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The study was aimed to introduce a design of a DICOM-RT-based tool box to facilitate 4D dose calculation based on deformable voxel-dose registration. The computational structure and the calculation algorithm of the tool box were explicitly discussed in the study. The tool box was written in MATLAB in conjunction with CERR. It consists of five main functions which allow a) importation of DICOM-RT-based 3D dose plan, b) deformable image registration, c) tracking voxel doses along breathing cycle, d) presentation of temporal dose distribution at different time phase, and e) derivation of 4D dose. The efficacy of using the tool box for clinical application had been verified with nine clinical cases on retrospective-study basis. The logistic and the robustness of the tool box were tested with 27 applications and the results were shown successful with no computational errors encountered. In the study, the accumulated dose coverage as a function of planning CT taken at end-inhale, end-exhale, and mean tumor position were assessed. The results indicated that the majority of the cases (67%) achieved maximum target coverage, while the planning CT was taken at the temporal mean tumor position and 56% at the end-exhale position. The comparable results to the literature imply that the studied tool box can be reliable for 4D dose calculation. The authors suggest that, with proper application, 4D dose calculation using deformable registration can provide better dose evaluation for treatment with moving target.

Ribonucleic acids (RNA) are hypothesized to have preceded their derivatives, deoxyribonucleic acids (DNA), as the molecular media of genetic information when life emerged on earth. Molecular biologists are accustomed to the dramatic effects a subtle variation in the ribose moiety composition between RNA and DNA can have on the stability of these molecules. While DNA is very stable after extraction from biological samples and subsequent treatment, RNA is notoriously labile. The short half-life property, inherent to RNA, benefits cells that do not need to express their entire repertoire of proteins. The cellular machinery turns off the production of a given protein by shutting down the transcription of its cognate coding gene and by either actively degrading the remaining mRNA or allowing it to decay on its own. The steady-state level of each mRNA in a given cell varies continuously and is specified by changing kinetics of synthesis and degradation. Because it is technically possible to simultaneously measure thousands of nucleic acid molecules, these quantities have been studied by the life sciences community to investigate a range of biological problems. Since the RNA abundance can change according to a wide range of perturbations, this makes it the molecule of choice for exploring biological systems; its instability, on the other hand, could be an underestimated source of technical variability. We found that a large fraction of the RNA abundance originally present in the biological system prior to extraction was masked by the RNA labeling and measurement procedure. The method used to extract RNA molecules from cells and to label them prior to hybridization operations on DNA arrays affects the original distribution of RNA. Only if RNA measurements are performed according to the same procedure can biological information be inferred from the assay read out.

Purpose: In this article, the breath-hold and gating concepts were combined for application of lung cancer radiation treatment. The tumor movement was immobilized based on deep inspiration breath hold (DIBH), in which the breath-hold consistency and stability were monitored by infrared (IR) tracking and controlled by gating with a predefined threshold. The authors' goal is to derive the benefits from both techniques, namely, the minimized treatment margin and the known advantages of deep inspiration. The efficacy of the technique in terms of tumor immobility and treatment setup accuracy was evaluated in the study., Methods: Fourteen patients who were diagnosed with non small cell lung cancer were included in this study. The control of tumor immobility was investigated interfractionally and intrafractionally. The intrabreath-hold tumor motion was devised based on the external marker movement, in which the tumor-marker correlation was studied. The margin of the planning target volume (PTV) was evaluated based on two factors: (1) The treatment setup error accounts for the patient setup and interbreath-hold variations and (2) the intrabreath-hold tumor motion in which the residual tumor motion during irradiation was studied., Results: As the result of the study, the group systematic error and group random error of treatment setup measured at the isocenter were 0.2(R) +/- 1.6, 1.0(A) +/- 2.0, and 0.3(S) +/- 1.5 mm in the left-right (LR), anterior-posterior (AP), and caudal-cranial (CC) directions, respectively. The Pearson correlation coefficient were 0.81 (LR), 0.76 (AP), and 0.85 (CC) mm and suggest tendency in linear correlation of tumor and marker movement. The intrabreath-hold tumor was small in all directions. The group PTV margins of 3.8 (LR), 4.6 (AP), and 4.8 (CC) mm were evaluated to account for both setup errors and residual tumor motion during irradiation., Conclusions: The study applies the DIBH technique in conjunction with IR positional tracking for tumor immobilization and treatment setup localization. The technique not only proved to be reliable in terms of good tumor immobility and accurate treatment positioning but also to be potentially useful for dose escalation treatment as regarding of the substantially reduced PTV margin and minimizing radiation toxicity from the fully expanded lung volume.

Purpose: To study the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma (NPC) who were treated with stereotactic radiotherapy (SRT)., Methods and Materials: Thirty patients with non-metastatic, locally recurrent NPC who were treated with curative intent between 1998 and 2002 were retrospectively analyzed. The International Union Against Cancer T-stage distribution at recurrence (rT) was as follows: rT1-14, rT2-7, rT3-3, and rT4-6. All patients were treated with SRT with a daily fractional dose of 2.5-4.5 Gy (median, 3 Gy) in 8-22 fractions (median, 18 fractions). Total equivalent dose (TED) was calculated by the linear-quadratic formula without a time factor correction., Results: The 5-year actuarial overall survival rate, disease-specific survival rate, and local failure-free survival (LFFS) rate for the whole group were 40%, 41.4%, and 56.8%, respectively. The 3-year LFFS rates of rT1-2 and rT3-4 diseases were 65% and 66.7%, respectively. Seven of nine patients who received a TED <55 Gy recurred locally compared with 4 of 21 patients who received > or =55 Gy. Their corresponding 5-year LFFS rates were 22.2% and 75.8% (p = 0.005). The TED was the only factor significant in affecting the local control on univariate analyses., Conclusion: SRT is an effective treatment for locally recurrent NPC. TED > or =55 Gy should be given to secure a higher local control rate. The late complication rates were acceptable for patients with rT1-2 disease. For patients with rT3-4 disease, more works need to be done to further decrease the late complications.

One-day-old male chickens were exposed via oral gavage to mixtures of perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorodecanoate (PFDA) at either a low dose (0.1 mg/kg body weight [b.w.]) or a high dose (1.0 mg/kg b.w.), or a saline/ethanol vehicle control, three times a week for 3 weeks. After 3 weeks of exposure, half of the chicks were sacrificed and the other half were allowed to depurate for a further 3 weeks. No dose-dependent statistically significant differences in body/organ weights were observed among treatment and control groups after 3 weeks of exposure or after three 3 of depuration. Neither 15 histological nor 14 measured plasma biochemical parameters were significantly different in chicks from the exposed groups and vehicle controls. PFOS, PFDA, and PFOA concentrations in blood/liver/kidney samples were measured throughout the exposure and depuration periods at different time intervals. PFOS and PFDA accumulated at much higher concentrations than PFOA during the experimental periods. Interestingly, PFOS and PFDA accumulation patterns in the blood were similar during the exposure and depuration periods. The half-lives for each PFC at the 0.1 and 1.0 mg/kg doses were, respectively, approximately 15 and 17 days for PFOS, 11 and 16 days for PFDA, and 3.9 and 3.9 days for PFOA. PFDA accumulation in organs was greater than or similar to that of PFOS: the liver was the main target during exposure and the blood was the main reservoir during depuration. These results indicate that exposure to a 1.0-mg mixture of PFOS/PFDA/PFOA/kg b.w. has no adverse effect on juvenile chickens.

We report 20 cases using hypofractionation stereotactic radiotherapy in medically inoperable stage I non-small cell lung cancer with dose escalation of 45-54 Gy prescribed at 85 or 90% isodose level in 3-4 fractions. Two-year local control and cancer-specific survival were 94.7 and 77.6%, respectively, with minimal toxicity. Though, large fraction size can be safely given to peripheral lung tumors, normal tissue tolerance to hypofractionated radiotherapy to esophagus, trachea, main bronchi, aorta and heart remains unknown. Therefore we also reported the maximum point doses to these critical organs to contribute information to extend this technique to more centrally located lung tumors in future.

Purpose: To investigate any possible therapeutic gain from dose escalation with brachytherapy for early T stage nasopharyngeal carcinoma (NPC)., Methods and Materials: One hundred forty-five patients with T1-2b N0-3 NPC were boosted with high-dose-rate intracavitary brachytherapy after completion of two-dimensional external radiotherapy (ERT) during the period from 1999 to 2003. To compare the efficacy of brachytherapy boost, another 142 patients with T1-2b N0-3 disease who were treated with ERT alone during 1994 to 1999 were evaluated. All patients were treated with ERT to a total dose of 66 Gy in 6.5 weeks. The brachytherapy boost group was given 10-12 Gy in 2 weekly fractions., Results: Dose escalation beyond 66 Gy with brachytherapy boost was shown to improve local control and survival. The 5-year actuarial local failure-free survival, regional failure-free survival, distant metastasis-free survival, progression-free survival, cancer-specific survival, and overall survival rates for the brachytherapy group and the control group were 95.8% and 88.3% (p = 0.020), 96% and 94.6% (p = 0.40), 95% and 83.2% (p = 0.0045), 89.2% and 74.8% (p = 0.0021), 94.5% and 83.4% (p = 0.0058), and 91.1% and 79.6% (p = 0.0062), respectively. The 5-year major-complication-free survival rate was 89.5% for the brachytherapy group and 85.6% for the control group (p = 0.23)., Conclusions: For patients who are treated with two-dimensional treatment techniques, dose escalation with brachytherapy boost improves local control and overall survival of patients with T1-T2a and possibly non-bulky T2b disease.

Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.

Aims: Tumour control and complication risk have been major concerns in the treatment of cervical carcinoma. A review of dose distribution for intracavitary treatment of cervical carcinoma revealed that modification of the Manchester dosimetry system is necessary for cases of narrow-sized vagina. A revised dosimetry system was introduced in the present study, with the objective of optimising the dose coverage for the parametrium while minimising the bladder and rectum dosage by restricting the rectal dose so as not to exceed 75% of the brachytherapy prescription dose., Materials and Methods: A suitable-sized applicator was selected according to the patient's anatomy. The revised system is optimised based on the fixed geometry of the applicator. The system was therefore predefined and the distribution of the treatment dose already determined before application. The revised system was applied to 135 cases, involving 540 applications. The clinical outcome in terms of local tumour control and complication rates is reported. The differences between the revised system and the Manchester system in terms of dose coverage for the parametrium and the rectum dose were compared., Results: The results showed that higher rectal and parametrial dosages were obtained with the Manchester system as compared with the revised system. Our study showed that over 50% of our patients would have received a rectal dose close to 100% of the point A dose if the Manchester system was applied, whereas it was restricted to below 75% using the revised system. Using the revised system, the significance of the parametrial dosage coverage in relation to local control was assessed: the mean dose to the rectum and the bladder as a percentage of point A was 65.7 +/- 5% (range 50-85%) and 66.4 +/- 14% (range 29-116%), respectively. The 5-year actuarial local failure-free survival rates were 90, 92.9, 86.8, 100, 69.7 and 0% for stages IB, IIA, IIB, IIIA, IIIB and IV (P < 0.0001), respectively. The 3-year actuarial complication rates (grade 3/4) for proctitis and cystitis were 1.4 and 0.5%, respectively. The dosage coverage for the parametrium was found to be significant (P = 0.029) in relation to local control for early-stage disease., Conclusions: The favourable local tumour control and low complication rates shown by our results indicate that the revised system presents an optimal dose distribution, particularly for the application of small ovoids, whereas morbidity was reduced to a lower level without compromising local control.

Background: Locally persistent nasopharyngeal carcinoma (NPC) carries an increased risk of local failure if additional treatment is not given. It has been shown that intracavitary brachytherapy is effective in the treatment of patients with T1 and T2a NPC, although its role in the treatment of T2b disease had remained uncertain. The objectives of the current study were to evaluate the outcomes of patients with T2b, locally persistent NPC who were treated with high-dose-rate (HDR) intracavitary brachytherapy and to explore whether routine brachytherapy boost could improve the local control of patients who had T2b NPC at initial diagnosis., Methods: Thirty-four patients with locally persistent NPC who were treated during 1992-2000 with HDR intracavitary brachytherapy were analyzed retrospectively. All patients had T2b disease at initial diagnosis. They were treated with HDR intracavitary brachytherapy at doses of 22.5-24.0 grays (Gy) in 3 weekly sessions. To compare the efficacy of brachytherapy, another 403 consecutive patients with nonmetastatic T2b NPC who were treated with curative intent by external radiotherapy (ERT) during the same period were evaluated., Results: An improvement in the 5-year actuarial local failure-free survival rate (brachytherapy group vs. ERT group: 96.9% vs. 81.5%; P = 0.024), the disease-specific survival rate (84.5% vs. 68.1%; P = 0.021), and the overall survival rate (78.3% vs. 63.1%; P = 0.034) was demonstrated in the group that had locally persistent NPC who were salvaged with brachytherapy. In assessing local control, the addition of brachytherapy was just short of statistical significance on multivariate analysis (P = 0.054). The complication rates were comparable between the brachytherapy group and the ERT group., Conclusions: The results suggested that patients with T2b NPC who have locally persistent disease can be salvaged effectively with brachytherapy. Their local control was even better than that achieved by patients who had clinical remission of local disease at the completion of ERT. Furthermore, it is possible that routine brachytherapy boost, after the completion of ERT, may improve local control in patients who have T2b disease at initial diagnosis. However, its exact benefit can be elucidated only by prospective, randomized studies., (Copyright 2005 American Cancer Society)

Two quality control devices, light-field device and radiation-field device, have been specially designed to facilitate the clinical implementation of conformal dynamic arc treatment (CDAT) and intensity modulated radiation therapy (IMRT). With the devices, the light field as well as the radiation field, projected from the individual beam at any treatment position (i.e. arbitrary gantry angle) can be evaluated. For application, the device was attached at the front end of the couch and was placed at the isocentre of the linear accelerator treatment system (LINAC). The devices are designed to be rotated parallel to the gantry head so that the light field and the radiation field projected from a direct beam can be assessed. The aim of the study is, with the aid of the devices, to evaluate the geometric precision of the beam placement and the dosimetric accuracy performed in CDAT and IMRT. The devices are placed separately from the LINAC during application and provide an independent check on the quality performance of the LINAC in three dimensions. The condition of gantry sag and any mechanical displacement resulting in field shift can be observed and traced during gantry rotation. Mistakes that occurred during the isocentre calibration can lead to significant displacement in the field projection, which would not be revealed with the conventional quality control setting (i.e. gantry 0(o)), was demonstrated with the aid of the devices here. The influence of gravitational acceleration in MLC leaf positioning error, which would consequently lead to inaccurate dose delivery, was investigated. The results of our study show that the existence of gravitational influence is statistically significant, although the magnitude of the dose inaccuracy has been found to be small.

Aims: This study introduces a non-invasive method based on computed tomography (CT) verification to ensure patients are accurately positioned before fractionated stereotactic radiotherapy. It enables quality control of mask positioning with reference to the CT images of the treatment plan., Materials and Methods: A mask system, together with a dental impression moulded mouth bite, was used for patient immobilisation. In order to facilitate relevant image comparison, special alignment during CT localisation was discussed in the study. The accuracy of patient set-up was studied by assessing the isocentre position in relation to the patient's anatomical structure. The planning CT images were applied as a reference and the study was applied to 261 cranial applications., Results: The results show that the mean and the maximum overall displacements at the isocentre were 0.7 and 2.5 mm, respectively. The mean and the maximum rotational displacement in the axial plane were 0.56 degrees and 2 degrees, respectively. The mean translational displacement and rotational displacement were close to zero when considering the direction of movement., Conclusions: The results indicate that the systematic error of the mask system and the verification method are minimal. Advantages of this technique include the simple set-up, three-dimensional quantification and short study time (10-15 min). It is therefore practical to implement on a routine basis. Investigation of the ability to relocate the mask is also recommended to justify the required safety margin between the clinical and planning target volumes.

Purpose: To review the treatment results and complications of high-dose-rate (HDR) intracavitary brachytherapy for patients with carcinoma of the cervix in a single institute and to compare them with those of low-dose-rate (LDR) brachytherapy reported in the literature., Methods and Materials: Two hundred twenty patients with carcinoma of the cervix were treated by primary radiotherapy between 1991 and 1998. The median age was 63 (range 24-84). The distribution according to Federation of Gynecology and Obstetrics (FIGO) staging system was as follows: Stage IB, 11.4%; IIA, 9.1%; IIB, 50.9%; IIIA, 3.6%; IIIB, 23.2%; and IVA, 1.8%. They were treated with whole pelvic irradiation giving 40 Gy to the midplane in 20 fractions over 4 weeks. This was followed by parametrial irradiation, giving 16-20 Gy in 8-10 fractions. HDR intracavitary brachytherapy was given weekly, with a dose of 7 Gy to point A for three fractions and, starting from 1996, 6 Gy weekly for four fractions. The median overall treatment time was 50 days (range 42-73 days). The median follow-up time was 4.7 years (range 3 months to 11.1 years). Multivariate analysis was performed using the Cox regression proportional hazards model., Results: The complete remission rate after radiotherapy was 93.4% (211/226). The 5-year actuarial failure-free survival (FFS) and cancer-specific survival (CSS) rates for stage IB, IIA, IIB, IIIA, IIIB, and IVA were 87.7% and 86.6%, 85% and 85%, 67.8% and 74%, 46.9% and 54.7%, 44.8% and 50.4%, 0% and 25%, respectively. On multivariate analysis, young age (< 50) (p = 0.0054), adenocarcinoma (p = 0.0384), and stage (p = 0.0005) were found to be independent poor prognostic factors. The 5-year actuarial major complication rates (Grade 3 or above) were as follows: proctitis, 1.0%; cystitis, 0.5%; enteritis, 1.3%; and overall, 2.8%. On multivariate analysis, history of pelvic surgery was a significant prognosticator. The two HDR fractionation schedules were not a significant prognosticator in predicting disease control and complications., Conclusion: Our experience in treating cervical cancer with HDR intracavitary brachytherapy is encouraging. Our treatment results and complication rates were compatible with those of the LDR series. Further studies are eagerly awaited to better define the optimal fractionation schedule for HDR brachytherapy and the schedule on how chemotherapy may be combined with it.

Background: High dose rate (HDR) interstitial brachytherapy of the oral tongue is a new treatment modality. Our study evaluates the outcomes of patients with early stage oral tongue cancer as treated by HDR interstitial implant., Methods: We reviewed the records of 19 patients who were seen between 1994 and 2000 with carcinoma of the oral tongue and whose primary tumors were treated solely with interstitial implant using HDR remote afterloading technique. Ten patients had T1 N0 disease, and the remaining 9 had T2 N0 disease. Elective neck treatment was withheld for 12 patients. The remaining seven patients had ipsilateral elective neck dissection. The male-female ratio was 1:0.9, and the median age was 60 years (range, 32-81 years). The median follow-up time was 43 months (range, 6-78 months). The afterloading catheters were positioned by the submandibular approach with the assistance of a template set. Fifteen patients had single planar implants, and the remaining four had double planar implants. The median number of catheters inserted was 5 (range, 4-9). The median dose given was 55 Gy in 10 fractions over 6 days. The minimal interfraction interval was 7 hours for the first 7 patients and was extended to 8 hours for the other 12. Mandibular shields were inserted before treatment., Results: The mucositis lasted for 6 to 20 weeks (median, 9 weeks). One patient had local failure, and the 4-year local failure-free survival rate was 94.7%. Three of the 12 patients without elective neck treatment had ipsilateral regional failure develop. They were salvaged by neck node dissection and regionally remained in control. One patient with multiple nodal metastases and extracapsular spread had biopsy-proven liver metastases and died 6 months after implant. One of the seven patients who were treated with elective neck dissection had multiple nodal metastases and extracapsular spread. She was treated with postoperative radiotherapy to the neck. She died 30 months after implant with evidence of regional and distant failure. One patient treated with double planar implant had grade II necrosis of the soft tissue and bone develop. The necrosis resolved with conservative treatment. Another four patients had small area of soft tissue deficit of the tongue attributed to aggressive debulking or biopsy before brachytherapy., Conclusions: Our experience in treating early stage tongue cancer with HDR remote afterloading technique is encouraging, because it gives a local control rate of 94.7% at 4 years with acceptable morbidity. Further studies are eagerly awaited to delineate the optimum schedule for this new treatment modality., (Copyright 2002 Wiley Periodicals, Inc.)

In the present study, we have used an in vitro model of apoptosis using primary human renal proximal tubular epithelial (RPTE) cells to investigate the mechanisms involved in renal cell apoptosis. Treatment of RPTE cells with okadaic acid for 24-48 h induced apoptosis in a concentration-dependent manner. Apoptosis was accompanied by the activation of the p38 mitogen-activated protein kinase (MAPK) pathway followed by the activation of caspase-9, -3, and -7. The induction of caspase activity correlated with the proteolytic cleavage of beta-catenin, suggesting that beta-catenin is a caspase substrate. The caspase inhibitor, Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), resulted in a dose-dependent inhibition of apoptosis and beta-catenin cleavage. These data suggest that okadaic acid-induced apoptosis is p38 MAPK and caspase-dependent and that proteolytic cleavage of beta-catenin by caspases is likely to be a downstream molecular event associated with the morphological and cytoskeletal changes induced during apoptosis.

1. The effect of carvedilol on renal function, structure and expression of TGF beta and the matrix proteins fibronectin, collagen I and collagen III, was evaluated in spontaneously hypertensive stroke-prone (SHR-SP) rats fed a high fat, high salt diet. 2. Carvedilol treatment for 11 to 18 weeks did not alter systolic blood pressure in SHR-SP rats, however, it resulted in a significant reduction in heart rate. 3. Carvedilol treatment reduced renal fibrosis and total, active and chronic renal damage to levels approaching those of WKY rats on a normal diet. 4. Urinary protein excretion was higher in SHR-SP rats (51+/-10 mg day(-1)) than WKY rats (18+/-2 mg day(-1)) and this was further increased when SHR-SP rats were fed a high fat, high salt diet (251+/-120 mg day(-1)). Treatment with carvedilol resulted in significantly lower urinary protein excretion (37+/-15 mg day(-1)). 5. The expression of TGF beta mRNA was significantly higher in SHR-SP rats compared to WKY rats and a further increase was observed when rats were fed a high fat, high salt diet. Renal TGF beta expression was significantly reduced by treatment with carvedilol. The expression of fibronectin and collagen I and collagen III mRNA showed a pattern similar to that observed with TGF beta mRNA expression. Collagen I mRNA expression followed a pattern similar to renal fibrosis. 6. These data indicate that carvedilol can provide significant renal protection in the absence of any antihypertensive activity and that the mechanisms involved in this action may include reduced expression of profibrotic factors such as TGF beta.

Purpose: To study the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma (NPC) and to explore whether a combination of high-dose-rate (HDR) intracavitary brachytherapy and external beam radiation therapy (ERT) could improve the therapeutic ratio., Methods and Materials: Ninety-one patients with nonmetastatic locally recurrent NPC who were treated with curative intent during the years 1990-1999 were retrospectively analyzed. Eighty-two patients had histologically proven carcinoma. The remaining 9 had clinical and imaging features suggestive of local recurrence. The Ho's T-stage distribution at recurrence (rT) was as follows: rT1-37, rT2-14, rT3-40. Total equivalent dose (TED) was calculated by the linear-quadratic formula without a time factor correction. For those treated by combined-modality treatment (CMT), the TED was taken as the summation of the equivalent dose by ERT and the absolute dose delivered to floor of the sphenoid by brachytherapy. Eight patients were treated solely with brachytherapy, all receiving 24-45 Gy in 3-10 sessions. Forty-one patients were treated with ERT alone receiving a median TED of 57.3 Gy (range, 49.8-62.5 Gy). Forty-two patients were treated by CMT with a median equivalent dose of 50 Gy (range, 40-60 Gy) given by ERT and 14.8 Gy by brachytherapy (range, 3-29.6 Gy). Multivariate analyses were performed using the Cox regression proportional hazards model., Results: The 5-year actuarial overall survival rate, disease specific survival rate and local failure-free survival (LFFS) rate for the whole group were 30%, 33. 3% and 37.8%, respectively. The 3-year LFFS rates of rT1, rT2, and rT3 diseases were 64%, 61.5%, and 18.4%, respectively (p = 0.001). Of the 8 patients treated with brachytherapy alone, 4 failed locally. Further analyses were concentrated on the ERT (41 patients) and CMT (42 patients) groups. The 3-year LFFS rates of rT1, rT2, and rT3 diseases were 66.7%, 66.7%, and 18.4%, respectively (p = 0.0008). Better local control for patients who received a TED of 60 Gy or greater was shown. The corresponding 3-year LFFS rates were 29% and 60% (p = 0.0004). Subgroup analysis on the ERT and CMT groups showed a 3-year LFFS rate of 33.5% and 57% (p = 0.003). ERT group had an excess of patients with rT3 disease. Further analysis was performed on the rT1-2 patients showing a trend toward improvement in local control in favor of the CMT group (3-year LFFS rates: CMT, 71.7%; ERT, 54%; p = 0.13). Multivariate analyses showed that rT stage (p = 0.002) and TED (p = 0.01; HR, 0.93; 95% confidence interval, 0.88-0. 98) remained significant. The 5-year major and central nervous system (CNS) complication-free rates were 26.7% and 47.8%. The following factors were found to be significant on univariate analyses for both complications in the ERT and CMT groups: (1) Modality of treatment: more complications with ERT group; and (2) rT stage. Multivariate analyses showed that the rT stage was significant for predicting the occurrence of major (p = 0.004) and CNS complications (p = 0.04)., Conclusion: For rT1-2 local recurrences, CMT with at least 60 Gy TED is recommended. The high incidence of major late complications is of serious concern. Ways of improving the local control of Ho's rT3 disease and reducing the risk of late complications should be explored.

The role of ANG II on renal and cardiac gene expression of matrix proteins was studied in rats with progressive renal disease. Induction of renal failure by five-sixths nephrectomy of Sprague-Dawley rats resulted in hypertension (163 +/- 19 vs. control pressures of 108 +/- 6 mmHg), proteinuria (83 +/- 47 vs. 14 +/- 2 mg/day), and increased renal expression of fibronectin, thrombospondin, collagen I and III, transforming growth factor-beta (TGF-beta), and plasminogen activator inhibitor-1 (PAI-1) mRNA. Treatment with the ANG II receptor antagonist, eprosartan (60 mg. kg(-1).day(-1)), lowered blood pressure (95 +/- 5 mmHg) and proteinuria (19 +/- 8 mg/d) and abrogated the increased TGF-beta, fibronectin, thrombospondin, collagens I and III, and PAI-1 mRNA expression. An increase in left ventricular weight was observed in five-sixths nephrectomized rats (0.13 +/- 0.01 vs. 0.08 +/- 0.01 g/100 g body wt), a response that was inhibited by eprosartan treatment (0.10 +/- 0.01 g/100 g). Left ventricular expression of TGF-beta and fibronectin was also increased in rats with renal disease; however, the small decreases in expression observed in eprosartan-treated rats did not reach statistical significance. These data suggest that eprosartan may be beneficial in progressive renal disease and that the mechanism of action includes inhibition of cytokine production in addition to antihypertensive activity.

Purpose: Locally persistent nasopharyngeal carcinoma (NPC) carries an increased risk of local failure if additional treatment is not given. This study was conducted to evaluate the outcomes of patients with locally persistent NPC as treated by high-dose-rate (HDR) intracavitary brachytherapy, and to explore whether routine brachytherapy boost could improve the local control., Methods and Materials: Eighty-seven patients with locally persistent NPC treated during 1990-1998 with HDR intracavitary brachytherapy were retrospectively analyzed. Fibreoptic nasopharyngoscopy was performed 3-6 weeks after completion of the primary external radiation therapy (ERT). Biopsies were only taken from suspicious areas. Those with complete regression of local disease were put on observation. Eighty-seven patients were shown to have persistent viable disease at a median time of 6 weeks post-RT. The distribution according to Ho's staging system at initial diagnosis was as follows: Stage I-8, II-33, III-41, IV-5; T1-19, T2-48, T3-20; N0-32, N1-22, N2-28, N3-5. CT scan for restaging was not performed after the documentation of persistent disease. Our policy was to treat all patients with persistent disease with brachytherapy irrespective of the extent of disease just prior to brachytherapy. They were treated with HDR intracavitary brachytherapy, with either cobalt sources or an iridium source, giving 22.5-24 Gy in 3 weekly sessions in all but 4 patients. This dose was prescribed at a distance of 1.5 cm from the center of the surface as defined by the sources in the first six patients and subsequently reduced to 1 cm for the others. Twelve patients were treated with neoadjuvant chemotherapy. To compare the efficacy of brachytherapy, another 383 consecutive nonmetastatic patients, treated with curative intent by ERT, during the years 1990-1993, were evaluated. Multivariate analysis was performed using the Cox regression proportional hazards model., Results: The 5-year actuarial local failure-free survival (LFFS) rates and disease-specific survival rates for the brachytherapy group and ERT group were 85% and 76.6% (p = 0.15), and 72% and 67.8% (p = 0.2), respectively. The corresponding 5-year actuarial LFFS rates for T1, T2, and T3 disease were 94.7%, 88.2%, 67.4%, and 84.1%, 79.8%, 62.6%. In assessing the local control, only the T staging was significant on multivariate analysis (p = 0.0004). Other parameters such as age, sex, and persistence of disease (giving brachytherapy) were all nonsignificant. Complications were comparable between the two groups. In the persistent group, the local failure rates of the patients treated with and without neoadjuvant chemotherapy were 17% (2/12) and 13% (10/75) respectively. When analyzed according to different brachytherapy sources, the 5-year LFFS rates of the T1, T2, and T3 patients treated with iridium and cobalt sources were 100% vs. 85.7 (p = 0.19), 93.6% vs. 70% (p = 0.04), and 67.7% vs. 60% (p = 0.72). The difference was statistically significant for the T2 groups. When early T-stage (T1 and T2) patients were grouped together for analysis, the iridium group again showed a statistically significant improvement in 5-year LFFS rate when it was compared with the cobalt group (95.3% vs. 76.5%, p = 0.03) and the ERT alone group (95.3% vs. 81.5%, p = 0.03). The improvement of local control is attributed to a higher nasopharyngeal mucosal dose that is achieved by using small-size flexible applicators with an iridium source. It is interesting to note that the 5-year LFFS rates for the ERT alone group (T1: 84.1%, T2: 79.8%, T3: 62.6%) are comparable to the corresponding rates of the cobalt group. This information supports our speculation that an adequate booster treatment could compensate for inadequate primary treatment. The prognosis of patients with locally recurrent NPC is grave. Maximizing the local control is therefore crucial for the survival of the patients. (ABSTRACT TRUNCATED)

Polycystic kidney disease (PKD) is characterized by the development of large renal cysts and progressive loss of renal function. Although the cause of the development of renal cysts is unknown, recent evidence suggests that excessive apoptosis occurs in PKD. With the use of terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, we have confirmed the presence of apoptotic bodies in cystic kidneys of congenital polycystic kidney (cpk) disease mice carrying a homozygous mutation at 3 wk of age. Apoptosis was localized primarily to the interstitium with little evidence of cell death in cyst epithelium or noncystic tubules. In addition, we observed that the expression of various caspases, bax and bcl-2, was upregulated in cystic kidneys. With the use of various substrates in enzyme activity assays, we have demonstrated a greater than sevenfold increase in caspase 4 activity and a sixfold increase in caspase 3 activity. These data suggest that there is a caspase-dependent apoptosis pathway associated with PKD and support the hypothesis that apoptotic cell death contributes to cyst formation in PKD.

Purpose: Two new indices, the peak index (PI) and the new geometry index (NGI), that quantify implant dose uniformity and quality are presented. Their advantages include independence to absolute treatment dose and high sensitivity compared with other adopted dose-uniformity measures. The applicability of these indices were evaluated through computer simulations and several clinically executed implant cases. Target coverage is assumed to be properly observed and will not be discussed herein., Methods and Materials: The natural volume-dose histogram serves as the basis of our investigation. The PI and NGI definitions are based on parameters derived from the histogram. Two computer-simulated implants and 12 clinically executed implants, using high-dose rate remote afterloading techniques, are studied. Various indices that quantify the dose uniformity of the implant, namely the quality index (QI), geometry index, as well as the PI and NGI, are computed, and the results are compared., Results: The PI demonstrated significantly increased sensitivity (up to 5 times) to dose-uniformity evaluation, compared with the QI. The deduced parameter NGI may thus offer a better measure of implant qualities, allowing a more meaningful assessment and correlation between implant qualities to the treatment results. The PI system also offers a guideline to the design of optimal implant geometry., Conclusion: The PI overcomes some of the shortcomings of the QI in that it provides more information about the peaking of the natural dose-volume histogram of a particular implant. The PI and NGI may offer better, more sensitive means to assess implant dose uniformity, independent of prescription dose, than other measures.

Netrins are secreted, diffusible proteins that direct axonal growth. To study the functions of netrins in the relatively simple and easily accessible nervous system of the leech Hirudo medicinalis, we have cloned a leech netrin and have characterized its expression during embryogenesis. By probing a leech cDNA library at low stringency with chick netrin probes, we have identified a complete cDNA clone that bears significant sequence similarity to netrins of other species. In situ hybridization and dye filling of individual neurons show that this leech netrin is expressed by several identifiable central neurons in every segmental ganglionic primordium during early stages of embryogenesis. Some of these neurons, including the bipolar cells which are thought to be involved in setting up longitudinal tracts, express this gene only transiently during embryogenesis, while others continue to express it in the adult. In addition, leech netrin is expressed by ventral but not dorsal longitudinal muscle cells in each segment before central neurons project their axons to the periphery. These highly specific expression patterns are consistent with the hypothesis that leech netrin plays a role in forming the major interganglionic neuronal tracts and in defining ventral versus dorsal domains of peripheral innervation., (Copyright 1999 John Wiley & Sons, Inc.)

Sequence analysis of a newly isolated Hirudo medicinalis cDNA containing an Antennapedia (Antp)-class homeobox suggests that the corresponding gene, Lox6, is an ortholog of the Drosophila Deformed (Dfd) gene. In situ hybridization of whole-mounted preparations shows that the major sites of Lox6 expression during embryogenesis are the central nervous system (CNS) and the peripheral sensory system. Lox6 mRNA can be detected in a subset of neurons in each ganglion from the subesophageal ganglion (RG2) to the most posterior ganglion, with the highest level of expression seen in RG3. Peripherally, Lox6 is expressed principally in the primordia of the sensillae and in the eyes. This pattern of expression of Lox6 suggests that one of its functions may be to contribute to the diversification of neuronal phenotypes.

High dose rate (HDR) interstitial tongue brachytherapy is a new treatment modality. This study describes important technical details required for its successful use. Thirteen patients with carcinoma of the oral tongue were treated solely with interstitial brachytherapy using HDR remote afterloading techniques during the years 1994-1997. The afterloading catheters were positioned by the submandibular approach with the assistance of a template set. Custom-made mandibular lead shields were inserted prior to treatment. Special reusable Tuen Mun Hospital (TMH) lead buttons were made for improved radiation protection. The median dose given was 55 Gy in ten fractions over 6 days. The interfraction interval was 7 hours for the first seven patients treated and was extended to 8 hours for the other six. Shrinking field techniques were employed and the treatment length of the last fraction was reduced by 5 mm. Commencing with the second patient treated with double planar implants, the medial plane was treated with eight fractions while the lateral plane received ten fractions. To reduce further the potential risk of tract seeding, additional coverage to the implantation tracts was given for the last four patients, with the resultant isodose curves resembling a 'comb rake/brush'. The mean and median measured doses on the inner face of the mandibular shields were 113% and 93% of the reference dose respectively (range 77-247). The dose to the corresponding sites on the gingival surface can be reduced by 75% if the 3 mm thick lead shield is placed successfully. With the use of the TMH button, the transmitted dose to the tissue in direct contact can be reduced by one-third. With the 'comb rake/brush' dose distribution, the high dose volume of the single planar implants could be reduced by 44%, compared with the low dose rate technique, if loading to just 5 mm short of the submandibular skin was required. The mean doses for the combination of eight double planar plus two single planar implants, and ten double planar implants, are on average 29% and 37% greater than the reference dose respectively. An 8% reduction in absolute dose in the region between the planes of the catheters would lead to an even greater magnitude of reduction in morbidity to late responding tissue. The prerequisite for the success of HDR interstitial implants is to develop a good technique in positioning the afterloading catheters and protection of the normal tissue. Its importance merits special attention if HDR remote afterloading interstitial tongue brachytherapy is to realize its full potential.

Purpose: The purpose of this study is to assess the feasibility of treating early-staged tongue cancer with high dose rate (HDR) remote afterloading technique. Furthermore, a new figure of merit, the Geometry Index (GI), is introduced to quantify the quality of the implants., Methods and Materials: Between 1994 and 1995, eight patients with carcinoma of the oral tongue were treated solely with interstitial implant using the HDR remote afterloading technique. Five patients had T1 N0 disease and the remaining three had T2 N0 disease. Elective neck treatment was withheld. The male-to-female ratio was 1:1, and the mean age 60 years (range: 32-72 years). The median follow-up time was 26 months (range: 6-30 months). The afterloading catheters were positioned through the submandibular approach with the assistance of templates. Six patients had single planar implant and the remaining two had double planar implant. The median number of catheters inserted was 5 (range: 4-9). The median dose given was 60 Gy in 10 fractions over 6 days. The interfraction interval was 7 h. Mandibular and maxillary shields were inserted prior to treatment. Thomadsen et al. introduced the use of Implant Quality Index (QI). We introduce a new parameter, GI, which is defined as ratio of the QI of the nonoptimized executed implant to the corresponding QI value of the nonoptimized idealized implant., Results: The mucositis lasted for 6 to 20 weeks (median: 10 weeks). There was no local failure up to a median follow-up of 26 months. Two patients developed ipsilateral neck node metastases at 2 and 4 months following implant, respectively. One patient had involvement at level II and the other failed at level I to III. Both patients were salvaged by neck node dissection and regionally remained in control. One patient with multiple nodal metastases and extracapsular spread developed biopsy-proven liver metastases and succumbed 6 months following implant. One patient treated with double planar implant developed Grade 3 necrosis of the soft tissue and bone. This complication is largely preventable now, as we have acquired more technical expertise. The mean GI values for the single and double planar implants were 0.88 (range: 0.84-0.91) and 0.8, respectively. This correlates with our practical experience that it is more difficult to maintain a good geometry as double planar implant is required. The GI gives a better view of the geometry of implant as it compares the nonoptimized QI of the executed implant with its ideal counterpart. The failure to achieve a high GI in double planar implants is presumed to relate to technical difficulties rather than variation in individual performance., Conclusion: Our preliminary experience in treating early-staged tongue cancer with the HDR remote afterloading technique is inspiring, as it gives a local control rate of 100% with acceptable morbidity. Further studies are eagerly awaited to delineate the optimum schedule for this modality of treatment. It is hoped that the GI values, which represents the skills of insertion, could be routinely reported so that treatment results between different centers could be compared in a more precise manner.

High dose rate (HDR) intracavitary brachytherapy is now more frequently incorporated into treatment programmes for patients with persistent and recurrent nasopharyngeal carcinoma (NPC). However, many centres still employ two-dimensional (2-D) image reconstruction for applicators with a three-dimensional (3-D) orientation. In this study, we introduced the use of a mobile modified Nucletron reconstruction box inside the brachytherapy suite for image reconstruction and quality assurance. Three-dimensional reconstruction of the applicators' configurations proved possible and the dose distributions generated by the 2-D and 3-D image reconstructions could be compared. Thirty-one applications were included in this part of the analysis. The results showed that, based on the 2-D planning method, the reference doses were under-prescribed by 1%-10% in all except one patient, whose dose was over-prescribed by 3%. The evaluated doses to the floor of the sphenoid, which was shown to be significant for subsequent local control, was shown to be underestimated by up to 19% or overestimated by 18%, with an average of 5.9% dose underestimation. With this system, the reliability of the anchoring techniques was verified by posttherapy radiographs. Any catheter displacement of more than 1 mm was counted as a failure. Nine of the 43 verified applications were classified as failures, although six of nine catheter displacements measured < or = 2.5 mm. We recommend the routine use of a modified reconstruction box for 3-D image reconstruction for dose calculation and prescription in the treatment of NPC with HDR intracavitary brachytherapy. Quality assurance programmes should be included as an integral part of any HDR treatment; their importance cannot be overemphasized.

A retrospective study on 61 patients, with local persistent or recurrent nasopharyngeal carcinoma (NPC), treated during 1990-1992 with high dose rate intracavitary brachytherapy alone or combined with external irradiation, is presented. All 39 patients with persistent disease were treated solely with brachytherapy. The actuarial 3-year local failure-free survival (LFFS) rates of the persistent and recurrent groups were 82% and 45% respectively. The corresponding disease specific survival rates were 82% and 62%. Fifteen patients with recurrence received the combined modality treatment and their 3-year LFFS rate was 65%. Three out of 7 patients treated by brachytherapy could be controlled locally. The total dose given to the floor of sphenoid was an important predictor of local control. Of the 23 patients with persistent disease treated with < 17.5 Gy to this area, 6 failed locally as opposed to none of the 16 patients receiving a higher dose (p = 0.031). For those with recurrence treated by the combined modality, none of the 7 patients given >/= 57.5 Gy recurred while 5 local failures were observed among those receiving a smaller dose (p = 0.041). The general implications of these results for the treatment of NPC recurrence are discussed.

The Antennapedia-class homeobox genes are likely to play a role in the specification of neuronal identities in invertebrates. The leech Hirudo medicinalis, a species well-suited for the analysis of these genes at the level of identified neurons, contains homologs of many Antennapedia-class and related genes. The expression pattern in the central nervous system of four leech homebox genes was examined in detail. Lox1 is expressed during early gangliogenesis in one pair of transient neurons present in every segment and, at later stages, in 15-20 pairs of neurons per segment. Lox2 is expressed in 25-30 pairs of neurons repeated in the posterior two-thirds of the midbody. Lox4 is present in 20-30 pairs of iterated neurons in the posterior half of the midbody, and in smaller subset of them in more anterior ganglia. Lox6 is expressed in 15-20 pairs of neurons of the third subesophageal neuromere and in fewer cells of more posterior ganglia. The subsets of neurons that express these homeobox genes are different but overlapping. Combinations of Lox genes could in theory generate enough variability to specify all central neurons in a leech ganglion.

Studies of the Antennapedia-class homeobox genes suggest that specific combinations of these transcription factors play a role in defining neuronal identities. We examined the expression of these genes in the leech Hirudo medicinalis, an organism well-suited for neurobiological research at the level of identified neurons. Leeches contain at least as many Antennapedia-class and related genes as insects do, despite the apparently lower complexity of the leech body plan. The CNS expression patterns of two Antennapedia-class leech homeobox genes (Lox genes) were examined in detail. Lox1 is expressed during early gangliogenesis in only one pair of transient neurons present in every segment (the Bipolar cells) and, at later stages of embryonic development, in 15-20 pairs of central neurons repeated in most segments. The monoclonal antibody Laz1-1 identified two pairs of Lox1-expressing neurons as the Bipolar cells and the L1 neurons. The Bipolar cells extended processes in the primordia of the longitudinal connective nerves and later degenerated. The L1 neurons were detected late in gangliogenesis and became stable neurons. Lox2 is expressed in an iterated set of neurons in the posterior two-thirds of the CNS. On the basis of cell body position and relative size, two pairs of Lox2-expressing cells were identified as the RPE-like neurons and the CV motor neurons. Other Lox genes are also expressed in segmentally repeated subpopulations of neurons. These neuronal subpopulations appear to be different from one another but partially overlapping. Different combinations of Lox genes that may be expressed in individual cells could in theory generate enough variability to specify all central neurons in a leech ganglion.

Blood monocyte function was tested in 43 untreated patients with carcinoma of the cervix (stages Ib to IIIb) and 50 age-matched controls. Monocyte counts, adhesion to glass, spreading on glass, phagocytosis and killing of Candida albicans, and chemotaxis under agarose were not significantly different between the patient and control groups. In 65% of a further series of 17 patient/control pairs, the plasma of cervical carcinoma patients was shown to contain a cell-directed inhibitor of monocyte chemotaxis. The accumulated evidence indicates that production of such factors by malignant tumors is an important mechanism in counteracting mononuclear phagocyte defense.