reviewed. Chronic intestinal pseudo-obstruction was diagnosed by clinical, radiographic findings and antroduodenal manometry. Intestinal full-thickness biopsies were performed in seven children. Results: Hypogammaglobulinemia was diagnosed in 18 patients (78%): 16 patients had various immunoglobulin deficiencies and 2 had selective antibody deficiency. Intravenous gammaglobulin was administered in 14 patients. Other medical conditions affecting the children are summarized as follows: autonomic dysfunction in 10 patients (43%), recurrent hypoglycemia in 9 (39%), asthma in 9 (39%), cholecystitis in 7 (30%), low serum carnitine level in 6 (26%), urinary dysfunction in 6 (26%), pancreatitis in 5 (22%), behavioral problems in 5 (22%), myopathy in 2 (9%), idiopathic thrombocytopenia in 2 (8%), velopharyngeal insufficiency in 1 (4%), oculocutaneous albinism in 1 (4%), Pierre-Robin syndrome in 1 (4%), and protein C deficiency in 1 (4%). Munchausen syndrome was suspected in two patients. Conclusions: Chronic intestinal pseudo-obstruction appears to be associated with immune deficiencies. It is unclear if the immune deficiencies, intestinal pseudo-obstruction, and the other medical conditions have a common underlying etiology. Repeated infections may be due to impaired immune function in children with chronic intestinal pseudo-obstruction. We recommend screening for immune deficiencies in children with chronic intestinal pseudo-obstruction.     

Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants

Objectives: A prospective study comparing the efficiacy and side-effects of oral sulindac with intravenous indomethacin in clinically stable preterm infants (<1750 g) requiring non-invasive closure of haemodynamically significant patent ductus arteriosus.
Methodology: As maturity and birthweight are the two major determinants of ductal closure, infants were matched as closely as possible for these parameters. An eligible patient was first assigned to the sulindac group and a subsequent patient with similar gestational age (± 1 week) and birthweight (±100 g) to the previously recruited infant would automatically receive indomethacin. A total of eight infants were enrolled in each group.
Results: The ductus arteriosus was successfully closed in all eight infants receiving indomethacin, and in seven of eight infants receiving sulindac. No significant differences were found with regards to the ductal size between the two groups at diagnosis or on each of the consecutive days of treatment ( P >0.25). More renal adverse effects were encountered in the indomethacin group. Significant differences in changes from baseline value for urine output, plasma sodium, urea and creatinine concentrations were noted at 24, 48 and 72 h after commencement of treatment between the two groups ( P <0.05). All the parameters returned to normal or pre-treatment levels 48 h after stopping therapy. Unexpectedly, severe gastrointestinal complications were encountered in the sulindac group.
Conclusions: Sulindac is capable of promoting ductal constriction in clinically stable preterm infants without compromising the renal function. The spectrum of gastrointestinal complications observed in sulindac treated infants were similar to those described for indomethacin. The use of sulindac for ductal closure in the preterm infant should remain experimental.     

Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy

McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994) and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the striking similarity in lifestyle risk factors for colorectal cancer and insulin resistance, proposed that the hyperinsulinemia, glycemia and hypertriglyceridemia associated with insulin resistance promotes colon cancer. To compare the effect of diet on colon cancer promotion and insulin resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids and energy in pairwise comparisons on average size of aberrant crypt foci (ACF) and on glucose intolerance in the same animals in a single experiment. Diets high in fat and energy increased and diets with increased n-3 fatty acids and calorie restriction decreased both ACF growth and glucose intolerance compared with control diets. The measures of promotion of colon cancer and insulin resistance were strongly correlated (n = 98, r = 0.67, P < 0.001). In addition, both were highly correlated with daily energy intake (r = 0.62 and 0.66) and were also correlated with basal (post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P < 0.01). We concluded that ACF growth and glucose intolerance are correlated for a wide range of diets and that increased circulating energy (glucose and triglycerides) may lead to both colon cancer promotion and insulin resistance.      

Angiogenesis is an early event in the development of chemically induced skin tumors

In this study we have analyzed the vascular response induced in the two- stage carcinogenesis model in SENCAR mice. The role of angiogenesis has not been explored in this model, which is the paradigm of multistage carcinogenesis and a model for neoplastic lesions derived from exophytic premalignant lesions (e.g. colon carcinoma, bladder papilloma). We investigated if angiogenesis is involved in the formation of papillomas and in the progression from papilloma to carcinoma. To this end we analyzed the vasculature of normal and hyperplastic skin, focal epidermal hyperplasias that are precursors of papillomas, papillomas at different stages and squamous cell carcinomas. We also analyzed the vascularization of papillomas induced in two strains of mice that differ in their susceptibility to malignant progression. We show here that angiogenesis is turned on in the earliest stages of papilloma formation. In late stages, regardless of state of progression, the predominant response is an increase in the size of blood vessels. Thus, in the SENCAR mouse model, representative of exophytic tumors, the angiogenesis switch is a very early event, probably mechanistically related to the development of the primarily exophytic lesions. Therefore, the density of blood vessels cannot be used as a predictor of malignant progression in this model.      

Measles outbreak in young adults in Victoria, 1999

OBJECTIVES: To describe an outbreak of measles in Victoria. DESIGN: Case series with cases identified through enhanced passive surveillance and outbreak-related active surveillance. SETTING: State of Victoria, 1999. MAIN OUTCOME MEASURES: Number of cases; epidemiological links and patterns of transmission; patient demographic features and vaccination status; complications. RESULTS: 75 cases were identified (74 laboratory-confirmed; and one epidemiologically linked to a laboratory-confirmed case), with onset between 11 February and 2 May 1999. The first case was in a 21-year-old woman who had recently holidayed in Bali and worked at a large cinema complex in Melbourne. Sixteen cases occurred in people who had contact with the index case at the cinema on one evening. The outbreak spread to regional Victoria and South Australia. Median age of patients was 22 years; 64 (85%) were born between 1968 and 1981, with only one patient in the age group targeted by the primary school component of the 1998 Australian Measles Control Campaign; this child had not been vaccinated. More than a third of patients (28) were hospitalised (total, 97 inpatient days), and five were healthcare workers. CONCLUSIONS: This outbreak was caused by international importation of measles virus. It highlights the change in epidemiology of measles in Australia, from a disease of childhood to one predominantly affecting young adults. A strong two-dose childhood vaccination program, vigilant surveillance, and rapid response to outbreaks will continue to be the basis of measles control, but better protection for young adults should be considered.