Lowering mortality risk in CR-HvKP infection in intestinal immunohistological and microbiota restoration.

Gut damage during carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-HvKP) infection is associated with a death risk. Understanding the mechanisms by which CR-HvKP causes intestinal damage and gut microbiota alteration, and the impact on immunity, is crucial for developing therapeutic strategies. This study investigated if gastrointestinal tract damage and disruption of gut microbiota induced by CR-HvKP infection undermined host immunity and facilitated multi-organ invasion of CR-HvKP; whether the therapeutic value of the rifampicin (RIF) and zidovudine (ZDV) combination was attributed to their ability to repair damages and restore host immunity was determined. A sepsis model was utilized to assess the intestinal pathological changes. Metagenomic analysis was performed to characterize the alteration of gut microbiota. The effects of the RIF and ZDV on suppressing inflammatory responses and improving immune functions and gut microbiota were evaluated by immunopathological and transcriptomic analyses. Rapid colonic damage occurred upon activation of the inflammation signaling pathways during lethal infections. Gut inflammation compromised host innate immunity and led to a significant decrease in probiotics abundance, including Bifidobacterium and Lactobacillus. Treatment with combination drugs significantly attenuated the inflammatory response, up-regulated immune cell differentiation signaling pathways, and promoted the abundance of Bifidobacterium (33.40 %). Consistently, supplementation of Bifidobacterium alone delayed the death in sepsis model. Gut inflammation and disrupted microbiota are key disease features of CR-HvKP infection but can be reversed by the RIF and ZDV drug combination. The finding that these drugs can restore host immunity through multiple mechanisms is novel and deserves further investigation of their clinical application potential.

Rural-Urban Differences in Vaccination and Hesitancy Rates and Trust: US COVID-19 Trends and Impact Survey on a Social Media Platform, May 2021-April 2022.

Objectives. To analyze rural-urban differences in COVID-19 vaccination uptake, hesitancy, and trust in information sources in the United States. Methods. We used data from a large survey of Facebook users. We computed the vaccination, hesitancy, and decline rates and the trust proportions among individuals hesitant toward COVID-19 information sources for rural and urban regions in each state from May 2021 to April 2022. Results. In 48 states with adequate data, on average, two thirds of states showed statistically significant differences in monthly vaccination rates between rural and urban regions, with rural regions having a lower vaccination rate at all times. Far fewer states showed statistically significant differences when comparing monthly hesitancy and decline rates for urban versus rural regions. Doctors and health professionals received the highest level of trust. Friends and family were also among the most trusted sources in rural areas where the vaccination uptake was low. Conclusions. Rural-urban difference in hesitancy rates among those still unvaccinated was much smaller than the rural-urban difference in vaccination rates, suggesting that access to vaccines may be another contributor to the lower vaccination rates in rural areas. (Am J Public Health. 2023;113(6):680-688. https://doi.org/10.2105/AJPH.2023.307274).

A three-year multifaceted intervention to prevent obesity in children of Mexican-heritage.

BACKGROUND: Obesity and overweight have increased dramatically in the United States over the last decades. The complexity of interrelated causal factors that result in obesity needs to be addressed within the cultural dynamic of sub-populations. In this study, we sought to estimate the effects of a multifaceted, community-based intervention on body mass index (BMI) among Mexican-heritage children. METHODS: Niños Sanos, Familia Sana (Healthy Children, Healthy Family) was a quasi-experimental intervention study designed to reduce the rate of BMI growth among Mexican-heritage children in California's Central Valley. Two rural communities were matched based on demographic and environmental characteristics and were assigned as the intervention or comparison community. The three-year intervention included parent workshops on nutrition and physical activity; school-based nutrition lessons and enhanced physical education program for children; and a monthly voucher for fruits and vegetables. Eligible children were between 3 and 8 years old at baseline. Intent-to-treat analyses were estimated using linear mixed-effect models with random intercepts. We ran a series of models for each gender where predictors were fixed except interactions between age groups and obesity status at baseline with intervention to determine the magnitude of impact on BMI. RESULTS: At baseline, mean (SD) BMI z-score (zBMI) was 0.97 (0.98) in the intervention group (n = 387) and 0.98 (1.02) in the comparison group (n = 313) (NS). The intervention was significantly associated with log-transformed BMI (ß = 0.04 (0.02), P = 0.03) and zBMI (ß = 0.25 (0.12), P = 0.04) among boys and log-transformed BMI among obese girls (ß = - 0.04 (0.02), P = 0.04). The intervention was significantly and inversely associated with BMI in obese boys and girls across all age groups and normal weight boys in the oldest group (over 6 years) relative to their counterparts in the comparison community. CONCLUSIONS: A community-based, multifaceted intervention was effective at slowing the rate of BMI growth among Mexican-heritage children. Our findings suggest that practitioners should consider strategies that address gender disparities and work with a variety of stakeholders to target childhood obesity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01900613 . Registered 16th July 2013.

Modeling COVID-19 Mortality Across 44 Countries: Face Covering May Reduce Deaths.

INTRODUCTION: Despite ongoing efforts to vaccinate communities against COVID-19, the necessity of face mask use in controlling the pandemic remains subject to debate. Several studies have investigated face masks and COVID-19, covering smaller and less diverse populations than this study's sample. This study examines a hypothesized association of face-covering mandates with COVID-19 mortality decline across 44 countries in 2 continents. METHODS: In a retrospective cohort study, changes in COVID-19‒related daily mortality rate per million population from February 15 to May 31, 2020 were compared between 27 countries with and 17 countries without face mask mandates in nearly 1 billion (911,446,220 total) people. Longitudinal mixed effect modeling was applied and adjusted for over 10 relevant demographic, social, clinical, and time-dependent confounders. RESULTS: Average COVID-19 mortality per million was 288.54 in countries without face mask policies and 48.40 in countries with face mask policies. In no mask countries, adjusted average daily increase was 0.1553 - 0.0017 X (days since the first case) log deaths per million, compared with 0.0900 - 0.0009 X (days since the first case) log deaths per million in the countries with a mandate. A total of 60 days into the pandemic, countries without face mask mandates had an average daily increase of 0.0533 deaths per million, compared with the average daily increase of 0.0360 deaths per million for countries with face mask mandates. CONCLUSIONS: This study's significant results show that face mask mandates were associated with lower COVID-19 deaths rates than the rates in countries without mandates. These findings support the use of face masks to prevent excess COVID-19 deaths and should be advised during airborne disease epidemics.

Using hierarchical clustering analysis to evaluate COVID-19 pandemic preparedness and performance in 180 countries in 2020.

OBJECTIVE: To rank and score 180 countries according to COVID-19 cases and fatality in 2020 and compare the results to existing pandemic vulnerability prediction models and results generated by standard epidemiological scoring techniques. SETTING: One hundred and eighty countries' patients with COVID-19 and fatality data representing the healthcare system preparedness and performance in combating the pandemic in 2020. DESIGN: Using the retrospective daily COVID-19 data in 2020 broken into 24 half-month periods, we applied unsupervised machine learning techniques, in particular, hierarchical clustering analysis to cluster countries into five groups within each period according to their cumulative COVID-19 fatality per day over the year and cumulative COVID-19 cases per million population per day over the half-month period. We used the average of the period scores to assign countries' final scores for each measure. PRIMARY OUTCOME: The primary outcomes are the COVID-19 cases and fatality grades in 2020. RESULTS: The United Arab Emirates and the USA with F in COVID-19 cases, achieved A or B in the fatality scores. Belgium and Sweden ranked F in both scores. Although no African country ranked F for COVID-19 cases, several African countries such as Gambia and Liberia had F for fatality scores. More developing countries ranked D and F in fatality than in COVID-19 case rankings. The classic epidemiological measures such as averages and rates have a relatively good correlation with our methodology, but past predictions failed to forecast the COVID-19 countries' preparedness. CONCLUSION: COVID-19 fatality can be a good proxy for countries' resources and system's resilience in managing the pandemic. These findings suggest that countries' economic and sociopolitical factors may behave in a more complex way as were believed. To explore these complex epidemiological associations, models can benefit enormously by taking advantage of methods developed in computer science and machine learning.

Quantification of prostate and seminal vesicle interfraction variation during IMRT.

PURPOSE: To quantify the interfraction variability in prostate and seminal vesicle (SV) positions during a course of intensity-modulated radiotherapy (IMRT) using an integrated computed tomography (CT)-linear accelerator system and to assess the impact of rectal and bladder volume changes. METHODS AND MATERIALS: We studied 15 patients who had undergone IMRT for prostate carcinoma. Patients had one pretreatment planning CT scan followed by three in-room CT scans per week using a CT-on-rails system. The prostate, bladder, rectum, and pelvic bony anatomy were contoured in 369 CT scans. Using the planning CT scan as a reference, the volumetric and positional changes were analyzed in the subsequent CT scans. RESULTS: For all 15 patients, the mean systematic internal prostate and SV variation was 0.1 +/- 4.1 mm and 1.2 +/- 7.3 mm in the anteroposterior axis, -0.5 +/- 2.9 mm and -0.7 +/- 4.5 mm in the superoinferior axis, and 0.2 +/- 0.9 mm and -0.9 +/- 1.9 mm in the lateral axis, respectively. The mean magnitude of the three-dimensional displacement vector was 4.6 +/- 3.5 mm for the prostate and 7.6 +/- 4.7 mm for the SVs. The rectal and bladder volume changes during treatment correlated with the anterior and superior displacement of the prostate and SVs. CONCLUSION: The dominant prostate and SV variations occurred in the anteroposterior and superoinferior directions. The systematic prostate and SV variation between the treatment planning CT and daily therapy as a result of the rectal and bladder volume changes emphasizes the need for daily directed target localization and/or immobilization techniques.

Daily bone alignment with limited repeat CT correction rivals daily ultrasound alignment for prostate radiotherapy.

PURPOSE: To compare the effectiveness of daily ultrasound (US)- and computed tomography (CT)-guided alignments with an off-line correction protocol using daily bone alignment plus a correction factor for systematic internal prostate displacement (CF(ID)). METHODS AND MATERIALS: Ten prostate cancer patients underwent CT scans three times weekly using an integrated CT-linear accelerator system, followed by alignment using US for daily radiotherapy. Intensity-modulated radiotherapy plans were designed with our current clinical margins. The treatment plan was copied onto the repeat CT images and aligned using several methods: (1) bone alignment plus CF(ID) after three off-line CT scans (bone+3CT), (2) bone alignment plus CF(ID) after six off-line CT scans (bone+6CT), (3) US alignment, and (4) CT alignment. The accuracy of the repeated US and CT measurements to determine the CF(ID) was compared. The target dosimetric effect was quantified. RESULTS: The CF(ID) for internal systematic prostate displacements was more accurately measured with limited repeat CT scans than with US (residual error, 0.0 +/- 0.7 mm vs. 2.0 +/- 3.2 mm). Bone+3CT, bone+6CT, and US provided equivalent prostate and seminal vesicle dose coverage, but bone+3CT and bone+6CT produced more precise daily alignments. Daily CT alignment provided the greatest target dose coverage. CONCLUSION: Daily bone alignment plus CF(ID) for internal systematic prostate displacement provided better daily alignment precision and equivalent dose coverage compared with daily US alignment. The CF(ID) should be based on at least three repeat CT scans, which could be collected before the start of treatment or during the first 3 treatment days. Daily bone alignment plus CF(ID) provides another option for accurate prostate cancer patient positioning.

Changes in the pelvic anatomy after an IMRT treatment fraction of prostate cancer.

PURPOSE: To quantify the three-dimensional variations of pelvic anatomy after a single treatment fraction. METHODS AND MATERIALS: Forty-six prostate cancer patients underwent computed tomography (CT) scanning with an in-room CT-on-rail system, before and immediately after one intensity-modulated radiotherapy (IMRT) session. To study the soft-tissue anatomy changes, the pre- and post-treatment CT images were registered using the bony structure with an in-house image registration software system. The center of volume for both the prostate and seminal vesicles was used to assess the relative displacement of the same structure after the treatment fraction. RESULTS: During one treatment fraction (21 +/- 4 min), both the prostate and seminal vesicles showed statistically significant systematic trends in the superior and anterior directions of the patient's anatomy. The net increase in bladder volume was huge (127 +/- 79 cm(3)), yet this change did not translate into large target displacements. Although the population mean displacements in either direction were 1.3 +/- 2.9 mm for the prostate and 1.2 +/- 4.1 mm for the seminal vesicles in the anterior direction, a few patients had displacements as large as 8.4 mm and 15.6 mm, respectively. These large displacements correlated strongly (p < 0.001) with large rectal volume increases caused by gaseous build-up in the rectum. CONCLUSION: The observed intrafraction variations in anatomy during prostate IMRT sessions suggest that, for any given fraction, the organ motion and volume changes can potentially lead to compromised target coverage in about 15% of patients in whom the prostate position shifted >4 mm.

Is a 3-mm intrafractional margin sufficient for daily image-guided intensity-modulated radiation therapy of prostate cancer?

PURPOSE: To determine whether a 3-mm isotropic target margin adequately covers the prostate and seminal vesicles (SVs) during administration of an intensity-modulated radiation therapy (IMRT) treatment fraction, assuming that daily image-guided setup is performed just before each fraction. MATERIALS AND METHODS: In-room computed tomographic (CT) scans were acquired immediately before and after a daily treatment fraction in 46 patients with prostate cancer. An eight-field IMRT plan was designed using the pre-fraction CT with a 3-mm margin and subsequently recalculated on the post-fraction CT. For convenience of comparison, dose plans were scaled to full course of treatment (75.6 Gy). Dose coverage was assessed on the post-treatment CT image set. RESULTS: During one treatment fraction (21.4+/-5.5 min), there were reductions in the volumes of the prostate and SVs receiving the prescribed dose (median reduction 0.1% and 1.0%, respectively, p<0.001) and in the minimum dose to 0.1 cm(3) of their volumes (median reduction 0.5 and 1.5 Gy, p<0.001). Of the 46 patients, three patients' prostates and eight patients' SVs did not maintain dose coverage above 70 Gy. Rectal filling correlated with decreased percentage-volume of SV receiving 75.6, 70, and 60 Gy (p<0.02). CONCLUSIONS: The 3-mm intrafractional margin was adequate for prostate dose coverage. However, a significant subset of patients lost SV dose coverage. The rectal volume change significantly affected SV dose coverage. For advanced-stage prostate cancers, we recommend to use larger margins or improve organ immobilization (such as with a rectal balloon) to ensure SV coverage.

Using a priori structural information from magnetic resonance imaging to investigate the feasibility of prostate diffuse optical tomography and spectroscopy: a simulation study.

Implementation of diffuse optical tomography (DOT) for prostate cancer is challenging because the prostate is a deep-seated organ. We investigated whether diffuse optical tomography (DOT) and spectroscopy could be applied to monitor the physiology of prostate cancer using a small probe that could be placed endorectally. We manually segmented the prostate, the intraprostatic tumor, and the rectum using data from endorectal magnetic resonance imaging. These structures were reconstructed and meshed with tetrahedral finite elements in three dimensions. A 2 x 4 cm probe that has ten sources and 52 detectors were placed to face the anterior wall of the rectum in our simulation. Optical properties of the organs were obtained from the literature in the near infrared regime. Diffusion approximation was used to simulate photon migration with finite element method. Five wavelengths were used to simulate tissue absorption with realistic water, oxy- and deoxyhaemoglobin concentrations in the prostate. We combined a global search based on genetic algorithm with gradient-driven local search methods to fit the simulated data. Our results suggest that the optical properties and the concentrations of the chromophores of the prostate and the prostate cancer can be reliably recovered from the measurements using an endorectal probe. Prostate DOT is worth further investigation for clinical application.

First-year PSA kinetics and minima after prostate cancer radiotherapy are predictive of overall survival.

PURPOSE: We analyzed whether first-year prostate-specific antigen (PSA) kinetics and minima are predictive of overall survival (OS). METHODS AND MATERIALS: The data set contained 1,174 patients treated with external beam radiotherapy (RT) from 1987 to 2001. The relative rate of change (lambda) in post-RT PSA values during the first year (13.5 months) was computed using regression analysis of ln(PSA) vs. time. We also computed the PSA minimum (mPSA) reached during the same period. Recursive partitioning analysis was used to identify the relevant cutpoints for the factors being investigated for its association with survival: age, pretreatment PSA, radiation dose, relative rate of change in PSA post-RT, and 1-year PSA minimum. For each of the other factors stage, Gleason score and risk group, all possible cutpoints were considered in the multivariate analyses. Significant factors were considered in the multivariate analyses to identify independent predictors for overall survival. RESULTS: The median value of lambda was -1.0 years(-1) (range, -11.0-5.1 years(-1)). The 1-year minimum had a median of 0.8 ng/mL (range, 0.01-30.9 ng/mL). Recursive partitioning analysis and Cox proportional hazards analyses identified the following pretreatment or treatment factors adversely related to OS: age, Gleason score, stage, and dose. First-year mPSA > or = 4 ng/mL and lambda > 0 were post-RT independent prognostic factors for worse OS. CONCLUSION: First-year post-RT PSA kinetics and minima are early response parameters predictive of overall survival for prostate cancer patients. These factors may be useful in selecting patients for early salvage therapy.

Tumor-specific apoptotic gene targeting overcomes radiation resistance in esophageal adenocarcinoma.

PURPOSE: To overcome radiation resistance in esophageal adenocarcinoma by tumor-specific apoptotic gene targeting using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). METHODS AND MATERIALS: Adenoviral vector Ad/TRAIL-F/RGD with a tumor-specific human telomerase reverse transcription promoter was used to transfer TRAIL gene to human esophageal adenocarcinoma and normal human lung fibroblastic cells (NHLF). Activation of apoptosis was analyzed by Western blot, fluorescent activated cell sorting, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate labeling (TUNEL) assay. A human esophageal adenocarcinoma mouse model was treated with intratumoral injections of Ad/TRAIL-F/RGD plus local radiotherapy. RESULTS: The combination of Ad/TRAIL-F/RGD and radiotherapy increased the cell-killing effect in all esophageal adenocarcinoma cell lines but not in NHLF cells. This combination also significantly reduced clonogenic formation (p < 0.05) and increased sub-G1 deoxyribonucleic acid accumulation in cancer cells (p < 0.05). Activation of apoptosis by Ad/TRAIL-F/RGD plus radiotherapy was demonstrated by activation of caspase-9, caspase-8, and caspase-3 and cleaved poly (adenosine diphosphate-ribose) polymerase in vitro and TUNEL assay in vivo. Combined Ad/TRAIL-F/RGD and radiotherapy dramatically inhibited tumor growth and prolonged mean survival in the esophageal adenocarcinoma model to 31.6 days from 16.7 days for radiotherapy alone and 21.5 days for Ad/TRAIL-F/RGD alone (p < 0.05). CONCLUSIONS: The combination of tumor-specific TRAIL gene targeting and radiotherapy enhances the effect of suppressing esophageal adenocarcinoma growth and prolonging survival.

Dosimetric comparison of four target alignment methods for prostate cancer radiotherapy.

PURPOSE: The aim of this study was to compare the dosimetric consequences of 4 treatment delivery techniques for prostate cancer patients treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: During an 8-week course of radiotherapy, 10 patients underwent computed tomography (CT) scans 3 times per week (243 total) before daily treatment with a CT-linear accelerator. Treatment delivery was simulated by realigning a fixed-margin treatment plan on each CT scan and calculating doses. The alignment methods were those based on the following: skin marks, bony registration, ultrasonography (US), and in-room CT. For the last two methods, prostate was the alignment target. The dosimetric effects of these alignment methods on the prostate, seminal vesicles, rectum, and bladder were compared. The average daily minimum dose to 0.1 cm3 was used as the metric for target coverage. RESULTS: Skin and bone alignments provided acceptable prostate coverage for only 70% of patients, US alignment for 90%, and CT alignment for 100%. CT-based alignment of the prostate provided seminal vesicle (SV) coverage of > or = 69 Gy for all patients; US and bone alignments provided SV coverage of > or = 60 Gy. This SV coverage may be acceptable for early-stage cancer (equivalent SV dose = 55.8 Gy at 1.8 Gy per fraction), but unacceptable for late-stage cancer (SV dose = 75.6 Gy). At 75.6 Gy, the acceptable rate for SV coverage was 40% for skin and bone alignments, 70% for US, and 80% for CT. CONCLUSIONS: Direct target alignment methods (US and CT) provided better target coverage. CT-guided alignment provided the best and most consistent dosimetric coverage. A larger planning target volume margin is needed for SV coverage when the alignment target is the prostate.

Radiotherapy sensitization by tumor-specific TRAIL gene targeting improves survival of mice bearing human non-small cell lung cancer.

PURPOSE: To sensitize non-small cell lung cancer (NSCLC) to radiotherapy by tumor-specific delivery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. EXPERIMENTAL DESIGN: The TRAIL was delivered to human NSCLC cell lines and normal human bronchial epithelial cells by the replication-defective adenoviral vector Ad/TRAIL-F/RGD using a tumor-specific human telomerase reverse transcriptase promoter. Cancer growth was studied using 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt and clonogenic assays. Activation of the apoptosis pathway was analyzed in a Western blot and sub-G(1) DNA accumulation. A xenograft mouse lung cancer model was treated by intratumoral injections of Ad/TRAIL-F/RGD and local radiotherapy; the other groups received one of these treatments alone or a control agent. Apoptosis and TRAIL expression in tumors were also analyzed. RESULTS: Ad/TRAIL-F/RGD specifically targets human NSCLC cells without significant effect in normal human bronchial epithelial cells. The combination of Ad/TRAIL-F/RGD and radiotherapy significantly improved cell-killing effect in all NSCLC cell lines tested (P < 0.05). Expression of TRAIL showed a dose-dependent relationship with Ad/TRAIL-F/RGD, and radiation seemed to increase TRAIL expression. Activation of the apoptosis by TRAIL and radiation was shown by activation of caspase-9, caspase-8, caspase-3, and poly(ADP-ribose) polymerase and increased DNA sub-G(1) accumulation. The combination of TRAIL and radiotherapy significantly increased apoptosis in vivo, inhibited tumor growth, and prolonged mean survival in mice bearing human NSCLC to 43.7 days compared with 23.7 days (TRAIL only) and 16.5 days (radiotherapy only; P < 0.05). CONCLUSIONS: The combination of Ad/TRAIL-F/RGD and radiotherapy significantly improved therapeutic efficacy in suppressing NSCLC tumor growth and prolonging survival. Ad/TRAIL-F/RGD may improve the therapeutic ratio of radiotherapy in NSCLC.

Analysis of SEER Adenosquamous Carcinoma Data to Identify Cause Specific Survival Predictors and Socioeconomic Disparities.

BACKGROUND: This study used receiver operating characteristic curve to analyze Surveillance, Epidemiology and End Results (SEER) adenosquamous carcinoma data to identify predictive models and potential disparities in outcome. MATERIALS AND METHODS: This study analyzed socio-economic, staging and treatment factors available in the SEER database for adenosquamous carcinoma. For the risk modeling, each factor was fitted by a generalized linear model to predict the cause specific survival. An area under the receiver operating characteristic curve (ROC) was computed. Similar strata were combined to construct the most parsimonious models. RESULTS: A total of 20,712 patients diagnosed from 1973 to 2009 were included in this study. The mean follow up time (S.D.) was 54.2 (78.4) months. Some 2/3 of the patients were female. The mean (S.D.) age was 63 (13.8) years. SEER stage was the most predictive factor of outcome (ROC area of 0.71). 13.9% of the patients were un-staged and had risk of cause specific death of 61.3% that was higher than the 45.3% risk for the regional disease and lower than the 70.3% for metastatic disease. Sex, site, radiotherapy, and surgery had ROC areas of about 0.55-0.65. Rural residence and race contributed to socioeconomic disparity for treatment outcome. Radiotherapy was underused even with localized and regional stages when the intent was curative. This under use was most pronounced in older patients. CONCLUSIONS: Anatomic stage was predictive and useful in treatment selection. Under-staging may have contributed to poor outcome.

Analysis of SEER Glassy Cell Carcinoma Data: Underuse of Radiotherapy and Predicators of Cause Specific Survival.

BACKGROUND: This study used receiver operating characteristic curve to analyze Surveillance, Epidemiology and End Results (SEER) for glassy cell carcinoma data to identify predictive models and potential disparities in outcome. MATERIALS AND METHODS: This study analyzed socio-economic, staging and treatment factors. For risk modeling, each factor was fitted by a generalized linear model to predict the cause specific survival. Area under the receiver operating characteristic curves (ROCs) were computed. Similar strata were combined to construct the most parsimonious models. A random sampling algorithm was used to estimate modeling errors. Risk of glassy cell carcinoma death was computed for the predictors for comparison. RESULTS: There were 79 patients included in this study. The mean follow up time (S.D.) was 37 (32.8) months. Female patients outnumbered males 4:1. The mean (S.D.) age was 54.4 (19.8) years. SEER stage was the most predictive factor of outcome (ROC area of 0.69). The risks of cause specific death were, respectively, 9.4% for localized, 16.7% for regional, 35% for the un-staged/others category, and 60% for distant disease. After optimization, separation between the regional and unstaged/others category was removed with a higher ROC area of 0.72. Several socio-economic factors had small but measurable effects on outcome. Radiotherapy had not been used in 90% of patients with regional disease. CONCLUSIONS: Optimized SEER stage was predictive and useful in treatment selection. Underuse of radiotherapy may have contributed to poor outcome.

Ultrasound-based localization.

Ultrasound is a noninvasive, relatively easy, rapid, and real-time imaging technique for organ targeting for radiotherapy. Its application has been developed to a greater extent in prostate cancer than in other sites in which it has been shown to improve the accuracy of daily treatment delivery. With the move toward dose escalation and the need to maximally spare the adjacent critical structures through more conformal therapy and smaller field margins, an innovative technique for accurate and reproducible tumor targeting is mandatory. Basic ultrasound principles and organ location lend themselves well to the application of this modality in prostate cancer. Promising results using daily ultrasound-guided B-mode acquisition and targeting for patients with upper abdominal tumors suggest an area for additional trials and study. For breast cancer radiotherapy, ultrasound serves to define involved primary and nodal sites, especially in patients in whom surgical evaluation will not be the first therapeutic step.

Prostate-specific antigen doubling time predicts clinical outcome and survival in prostate cancer patients treated with combined radiation and hormone therapy.

PURPOSE: To determine whether prostate-specific antigen (PSA) doubling time predicts clinical outcomes in patients with prostate cancer that has been treated with combined radiation and hormone therapy. METHODS AND MATERIALS: We reviewed the medical records of 621 men with nonmetastatic prostate cancer treated with radiation therapy and hormone therapy between 1989 and 2003. "Any" clinical failure was defined as any distant, nodal, or local failure, or the use of salvage therapy. "True" clinical failure was defined as any distant, nodal, or local failure. PSA doubling time was calculated by using the log PSA values from patients with a PSA failure as defined by the American Society of Therapeutic Radiology Oncology consensus statement. One hundred thirty-seven men were at intermediate risk for PSA failure (as determined by T2b, Gleason score of 7, or PSA 10.1-0 ng/mL) and 484 men were at high risk for failure (T2c-4; Gleason 8-10; or PSA >20 ng/mL). Pretreatment PSA value, Gleason score, tumor stage, timing and duration of hormone therapy, radiation therapy dose, and PSA doubling time were analyzed for any associations with time to clinical failure by using Cox regression analysis. Estimates of survival were calculated by using the Kaplan-Meier method. Pairwise comparisons were made by using the log-rank test. RESULTS: Sixty-two men experienced any clinical failure, and 22 men experienced true clinical failure. Multivariate analysis revealed that pretreatment PSA (p = 0.013), Gleason score (p = 0.0019), and a PSA doubling time (PSADT) < or =8 months (p < 0.001) were independently associated with time to any clinical failure. Tumor stage, hormone therapy timing, hormone therapy duration, and radiation therapy dose were not statistically significant on multivariate or univariate analysis. Only hormone therapy duration (p = 0.008) and PSADT < or =8 months (<0.001) were significantly associated with time to true clinical failure. The estimated 5-year rate of any clinical failure was 9.4% for men with a PSADT >8 months and 60.4% for men with a PSA doubling time < or =8 months (p < 0.001). The estimated 5-year rate of true clinical failure was 6.5% for men with a PSADT >8 months and 68.5% for men with a PSADT < or =8 months (p < 0.001). Lower radiation dose was the only significant predictor of PSADT < or =8 months on multivariate regression analysis. The estimated 6-year overall survival rate after PSA failure was 79.1% for men with a PSADT >8 months and 29.7% for men with a PSADT < or =8 months. The median overall survival time for patients with a PSADT >8 months was not reached in this study. The median overall survival time for patients with a PSADT < or =8 months was 61.8 months (p = 0.015). CONCLUSION: In men with prostate cancer that has been treated with combined hormone and radiation therapy, a posttreatment PSADT of < or =8 months is associated with worse clinical outcomes and may be an early surrogate marker for decreased survival. These patients should be considered for more aggressive salvage therapy protocols.

Assessing the impact of an alternative biochemical failure definition on radiation dose response for high-risk prostate cancer treated with external beam radiotherapy.

PURPOSE: The American Society for Therapeutic Radiology and Oncology (ASTRO) biochemical failure definition has recently been compared with various alternative definitions. We assessed the effect of using an alternative failure definition on the dose-response characteristics of high-risk prostate cancer treated with radiotherapy alone. METHODS AND MATERIALS: This study included 363 high-risk prostate cancer patients treated with external beam radiotherapy alone from 1987 to 1999. These patients have one or more of the following: 1992 American Joint Committee on Cancer (AJCC) digital rectal examination (DRE) stage > or = cT3, prostate-specific antigen (PSA) > 20 ng/mL, and/or biopsy Gleason score > or = 8. We previously reported the dose response based on the ASTRO definition for these patients. In this study, a biochemical failure is defined as a PSA rise > or = 2 ng/mL above the current nadir PSA (CN + 2). The failure date is defined as the time at which the event occurred (i.e., the call date). RESULTS: Using CN + 2, the tumor control probability (TCP) continues to decrease with time as opposed to reaching a plateau as with the ASTRO definition. At 5 years, TCD50 (95% CI), the dose to achieve 50% tumor control, for high-risk prostate cancer, is 70.4 (68.0-72.9) Gy using CN + 2 [ASTRO: 75.5 (70.7-80.2) Gy]. The relative slope, gamma50 (95% CI) is 1.8 (0.8-2.8) [ASTRO: 1.7 (0.7-2.7)]. Recursive partitioning again identified two subgroups: PSA < vs. > or = 13 ng/mL (ASTRO: PSA < or = vs. > 20 ng/mL). The difference in TCD50 between the two subgroups is about 20 Gy at 5 years (ASTRO: about 15 Gy at 5 years). CONCLUSION: This analysis using the CN + 2 failure definition continues to show a dose response for the high-risk group of patients. However, the dose-response characteristics differ from those estimated using the ASTRO definition. We observed that the position (TCD50) and steepness (gamma50) of the dose-response curve changed with time as long as the TCP continued to decrease. This suggests that the dose response characteristics derived from data with longer follow-up may be different from those derived with shorter follow-up using the CN + 2 or similar failure definitions which do not back-date the failure. These changes in dose-response characteristics as well as the time dependence of dose response should be noted when investigators design dose escalation trials for the high-risk prostate cancer patients.

Implementation and validation of a three-dimensional deformable registration algorithm for targeted prostate cancer radiotherapy.

PURPOSE: Daily prostate deformation hinders accurate calculation of dose, especially to intraprostatic targets. We implemented a three-dimensional deformable registration algorithm to aid dose tracking for targeted prostate radiotherapy. METHODS AND MATERIALS: The algorithm registers two computed tomography (CT) scans by iteratively minimizing their differences in image intensity. For validation, we measured the accuracy in registering (a) a pelvic CT set to its mathematically deformed counterpart, (b) CT scans of a deformable pelvic phantom with and without an endorectal balloon inflated, to simulate intraprostatic targets, 23 CT-opaque seeds were embedded in the prostate, and (c) two pelvic CT scans of a patient obtained on 2 separate days. RESULTS: The mean (SD) error in registering the pelvic CT set to its transformed set was 0.5 mm (1.5), with correlation coefficient improvement from 0.626 to 0.991. Using the deformable pelvic phantom, the correlation coefficient improved from 0.543 to 0.816 after registration. The mean (SD) error in tracking the intraprostatic seeds was 0.8 mm (0.5). The correlation coefficient improved from 0.610 to 0.944 after registration of the two patient CT sets. CONCLUSION: The algorithm had an accuracy of about 1 mm. It could be used for optimizing dose calculation and delivery for prostate radiotherapy.