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Radical treatment of organ-localized and locally advanced prostate cancer in Norway--an overview.

In 1998, 28.5% of diagnosed prostate cancer patients in Norway were aged < 71 years and had organ-localized disease and 74.5% of prostate cancer patients aged < 71 years had organ-localized disease. This study compares the number of prostate cancer patients aged < 71 years with organ-localized disease in the five health regions of Norway with the number of patients who were treated with radical intent. In 1998, only 52% of these patients were treated with radical intent; in 1999 this proportion had increased to 73% but large regional differences existed.

Aged↗

Drinking habits of central Queensland adolescents: local research for local needs.

This study examined the utility of monitoring adolescent drinking habits in order to assist the development of local drug education programmes. Drinking patterns are reported for a quota-sample of 1154 adolescents aged from 13 to 18 years in central Queensland. Results showed that the prevalence of drinking increased according to age, with 47% of 13-year-olds reporting that they have used alcohol (not just sips or tastes), through to 93% among the 18-year-old group. Older teenagers were more likely to report drinking in the past month and the past week, though their consumption patterns are very similar to young people in other studies. Locations for drinking varied with age, younger groups drinking more often in home settings while older groups enjoyed a greater range of public and private venues. Beverage preferences again showed some age and sex differences, but overall males expressed a preference for regular beer and spirits, while females reported a preference for spirits and wine coolers. The importance of conducting local research to address local needs is discussed.

Journal Article↗

Microdomain Ca2+ activation during exocytosis in Paramecium cells. Superposition of local subplasmalemmal calcium store activation by local Ca2+ influx.

In Paramecium tetraurelia, polyamine-triggered exocytosis is accompanied by the activation of Ca2+-activated currents across the cell membrane (Erxleben. C., and H. Plattner. 1994. J. Cell Biol. 127:935-945). We now show by voltage clamp and extracellular recordings that the product of current x time (As) closely parallels the number of exocytotic events. We suggest that Ca2+ mobilization from subplasmalemmal storage compartments, covering almost the entire cell surface, is a key event. In fact, after local stimulation, Ca2+ imaging with high time resolution reveals rapid, transient, local signals even when extracellular Ca2+ is quenched to or below resting intracellular Ca2+ concentration ([Ca2+]e, < or = [Ca2+]i). Under these conditions, quenched-flow/freeze-fracture analysis shows that membrane fusion is only partially inhibited. Increasing [Ca2+], alone, i.e., without secretagogue, causes rapid, strong cortical increase of [Ca2+]i but no exocytosis. In various cells, the ratio of maximal vs. minimal currents registered during maximal stimulation or single exocytotic events, respectively, correlate nicely with the number of Ca stores available. Since no quantal current steps could be observed, this is again compatible with the combined occurrence of Ca2+ mobilization from stores (providing close to threshold Ca2+ levels) and Ca2+ influx from the medium (which per se does not cause exocytosis). This implies that only the combination of Ca2+ flushes, primarily from internal and secondarily from external sources, can produce a signal triggering rapid, local exocytotic responses, as requested for Paramecium defense.

Animals↗

Local intratumoral tumor necrosis factor-alpha and systemic IFN-alpha 2b in patients with locally advanced prostate cancer.

To examine tolerability and activity of local, intratumoral tumor necrosis factor-alpha (TNF-alpha) and systemic interferon-alpha2b (IFN-alpha2b) in locally advanced, hormone-resistant prostate cancer (LA-HRPC), 10 patients with LA-HRPC (T4N x M0, n = 3, T4N x M1, n = 5; T4N1M1, n = 2) were treated with recombinant TNF-alpha injected locally into prostate tumor tissue at 4-week intervals (maximum of four cycles) combined with intermittent subcutaneous (s.c.) administration of 5 x 10(6) IU IFN-alpha2b. Twenty-nine TNF-alpha cycles were administered. Despite significant TNF-alpha leakage into the systemic circulation 2 h after intraprostatic application (from a mean of 9 to a mean of 416 pg/ml; p = 0.0034), TNF-alpha (and IFN-alpha2b) was well tolerated (WHO grade 1-2 toxicity), possibly because of its rapid neutralization by increasing soluble 55-kDa and 75-kDa TNF receptor levels in the serum (mean increase 268% and 91%, respectively) at the same time. TNF-alpha induced prostate tumor cell necrosis in all patients, leading to a significant reduction of prostate volume in 9 of 10 cases (mean 38%; p = 0.0025). The significant short-term increase of prostate-specific antigen (PSA) (mean 65%; p < 0.001), tissue polypeptide-specific antigen (TPS) (mean 85%; p = 0.001), and possibly interleukin-8 (IL-8) (mean 2687%; p < 0.009) serum levels within 4 h after TNF-alpha confirmed the cytotoxic effect in vivo. In the long term, serum PSA levels dropped by 18%-87%, reaching the nadir value 7 weeks after baseline. Objective responses of metastases were not seen. Intraprostatic administration of TNF-alpha is feasible at a tolerable toxicity in patients with LA-HRPC and, thus, may be a new treatment option for these patients.

Aged↗

Localized and diffuse mesotheliomas of the genital tract and peritoneum in women. A clinicopathologic study of nineteen true mesothelial neoplasms, other than adenomatoid tumors, multicystic mesotheliomas, and localized fibrous tumors.

Peritoneal mesotheliomas are rare in women, compared to serous epithelial neoplasms with which they are often confused. We evaluated the clinicopathologic features of 19 true mesothelial neoplasms affecting the genital tract or peritoneum of women (other than adenomatoid tumors, benign multicystic mesotheliomas, and localized fibrous tumors) to characterize their clinicopathologic features and to determine their clinical behavior. Six tumors were localized to one anatomic site at presentation, and 13 involved more than one anatomic site. The six localized tumors were solitary, small (0.8-2.0 cm), polypoid or nodular lesions, five of which were incidental findings. All had a predominantly tubulopapillary pattern, either pure or mixed with adenomatoid-like or small solid foci. Nuclear grade ranged from 0 to 2. Mitotic figures (MF) were absent in two tumors. The mitosis count in the other four tumors was < 1 MF/10 high-power microscopic fields (HPF) (average method) and ranged from 1 to 3 MF/10 HPF (highest count method). Five patients were alive without recurrence after postoperative intervals ranging from 19 months to 9 years (median, 5 years); one patient died of metastatic gastric carcinoma at 14 months. Thirteen tumors involved more than one anatomic site and were classified as diffuse mesothelioma. Typically, these tumors were symptomatic and accompanied by ascites. The tumors had either a plaque-like or endophytic configuration. Eleven were purely epithelial mesotheliomas, and two had a minor sarcomatoid component. Tubulopapillary patterns were present in 10 tumors, usually admixed with focal adenomatoid-like or solid patterns, and three had a purely solid pattern. All 13 tumors had grade 3 nuclei. The mitosis count ranged from < 1 to 2 MF/10 HPF (average count method) with a range of 1-4 MF/10 HPF by the highest count method. Immunohistochemically, 13/13 tumors stained for cytokeratin (AE1/AE3). None were immunoreactive for polyclonal carcinoembryonic antigen (CEA), Leu-M1, or B72.3. One diffuse mesothelioma stained focally for Ber-EP4, and electron microscopy confirmed the mesothelial nature of this tumor. Nine patients died of tumor after postoperative intervals ranging from 1 month to 6 years. Eleven patients had received postoperative adjuvant intraperitoneal or systemic chemotherapy. One patient died with increased abdominal girth 8 years after operation and one course of intraperitoneal chemotherapy, though the role of mesothelioma in her death was uncertain. One patient was alive with diffuse tumor and persistent ascites 25 months after six courses of intraperitoneal chemotherapy. One patient was alive without evidence of disease 4 months after two courses of systemic chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenomatoid Tumor↗

Localized hyperplastic gastropathy of the mucous cell- and mixed cell-type (localized Ménétrier's disease): a report of 11 patients.

Clinical and pathologic findings in five women and six men with the rare localized form of hyperplastic gastropathy of the mucous cell-(foveolar) or mixed cell-(mucous cell and glandular) type are reported. Upper abdominal discomfort, loss of appetite, loss of weight, and anemia were the principal symptoms. Preoperative hypoproteinemia was documented in two patients. Gross findings consisted of a circumscribed area of giant folds, well demarcated from the surrounding normal-appearing mucosa, located predominantly in the corpus in six patients and predominantly in the antrum in four patients. Histologically they corresponded to an increase in the epithelial cell mass principally of mucous cells with elongated and sometimes cystically dilated foveolae, accompanied by a mild inflammatory infiltrate. This so-called localized form of hyperplastic gastropathy has been known since the first description of the disease but has gained relatively little attention in the literature. However, its recognition seems diagnostically important and pathogenetically interesting. Etiology, pathogenesis, and the natural history are mostly unknown. Five of the 11 patients had concomitant adenocarcinoma of the stomach. In four of them the carcinoma was not located within but outside the area of hyperplasia. Because of that and because of a rather unusual accumulation of other tumors of the gastrointestinal tract in these patients, it is suggested that localized hyperplastic gastropathy could be an indicator of an increased risk for gastrointestinal tumors in general more than a possibly premalignant lesion by itself.

Adenocarcinoma↗

Late urinary morbidity with high dose prostate brachytherapy as a boost to conventional external beam radiation therapy for local and locally advanced prostate cancer.

PURPOSE: Late urinary retention (UR) is a known complication that may occur when using high dose rate brachytherapy (HDR-B) to boost external beam radiation therapy (EBRT) when treating prostate cancer. However, the dosimetric, treatment and clinical factors associated with this complication are not well-known. MATERIALS AND METHODS: From March 1997 to March 2000 a total of 108 patients with local or locally advanced prostate adenocarcinoma were treated with EBRT (45 Gy) and HDR-B as a boost, when 16 to 20 Gy was given in 4 fractions twice daily. Median patient age was 68 years and median followup was 44 months (range 36 to 72). Each implant was performed using 8 to 18 needles with a median active length of 3 cm. Planning ultrasound target volume ranged from 23 to 65 cc. RESULTS: Biological effective doses for the urethral region ranged from 107 to 138 Gy3 (median 113). Crude and 5-year actuarial UR-free survival were 95.4% and 86.2%, respectively. Predictive factors for UR on univariate analysis were age more than 65 years (p = 0.0416), planning ultrasound target volume greater than 35 cc and active length of needles more than 3.5 cm (p = 0.0158). On multivariate analysis by Cox regression age was the only predictive factor (p = 0.027). CONCLUSIONS: HDR-B appears to offer a safe, reproducible and effective method of boosting conventional EBRT in patients with locally advanced prostate cancer. Results with this technology reveal late urinary morbidity rates paralleling those achieved with other forms of treatment, but further long-term followup is still needed to warrant a definitive conclusion.

Adenocarcinoma↗

Long-term outcome of neoadjuvant therapy for locally advanced breast carcinoma: effective clinical downstaging allows breast preservation and predicts outstanding local control and survival.

OBJECTIVE: To review the long-term follow-up data from the authors' institutional experience of 62 patients with locally advanced breast cancer (LABC) treated with a uniform multimodality regimen. The authors determined the rate of breast preservation, the disease-free and overall survival, and the factors associated with locoregional and distant recurrent disease. SUMMARY BACKGROUND DATA: It remains a challenge to achieve local and distant control of LABC. Over the last decade, preoperative or neoadjuvant chemotherapy has emerged as the standard of care for these patients. Successful tumor downstaging has been associated with increased rates of breast-conserving therapy (BCT), but the overall effect on long-term survival remains to be seen. METHODS: This study examines a cohort of 62 patients with LABC treated at the authors' institution from 1992 to 1998. The uniform treatment regimen consisted of neoadjuvant doxorubicin (Adriamycin), followed by operation (BCT if sufficient clinical downstaging), followed by non-cross-resistant cyclophosphamide/methotrexate/5-fluorouracil, followed by radiation therapy. Treatment was both dose-intensive and time-intensive, with a total treatment time of 32 to 35 weeks. RESULTS: In this patient population, the median age was 44 years, with approximately two thirds white patients and one third African American. Eighty-two percent of patients were clinical stage III at presentation, 13 patients had T4d inflammatory cancers, and 3 patients were stage IV at diagnosis. Eighty-four percent of patients demonstrated a significant clinical response to doxorubicin. Twenty-eight patients had sufficient clinical downstaging to attempt BCT, and 22 (45%) of 49 noninflammatory patients underwent successful BCT. Pathologic complete response was seen in 15% of patients. Median follow-up for the cohort was 70 months. The local recurrence rate was 14%, including two ipsilateral breast tumor recurrences (10%) in the BCT patients. Seven (12%) patients developed a new primary cancer in the contralateral breast. Distant metastases occurred in 18 (31%) patients, and the 5-year overall survival rate for the cohort was 76%. Furthermore, in the patients who underwent an attempt at BCT, the survival rate was 96% at 5 years. CONCLUSIONS: Dose-intensive and time-intensive multimodality neoadjuvant therapy was successfully administered to a mixed racial group over shortened times. Patients who had sufficient clinical downstaging to allow BCT have the best long-term outcome. Patients who required mastectomy are at a higher risk of relapse, as well as the development of new contralateral cancers, yet have 5-year survival rates of over 50%.

Adult↗

Genetically defined nuclear localization signal sequence of bovine papillomavirus E1 protein is necessary and sufficient for the nuclear localization of E1-beta-galactosidase fusion proteins.

The 605 amino acid E1 protein of bovine papillomavirus type 1 (BPV-1) is a multifunctional nuclear protein required for viral DNA replication. A nuclear localization signal (NLS) sequence was previously defined by point mutations in three short adjacent clusters of basic amino acids located in the amino-terminal region of the E1 protein. In this study, we used a fusion protein approach to evaluate the contribution of other regions of the E1 protein to nuclear transport. The nearly full-length E1 gene and six non-overlapping subfragments were each fused in-frame with the lacZ gene in a eukaryotic expression vector. Each clone was electroporated into COS-1 cells, and the intracellular location of the E1-beta-galactosidase fusion proteins was determined by immunofluorescence. Only the constructs containing the full-length E1 or a single subregion (E1-259; amino acids 84 to 166) produced fusion proteins that entered the nucleus. Point mutations in the NLS sequences of the E1-259-lacZ construct prevented nuclear translocation of the corresponding fusion protein. This confirms the previous result that the cluster of basic amino acids is critical for nuclear transport. Furthermore, the data obtained in this investigation indicated that the region of E1 containing the NLS sequence was not only necessary, but was also sufficient for nuclear localization. No other region of E1 contained independent nuclear localization activity.

Amino Acid Sequence↗

Dynamical localization and partial-barrier localization in the Paul trap

We investigate the nature of quantum localization exhibited by the center-of-mass motion of an ion in a Paul trap interacting with a standing laser field. Depending upon system parameters and the initial location of the ion, quantum suppression of chaotic diffusion is dominated by dynamical localization or localization due to partial barriers formed of broken separatrices and cantori.

Journal Article↗

Cytochemical localization of ATPase activity in oat roots localizes a plasma membrane-associated soluble phosphatase, not the proton pump.

Cytochemical techniques employing lead-precipitation of enzymically released inorganic phosphate have been widely used in attempts to localize the plasma membrane proton pump (H(+)-ATPase) in electron micrographs. Using Avena sativa root tissue we have performed a side-by-side comparison of ATPase activity observed in electron micrographs with that observed in in vitro assays using ATPases found in the soluble and plasma membrane fractions of homogenates. Cytochemical analysis of oat roots, which had been fixed in glutaraldehyde in order to preserve subcellular structures, identifies an ATPase located at or near the plasma membrane. However, the substrate specificity and inhibitor sensitivity of the in situ localized ATPase appear identical to those of an in vitro ATPase activity found in the soluble fraction, and are completely unlike those of the plasma membrane proton pump. Further studies demonstrated that the plasma membrane H(+)-ATPase is particularly sensitive to inactivation by the fixatives glutaraldehyde and formaldehyde and by lead. In contrast, the predominant soluble ATPase activity in oat root homogenates is less sensitive to fixation and is completely insensitive to lead. Based on these results, we propose a set of criteria for evaluating whether a cytochemically localized ATPase activity is, in fact, due to the plasma membrane proton pump.

Journal Article↗

Local production and localization of transforming growth factor-beta in tuberculous pleurisy.

Transforming growth factor-beta (TGF-beta) is one of the cytokines which play an immunosuppressive role in an inflammatory process. To investigate the local production of TGF-beta, we evaluated the levels of TGF-beta in tuberculous pleural effusions (TBPE) and non-tuberculous benign pleural effusions (non-TBPE) by the growth inhibition assay with Mv1Lu mink lung epithelial cells. The mean level of TGF-beta in TBPE (46.1 +/- 31.5 pM; mean +/- s.d.) was higher than in non-TBPE (21.7 +/- 12.3 pM) (P < 0.05). Although the level of interferon-gamma (IFN-gamma) in TBPE measured by ELISA was significantly higher than in non-TBPE, there was no significant difference in the levels of tumour necrosis factor-alpha (TNF-alpha) measured by ELISA between these two groups. Moreover, to elucidate localization of TGF-beta in tuberculous pleurisy, immunohistochemical studies of pleura, using the rabbit polyclonal antibody Ab39 against latent TGF-beta 1 binding protein (LTBP) were performed. Results revealed that LTBP was localized in immature fibrotic areas where infiltrations of T lymphocytes and macrophages were absent. Importantly, the major sources of LTBP in these areas were thought to be mesothelial cells and fibroblasts. LTBP was not found in granulomas and mature fibrotic areas. Our data suggest that TGF-beta in tuberculous pleurisy may play important roles for regression of granulomatous inflammation and pleural fibrosis for tissue repair.

Animals↗

Local thermo-radiotherapy in carcinoma cervix: improved local control versus increased incidence of distant metastasis.

In 1986, 50 patients with stages II and III carcinoma of the cervix were entered into this prospective randomized study. Twenty-five cases (Group I) were treated only by radical radiation whereas remaining 25 cases (Group II) received local hyperthermia in addition to radical radiation. Hyperthermia was delivered by intracavitary brachyhyperthermia approach using an endotract applicator. Both the groups were followed up for a minimum period of 18 months. Group II patients achieved better local control (14 out of 20 evaluable cases) than the Group I patients (11 out of 22 evaluable cases). A disturbing observation was the increased incidence of distant metastasis in Group II (4 out of 23 cases) as compared to Group I (1 out of 23 cases), though most of them remained disease free locally. The increasing use of hyperthermia in the management of various cancers needs to be reviewed in this context.

Brachytherapy↗

Clinical response to local delivery of tetracycline in relation to overall and local periodontal conditions.

The purpose of this study was to determine the clinical response to local delivery of tetracycline in relation to clinical and microbiological conditions of the other teeth. 4 deep pockets were monitored in 19 subjects with multiple deep periodontal lesions and high counts of P. gingivalis. In 9 patients (LT) only 2 of the selected lesions were treated by placement of tetracycline fibers (Actisite), while the rest of the dentition was left untreated. In the other 10 patients, all teeth were supragingivally scaled and then treated by application of polymeric tetracycline HCl containing fibers, the whole dentition was subject to full mouth scaling and root planing, and the patients rinsed with 0.2% chlorhexidine (FT). A significant reduction in mean PPD was observed in all treated sites after two months. This reduction was maintained over the following 4 months. The magnitude of the effect was significantly greater in the FT group (1.74 mm) than in the LT group (0.88 mm). The mean attachment level changes were similar after 2 months in locally and fully treated subjects. A tendency of relapse was noted for treated sites in LT patients from month 2 to 6. A level of statistical significance was not reached for this effect. Data from measurements recorded at 6 sites around all teeth in the full mouth treated patients were analyzed using multiple linear regression. This analysis showed local changes in PPD and AL were significantly and strongly correlated with the baseline value of the respective parameter at the same site. In addition, more pocket depth reduction was noted if a site was not bleeding on probing at 6 months, if the location of a site was not approximal and if the tooth was not a second molar. Sites located on second molars showed also less AL gain than sites located on other teeth. Smokers showed significantly less reduction in PPD and significantly less AL gain. Furthermore, if subjects had a high % of pockets deeper than 4 mm at baseline they showed significantly less attachment gain.

Adult↗

Local muscle damage and oily vehicles: a study on local reactions in rabbits after intramuscular injection of neuroleptic drugs in aqueous or oily vehicles.

The local muscle damaging effect of a series of neuroleptics formulated in water or in oily vehicles (Viscoleo, sesame oil, methyl oleate or squalane) has been investigated after intramuscular injection in rabbits. Each drug preparation (2 ml) was administered intramuscularly in the central part of the longissimus dorsi muscle of four rabbits. The rabbits were killed three days after the injection, and the injection site was examined macroscopically. Areas of necrotic muscle tissue were isolated by dissection and weighed. All preparations in aqueous solution caused local muscle damage (large necrotic area) at the injection site. This effect was almost completely neutralized by the Viscoleo vehicle. The sesame oil, methyl oleate and squalane vehicles also neutralized the local damaging effect, but not to the same extent as that of the Viscoleo vehicle.

Animals↗

Local factors affecting the tendency to bypass local hospitals for inpatient mental health care: an exploratory analysis.

Using the records of 2,171 rural residents of Illinois who received inpatient treatment for mental illness or substance abuse, this paper examines factors that influence the tendency to seek service from a distant rather than a local hospital. Results indicate that the age and insurance coverage of the individual, the per capita income of the community area, surrogates for the service orientation of the local hospital and the proximity of the patient's residence to an urban center are significant influences. With the exceptions of drug abuse requiring detoxification or other symptomatic treatment, drug abuse accompanied by comorbidity and psychosocial disorders, psychosis, and childhood disorders, the primary diagnosis of the individual failed to have a significant effect on the propensity to bypass local sources of inpatient treatment.

Adult↗

Automated registration of breast lesions in temporal pairs of mammograms for interval change analysis--local affine transformation for improved localization.

Analysis of interval change is important for mammographic interpretation. The aim of this study is to evaluate the use of an automated registration technique for computer-aided interval change analysis in mammography. Previously we developed a regional registration technique for identifying masses on temporal pairs of mammograms. In the current study, we improved lesion registration by including a local alignment step. Initially, the lesion position on the prior mammogram was estimated based on the breast geometry. An initial fan-shaped search region was then defined on the prior mammogram. In the second stage, the location of the fan-shaped region on the prior mammogram was refined by warping, based on an affine transformation and simplex optimization in a local region. In the third stage, a search for the best match between the lesion template from the current mammogram and a structure on the prior mammogram was carried out within the search region. This technique was evaluated on 124 temporal pairs of mammograms containing biopsyproven masses. Eighty-seven percent of the estimated lesion locations resulted in an area overlap of at least 50% with the true lesion locations and an average distance of 2.4 +/- 2.1 mm between their centroids. The average distance between the estimated and the true centroid of the lesions on the prior mammogram over all 124 temporal pairs was 4.2 +/- 5.7 mm. The registration accuracy was improved in comparison with our previous study that used a data set of 74 temporal pairs of mammograms. This improvement in accuracy resulted from the improved geometry estimation and the local affine transformation.

Biophysical Phenomena↗

Computed tomography localization of radiation treatment delivery versus conventional localization with bony landmarks.

A computed tomography (CT) scanner was installed in the linear accelerator room (Primatom) at Morristown. Since June 2000, we have been providing prostate, lung, and liver cancer patients with fusion of CT and linac radiation treatment. This paper describes our registration methods between planning and treatment CT images, and compares treatment localization by CT versus conventional localization by bony landmarks such as portal imaging. For image registration, we printed out beforehand the beam's eye view of the treatment fields. Prostate tumor volume from each Primatom CT slice was mapped on the printouts, and the necessary isocenter shift relative to the skin marks was deduced. No port film was necessary for our Primatom patients. For ten patients we generated digitally-reconstructed radiographs (DRRs) with bone contrast from the CT scans, and deduced the required shift as the difference between the DRRs of the Primatom CT versus the planning CT. This represented the best observable shift should portal imaging be employed. Shift from bony landmark significantly correlated with the Primatom CT shift. Positioning adjustment based on bony anatomy was generally in the same direction as the CT shift for individual patient, but frequently did not go far enough. Our study confirmed that prostate organ motion relative to the bones has an average length of 4.7 mm (with standard deviation of 2.7 mm), and indicated the superiority of CT versus conventional bony structure (such as portal imaging) localization.

Humans↗