A Phase 1b Clinical Study of Intravesical Photodynamic Therapy in Patients with Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer.

Background: A phase 1b study of photosensitizer TLD-1433-mediated photodynamic therapy (PDT) was performed in bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. Objective: The primary objectives were safety and tolerability of PDT, with secondary objectives of (1) pharmacokinetic (PK) properties of TLD-1433 and (2) efficacy, as evaluated by recurrence-free survival and complete response (CR) at 90 and 180 d for patients treated at the maximum recommended starting dose (0.35 mg/cm2 bladder surface area) and the therapeutic dose (0.70 mg/cm2). Design setting and participants: Six BCG-unresponsive patients were enrolled in an open-label, single-arm, dose-escalating study of PDT. TLD-1433 was instilled intravesically for 60 min preoperatively. PDT was performed under general anesthesia using intravesically delivered irradiation of the bladder wall with green light (520 nm) to a dose of 90 J/cm2. Outcome measurements and statistical analysis: Patients were followed by standard cystoscopy and cytology for up to 18 mo to assess time to recurrence. Results and limitations: PDT was well tolerated by all patients. All patients experienced at least one grade ≤2 adverse event (AE). There were no patient deaths or light sensitivity reactions. The most common AE was moderate bladder irritability, which resolved within the first weeks after treatment. AEs were independent of the TLD-1433 dose. TLD-1433 was cleared in the urine and from the plasma within 24 and 72 h, respectively. Of three patients treated at the therapeutic dose, two achieved a CR at 180 d, which was durable at 18 mo. The other patient was diagnosed with metastatic disease at 138 d. Conclusions: PDT with TLD-1433 appears safe for the treatment of BCG-unresponsive NMIBC. Early efficacy signals from full-dose photosensitizer are encouraging and warrant phase 2 trial investigation. The safety and PK results obtained support the potential for administration of consecutive PDT treatments as required. Patient summary: Photodynamic therapy with TLD-1433 appears to be safe and effective for the treatment of bacillus Calmette-Guérin (BCG)-unresponsive bladder cancer.

The Relationship Between Preoperative Physical Activity With American Society of Anesthesiologists Score and Postoperative Length of Stay in Patients Undergoing Radical Prostatectomy.

BACKGROUND: The relationship between preoperative physical activity (PA) and hospital length of stay (LOS) following radical prostatectomy (RP) is poorly understood. In addition, the relationship between PA and the American Society of Anesthesiologists Physical Status score (ASA PS), an established prognosticator of surgical risk, has not been studied. The authors assessed the relationship between leisure-time PA (LTPA), ASA PS, and LOS in individuals undergoing RP. METHODS: This retrospective cohort study was conducted using data from an institutional database. Ordinal logistic regression was used to assess the relationship between preoperative LTPA and physical status as indicated by the ASA PS. Binary logistic regression was used to assess the relationship between preoperative LTPA and LOS. RESULTS: A sample of 1064 participants were included in the analyses. The participants in the highest preoperative LTPA quartile had 45% reduced odds (P = .015) of a worse ASA PS classification compared with participants in the lowest quartile. The participants engaging in vigorous LTPA preoperatively had 35% lower odds (P = .014) of a >2-day LOS following RP compared with participants who were not engaging in preoperative vigorous LTPA. CONCLUSIONS: Our findings suggest that total and vigorous preoperative LTPA is associated with improved preoperative American Society of Anesthesiologists scores and LOS following RP, respectively.

Benefit of a more extended pelvic lymph node dissection among patients undergoing radical prostatectomy for localized prostate cancer: A causal mediation analysis.

BACKGROUND: The therapeutic role of extended (ePLND) versus nonextended pelvic lymph node dissection (nePLND) to remove occult micrometastases in men undergoing radical prostatectomy for localized prostate cancer (PC) is conflicting. Therefore, our aim was to quantify the direct effect of ePLND versus nePLND (removal of occult micrometastases), which is not mediated through the detection of nodal disease and potential adjuvant therapy (indirect effect). METHODS: Retrospective, bi-center cohort study of consecutive patients undergoing radical prostatectomy and PLND for PC (January 2006 and December 2016). Patients were followed until April 2018 for the occurrence of either biochemical recurrence or secondary therapy (composite outcome). ePLND was compared to nePLND by unweighted and weighted survival analysis (total effect) as well as by causal mediation analysis (direct and indirect effect). RESULTS: Positive nodal disease was detected in 71 (7%) out of 1008 patients undergoing radical prostatectomy and PLND for PC (ePLND: 368 [36.5%]; nePLND: 640 [63.5%]). Survival analysis demonstrated results in favor of ePLND (unweighted hazard ratio: 0.77 [95% confidence interval: 0.59-1.01], p = .056; weighted hazard ratio: 0.75 [0.56-0.99], p = .044). The causal mediation analysis confirmed the total effect of 0.77 (0.71-0.82). After disentangling this total effect into an indirect effect (via detection of nodal disease and potential adjuvant therapy) and a direct effect (via removal of occult micrometastases), we identified an even more protective direct effect of 0.69 (0.63-0.75). CONCLUSIONS: Our results not only indicate the utility of ePLND but also that its impact is not restricted to a staging benefit and probably involves a therapeutic benefit mediated through the removal of occult micrometastases.

Minimal required PDT light dosimetry for nonmuscle invasive bladder cancer (Erratum).

The erratum corrects a misspelled author surname.

Associations between self-reported physical activity, quality of life, and emotional well-being in men with prostate cancer on active surveillance.

OBJECTIVE: The relationship between physical activity (PA) and quality of life (QOL) relative to active treatment for prostate cancer (PCa) has been well-studied; however, little is known about this relationship during active surveillance (AS). Moreover, whether PA is associated with better emotional well-being (EWB) in men with low-risk PCa requires further investigation. Accordingly, we examined the association between self-reported PA and the average change in QOL and EWB over time during AS. METHODS: A total of 630 men on AS were included in this retrospective, longitudinal study from AS initiation until AS discontinuation. Generalized estimated equations were used to determine the association between self-reported PA (independent variable) and QOL and EWB (dependent variables) over time, adjusting for participants' age. RESULTS: QOL was higher over time in active ( ß^ (95%CI) = 1.14 (0.11, 2.16), P = .029) and highly active participants ( ß^ (95%CI) = 1.62 (0.58, 2.67), P = .002) compared to their inactive counterparts. Highly active participants had 55% greater odds of experiencing high EWB relative to inactive participants (OR (95%CI) = 1.55 (1.11, 2.16), P = .010). In men with low EWB at baseline (median = 3 months after diagnosis), the highest levels of PA (>1000 metabolic equivalent-minutes per week) were associated with high EWB over time (OR (95%CI) = 2.17 (1.06, 4.46), P = .034). CONCLUSIONS: These data further support the importance of PA as a supportive care strategy for men on AS. Our findings suggest that engaging in higher volumes of PA post-diagnosis may be beneficial particularly for men exhibiting low emotional well-being early on during AS.

Influence of physical activity on active surveillance discontinuation in men with low-risk prostate cancer.

PURPOSE: Epidemiologic data suggest that high levels of physical activity (PA) may reduce the risk of disease progression in men with prostate cancer (PCa), but it is unknown whether PA can delay the requirement for definitive treatment for those on active surveillance (AS). We investigated the influence of PA post-diagnosis on AS discontinuation in men with low-risk disease. METHODS: The effect of PA on the time to AS discontinuation was assessed in 421 patients, of whom 107 underwent additional PCa treatment over a median of 2.5 years. RESULTS: Using Cox regression models, we found that PA was not significantly associated with time to curative treatment initiation. Prostate-specific antigen (PSA) most proximal to AS initiation (HR, 1.11; 95% CI 1.03 to 1.21) and the number of positive cores (HR, 1.34; 95% CI 1.12 to 1.61) at diagnosis were associated with a significantly increased risk of discontinuing AS. CONCLUSION: Our findings suggest that PA during AS for PCa does not significantly influence time to curative treatment.

International Multicenter Validation of an Intermediate Risk Subclassification of Prostate Cancer Managed with Radical Treatment without Hormone Therapy.

PURPOSE: The NCCN Guidelines® recently endorsed a subclassification of intermediate risk prostate cancer into favorable and unfavorable subgroups. However, this subclassification was developed in a treatment heterogeneous cohort. Thus, to our knowledge the natural history of androgen deprivation treatment naïve favorable and unfavorable intermediate risk prostate cancer cases remains unknown. MATERIALS AND METHODS: Groups at 3 academic centers pooled data on patients with intermediate risk prostate cancer treated with radical monotherapy (dose escalated external beam radiotherapy, brachytherapy or radical prostatectomy) without combined androgen deprivation treatment. We used the cumulative incidence with competing risk analysis to estimate biochemical recurrence, distant metastasis and prostate cancer specific mortality. RESULTS: A total of 2,550 men at intermediate risk were included in study, of whom 1,063 and 1,487 were at favorable and unfavorable risk, respectively. Of the men 1,149 underwent radical prostatectomy, 1,143 underwent dose escalated external beam radiotherapy and 258 underwent brachytherapy. Median followup after the different treatments ranged from 60.4 to 107.4 months. The 10-year cumulative incidence of distant metastasis in the favorable vs unfavorable risk groups was 0.2% (95% CI 0.2-0.2) vs 11.6% (95% CI 7.7-15.5) for radical prostatectomy (p <0.001), 2.8% (95% CI 0.8-4.8) vs 13.5% (95% CI 9.6-17.4) for dose escalated external beam radiotherapy (p <0.001) and 3.5% (95% CI 0-7.4) vs 10.2% (95% CI 4.3-16.1) for brachytherapy (p = 0.063). The 10-year rate of prostate cancer specific mortality in the favorable vs unfavorable risk groups was 0% (95% CI 0-0) vs 3.7% (95% CI 1.7-5.7) for radical prostatectomy (p = 0.016), 0.5% (95% CI 0.5-0.5) vs 5.6% (95% CI 3.6-7.6) for dose escalated external beam radiotherapy (p = 0.015) and 0% (95% CI 0-0) vs 2.5% (95% CI 0.5-4.5) for brachytherapy (p = 0.028). CONCLUSIONS: This multicenter international effort independently validates the prognostic value of the intermediate risk prostate cancer subclassification in androgen deprivation treatment naïve cases across all radical treatment modalities. It is unlikely that treatment intensification would meaningfully improve oncologic outcomes in men at favorable intermediate risk.

Evaluation of an Aggressive Prostate Biopsy Strategy in Men Younger than 50 Years.

PURPOSE: Longitudinal cohort studies and guidelines demonstrate that prostate specific antigen 1 ng/ml or greater in younger patients confers an increased risk of delayed prostate cancer death. At our institution we have used an aggressive biopsy strategy in younger patients with prostate specific antigen 1 ng/ml or greater. Our objective was to determine the proportion of detected cancer and specifically clinically significant cancer by this strategy. MATERIALS AND METHODS: The prostate biopsy database at Princess Margaret Cancer Centre was queried for patients younger than 50 years who underwent a first prostate biopsy between 2000 and 2016. We included only patients who underwent prostate biopsy due to prostate specific antigen 1 ng/ml or greater and those with a suspicious digital rectal examination, a positive family history or a suspicious lesion on transrectal ultrasound. All clinical and pathological parameters were analyzed. Patients were stratified according to specific prostate specific antigen values. Multivariable logistic regression was performed to ascertain predictors of any prostate cancer diagnosis and of clinically significant prostate cancer. RESULTS: Of the 199 patients who met study inclusion criteria 37 (19%) were diagnosed with prostate cancer and 8 (22%) had a Gleason score of 7 or greater. Of those diagnosed with prostate cancer 25 (68%) had prostate specific antigen 1.5 ng/ml or greater and all men with a Gleason score of 7 or greater had prostate specific antigen 1.5 ng/ml or greater. Notably 19 patients (51%) had prostate cancer exceeding the Epstein criteria for active surveillance. Factors predicting prostate cancer included a positive family history, rising prostate specific antigen and lower prostate volume. CONCLUSIONS: Our results justify adopting an aggressive prostate biopsy strategy in men younger than 50 years with prostate specific antigen 1.5 ng/ml or greater while patients with prostate specific antigen less than 1.5 ng/ml are unlikely to have significant cancer. Special attention should be given to patients with a smaller prostate and a positive family history.

Variant Histology and Clinicopathological Features of Prostate Cancer in Men Younger than 50 Years Treated with Radical Prostatectomy.

PURPOSE: While prostate cancer is primarily a disease of older men, young age prostate cancer represents an important clinical subgroup which has not been adequately studied. We evaluated the histopathological features and associated clinical behavior of prostate cancer in a cohort of younger men treated with radical prostatectomy. MATERIALS AND METHODS: The study included 171 men younger than 50 years with prostate cancer who were treated with radical prostatectomy at an academic institution between 2001 and 2015. Comprehensive pathology review was performed. Clinical and followup data were obtained from a prospectively maintained institutional database. RESULTS: Median age was 43 years (range 38 to 49). Of the tumors 42% were Gleason score 3 + 3 and 45% were 3 + 4 while Gleason score 4 + 3, 4 + 4 and 4 + 5 disease comprised 10.5%, 0.5% and 1% of cases, respectively. Mucinous carcinoma (greater than 25% extracellular mucin), an uncommon histological variant which comprises 0.2% of prostate cancers, was noted in 11 of our cases (6%). A further 21 cases (12%) of acinar adenocarcinoma had a less than 25% mucinous component. Followup data were available on 156 men (91%). Biochemical recurrence developed in 12 patients (19%) but there was no documented postoperative metastasis or death from disease in the cohort. All cases of mucinous carcinoma were associated with favorable clinicopathological characteristics. CONCLUSIONS: Our findings provide additional evidence that younger men with prostate cancer who are treated with radical prostatectomy mostly have favorable disease characteristics and outcomes. While the histopathological features in our series were generally comparable to those of older onset carcinoma, our cohort was enriched for tumors with a mucinous phenotype. Correlation with molecular-genetic analysis in this subset of tumors may be valuable.

Influence of Metabolic Syndrome on Prostate Cancer Stage, Grade, and Overall Recurrence Risk in Men Undergoing Radical Prostatectomy.

OBJECTIVE: Metabolic syndrome (MetS) is associated with an increased risk of finding prostate cancer overall and high-grade disease on biopsy. This study sought to determine if MetS is associated with adverse final pathology and risk of overall recurrence in men undergoing radical prostatectomy (RP). METHODS: Men undergoing RP (2004-2013) were identified using our prospectively maintained institutional database. MetS was defined by ≥3 of 5 components (obesity, dysglycemia, hypertension, low high-density lipoprotein-cholesterol, and high triglycerides). Multivariable logistic regression models were created for prostate cancer grade and stage on final pathology. Kaplan-Meier and multivariable Cox regression analyses were performed to model overall recurrence, defined by biochemical recurrence (postoperative serum prostate-specific antigen ≥0.2 ng/mL) or use of salvage therapies. RESULTS: Of 1939 men, 439 (22.6%) had MetS. MetS (≥3 vs. 0 components) was associated with an increased odds of Gleason 8-10 disease (odds ratio [OR] = 2.49, 95% confidence interval [CI] = 1.32-4.67, P = .005) and extraprostatic disease (OR = 1.35, 95% CI = 1.02-1.80, P = .04). Decreased use of nerve-sparing in men with MetS was noted. In unadjusted analyses, MetS was associated with a significantly increased risk of receiving salvage therapy (hazard ratio [HR] = 1.38, 95% CI = 1.04-1.83, P = .03) and a near-significant increased overall recurrence risk (HR = 1.20, 95% CI = 0.94-1.53, P = .15). These associations were attenuated upon adjusting for disease-specific parameters (salvage therapy: HR = 1.03, 95% CI = 0.76-1.40, P = .87; overall recurrence: HR = 0.94, 95% CI = 0.72-1.21, P = .62). CONCLUSION: MetS is associated with an increased odds of extraprostatic and high-grade disease on final RP pathology, which appears to drive an increased risk of needing salvage therapy after RP. However, with more aggressive resection, differences in failure-free outcomes were attenuated, suggesting that men with MetS should not be precluded from RP.

Health-related quality of life in robotic versus open radical prostatectomy.

INTRODUCTION: It is unclear whether health-related quality of life (HRQoL) outcomes are superior in robot-assisted radical prostatectomy (RARP) compared to open prostatectomy (ORP). METHODS: We retrospectively analyzed records from men who received ORP or RARP at our institution between January 2009 and December 2012. Patients completed a demographics questionnaire and the Patient-Oriented Prostate Utility Scale (PORPUS), a validated disease-specific HRQoL instrument prior to surgery and every 3 months up to 15 months after surgery. RESULTS: In total, 974 men met the inclusion criteria (643 ORP and 331 RARP patients). At baseline, RARP patients were significantly younger (p < 0.001), had lower body mass index (BMI) (p < 0.001), lower preoperative prostate-specific antigen (PSA) (p < 0.001), fewer comorbidities (p < 0.004), and higher baseline PORPUS scores (p = 0.024). On follow-up, unadjusted PORPUS scores were significantly higher in the RARP group at each point. On multivariable analysis adjusting for age, ORP versus RARP procedure, Gleason score, BMI, first PSA, comorbidity, ethnicity, and baseline PORPUS scores, PORPUS score was higher for the RARP group at 3 months (p = 0.038) and 9 months (p = 0.037), but not at 6, 12, and 15 months (p = 0.014). No difference met pre-defined thresholds of clinical significant. CONCLUSIONS: Though unadjusted HRQoL outcomes appeared improved with RARP compared to ORP differences, adjusted differences were seen at only 2 of 5 postoperative time points, and did not meet pre-defined thresholds of clinical significance. Further randomized trials are needed to assess whether one treatment option provides consistently better HRQoL outcomes.

An observational study assessing completion time and accuracy of completing the tactical combat casualty care card by combat medic trainees.

INTRODUCTION: Prehospital care documentation is crucial to improving battlefield care outcomes. Developed by United States Army Ranger Special Operations Combat Medics (SOCMs), the Tactical Combat Casualty Care (TCCC) is currently fielded to deployed units to record prehospital injury data. This study documents length of time and accuracy of U.S. Army Combat Medic trainees in completing the minimum preestablished required fields on the TCCC card, establishing a baseline for point-of-injury cards. DESIGN AND METHODS: This was a prospective observational study in which U.S. Army combat medic trainees were timed while recording data on the TCCC card in both the classroom and simulated combat environment. We hypothesized that trainees could complete the TCCC card in less than 1 minute with 90% or greater accuracy. RESULTS: We enrolled 728 U.S. Army Combat Medic trainees in the study during May?June 2011 at Fort Sam Houston, TX. We observed an average TCCC card completion time of less than 1 minute with greater than 90% accuracy in the unstressed classroom environment but an increase to nearly 2 minutes on average and a decrease to 85% accuracy in the simulated combat environment. CONCLUSION: RESULTS imply that the TCCC card is well designed to quickly and accurately record prehospital combat injury information. Further investigation and future studies may compare other prehospital data collection methods with the TCCC card in terms of timely and accurate data collection.

Genomic organization and evolution of the trace amine-associated receptor (TAAR) repertoire in Atlantic salmon (Salmo salar).

There is strong evidence that olfaction plays a key role in the homing of salmonids to their natal spawning grounds, particularly in the freshwater phase. However, the physiological and genetic mechanisms behind this biological phenomenon are largely unknown. It has been shown that Pacific salmon respond to dissolved free amino acids from their natal streams. This indicates that amino acids comprise part of the olfcatory cues for imprinting and homing in salmonids. As trace amine-associated receptors (TAARs), a class of olfactory receptors that are close relatives of the G protein-coupled aminergic neurotransmitter receptors, recognize amino acid metabolites, we hypothesize that TAARs play an important role in salmon homing by recognizing olfactory cues. Therefore, to better understand homing in Atlantic salmon, we set out to characterize the TAAR genes in this species. We searched the first assembly of the Atlantic salmon genome for sequences resembling TAARs previously characterized in other teleosts. We identified 27 putatively functional TAAR genes and 25 putative TAAR pseudogenes, which cluster primarily on chromosome 21 (Ssa21). Phylogenetic analysis of TAAR amino acid sequences from 15 vertebrate species revealed the TAAR gene family arose after the divergence of jawed and jawless vertebrates. The TAARs group into three classes with salmon possessing class I and class III TAARs. Within each class, evolution is characterized by species-specific gene expansions, which is in contrast to what is observed in other olfactory receptor families (e.g., OlfCs and oras).

Concordance between transrectal ultrasound guided biopsy results and radical prostatectomy final pathology: Are we getting better at predicting final pathology?

INTRODUCTION: Inaccuracy in biopsy Gleason scoring poses a risk to men who may then receive inappropriate treatment. We assess whether there was a change in discordance rates between biopsy and radical prostatectomy at our institution in recent years, while considering the implementation of active surveillance and the shift in biopsy scores caused by the 2005 International Society of Urologic Pathology update to the Gleason scoring protocol. METHODS: We reviewed patients who underwent radical prostatectomy at our institution between May 2004 and April 2011. We analyzed clinical and pathological correlates of upgrading in 3 subgroups: Gleason sum (GS) 6/6, GS6/7 and GS7/7, where the sum preceding the dash was determined from biopsy and the subsequent sum was determined from the radical prostatectomy specimen. We applied the log-rank test and Cox model to a Kaplan Meier analysis of biochemical recurrence in the subgroups, and also mapped GS6/7 discordance over time. RESULTS: In total, 1717 patients met our inclusion criteria. The 3 subgroups had significantly different mean prostate-specific antigen, patient age, tumour volume, margin status, pathologic stage, prostate weight, transrectal ultrasound volume and rate of progression (p < 0.05). We noted a multiphasic trend with a fall in discordance after 2005. However, there was no sustained trend over the study period taken as a whole (p = 0.06). CONCLUSIONS: Although no sustained trend was observed, the falling discordance after 2005 may reflect the accommodation to the Gleason scoring update, while the gradual adoption of active surveillance may have led to the otherwise increasing trends. However, our observations may also be spurious biopsy sampling errors.

The effects of standardized trauma training on prehospital pain control: have pain medication administration rates increased on the battlefield?

BACKGROUND: The US Military has served in some of the most austere locations in the world. In this ever-changing environment, units are organized into smaller elements operating in very remote areas. This often results in longer evacuation times, which can lead to a delay in pain management if treatment is not initiated in the prehospital setting. Early pain control has become an increasingly crucial military prehospital task and must be controlled from the pain-initiating event. The individual services developed their standardized trauma training based on the recommendations by Frank Butler and the Defense Health Board Committee on Tactical Combat Casualty Care. This training stresses evidence-based treatment modalities, including pain control, derived from casualty injury analysis. Inadequate early pain control may lead to multiple acute and potentially chronic effects. These effects encompass a wide range from changes in blood pressure to delayed wound healing and posttraumatic stress disorder. Therefore, it is essential that pain be addressed in the prehospital environment. METHODS: Institutional Review Board approval was obtained to conduct a retrospective Joint Theater Trauma Registry comparative study evaluating whether standardized trauma training increased prehospital pain medication administration between 2007 and 2009. These years were selected on the basis of mandatory training initiation dates and available Joint Theater Trauma Registry records. Records were analyzed for all US prehospital trauma cases with documented pain medication administration from Operations Enduring Freedom and Iraqi Freedom for the specified years. RESULTS: Data analysis revealed 232 patients available for review (102 for 2007 and 130 for 2009). A statistically significant prehospital pain treatment increase was noted, from 3.1% in 2007 to 6.7% in 2009 (p < 0.0005; 95% confidence interval, 2.39-4.93). CONCLUSION: Standardized trauma training has increased the administration of prehospital pain medication and the awareness of the importance of early pain control.

Prehospital medical documentation in the Joint Theater Trauma Registry: a retrospective study.

BACKGROUND: Prehospital care of combat casualties is a critical phase of emergency medical practice on the battlefield. The Joint Theater Trauma Registry (JTTR) was developed to standardize a system of data collection for combat casualty care; however, the degree of population and granularity of prehospital data were unknown. METHODS: This is a retrospective comparative study of all US military personnel who sustained battle injuries in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). The JTTR was queried for all US military battle casualties from OIF and OEF entered between January 2002 and July 2009 containing any data entered into the prefacility fields. Data were separated based on origination, OIF, or OEF. A comparative analysis was performed. RESULTS: During the period studied, 13,080 (66%) entries into the JTTR were recorded in the category of "Battle Injury" and met study inclusion criteria; 3,187 (24%) battle injury entries contained prehospital data (n = 3,187). The percentage of casualty records containing prehospital data were 18.6% for OEF and 25.4% for OIF (p < 0.01). CONCLUSION: Both poor population of data points and poor granularity of prehospital data entered into the JTTR were observed. It appears that the volume and quality of reporting of role-I data were better for OIF than OEF for this study period. Further investigations into the obstacles to free flow of role-I casualty clinical data, and the means to mitigate this situation, are warranted.

Association of tissue promoter methylation levels of APC, TGFß2, HOXD3 and RASSF1A with prostate cancer progression.

Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer (PCa). We correlated quantitative promoter methylation levels of APC, TGFß2 and RASSF1A in 219 radical prostatectomies diagnosed between 1998 and 2001 with clinicopathological follow-up data available including Gleason Pattern (GP), Gleason Score (GS) and pathological stage and explored their potential in predicting biochemical recurrence using univariate and multivariate analyses. We observed that the average methylation levels of APC increased significantly from GS ≤ 6 to GS7, and pT2 to pT3a, and that of TGFß2 increased from GS ≤ 6 to GS7, but not for RASSF1A. PCa samples were also stratified into high methylation (HM) and low methylation (LM) groups based on the PMR scores of all cases analyzed for each marker. The HM frequency of APC was greater in pT3a than pT2, and in GS ≥ 8 than GS ≤ 6. The HM frequency also increased significantly from GP3 to GP4 for APC, TGFß2 and RASSF1A. APC methylation level was a significant predictor of biochemical recurrence in univariate analysis (p-value = 0.028). Finally, we combined methylation data of these three genes with the previously reported novel methylation biomarker HOXD3. Quantitative methylation assessment of a multiplex panel of markers, consisting of APC, HOXD3 and TGFß2, outperforms any single marker for the prediction of biochemical recurrence (p-value = 0.017). Our study demonstrated that quantitative increase in promoter methylation levels of APC, HOXD3 and TGFß2 are associated with PCa progression.

Current practice of thermoregulation during the transport of combat wounded.

BACKGROUND: This study evaluated the progress in the treatment and prevention of hypothermia in combat wounded since the October 2, 2006 Joint Theater Trauma System Clinical Practice Guideline (CPG) publication and evaluated the frequency of use and effectiveness of the methods described in the CPG. METHODS: The authors used data obtained from the Joint Trauma Theater Trauma Registry maintained by the US Army Institute of Surgical Research for our analysis. RESULTS: The issuance of the CPG was associated with a decrease in the incidence of hypothermia (p value = <0.0001). None of the thermoregulatory methods were associated with significantly higher overall temperatures when compared with the others (p value = 0.1062-0.3686) or with hypothermia (p value = 0.1367-0.7992); however, lack of entered prehospital data resulted in a suboptimal number of patients for evaluation in this portion of the study. The wool blanket was the most commonly used thermoregulatory method (prehospital, 72%; interfacility, 49%). CONCLUSIONS: (1) The incidence of hypothermia decreased after the issuance of the JTTS CPG. (2) The standard Army wool blanket is the most commonly used thermoregulatory method during transport in theater. (3) This study did not find a significant difference in the capability of maintaining temperatures between the different thermoregulatory methods used in theater during either prehospital or interfacility transport, or in the incidence of hypothermia between patients presenting from the site of injury or from interfacility transport. (4) Data collected before a Level III facility is not consistently entered into the Joint Theater Trauma Registry.

DNA methylation of HOXD3 as a marker of prostate cancer progression.

DNA methylation in gene promoters causes gene silencing and is a common event in cancer development and progression. The ability of aberrant methylation events to serve as diagnostic and prognostic markers is being appreciated for many cancers, including prostate cancer. Using quantitative MethyLight technology, we evaluated the relationship between HOXD3 methylation and clinicopathological parameters including biochemical recurrence, pathological stage, Gleason score (GS), and Gleason pattern in a series of 232 radical prostatectomies performed between 1998 and 2001. HOXD3 methylation was significantly greater in GS 7 cancers vs GS < or = 6 cancers (P-value <0.001) as well as pT3/pT4 vs pT2 cancers (P-value <0.001). The proportion of cases with high methylation in GS 7 vs < or = GS 6 and pT3/pT4 vs pT2 were also significantly different (P-values=0.002 and 0.005, respectively). There were also significant increases in methylation from Gleason pattern 2-3 and from pattern 3 to 4/5 (paired t-test P-values=0.01 and <0.001, respectively), whereas methylation from lymph node metastases was decreased when compared with matched tumor tissue (P-value=0.029). HOXD3 methylation was associated with biochemical recurrence in univariate analysis (P-value=0.043) and showed evidence for interaction with pathological stage as a predictor variable in Cox regression analysis (P-value=0.028). The results indicate that HOXD3 methylation distinguishes low-grade prostate cancers from intermediate and high-grade ones and may also have prognostic value when considered together with pathological stage.

Impact of positive surgical margins after radical prostatectomy differs by disease risk group.

PURPOSE: Positive surgical margins have a negative impact on disease outcomes after radical prostatectomy, yet their prognostic value may vary depending on specific pathological characteristics. We examined the relationship of positive surgical margins to biochemical progression according to several clinicopathological features. MATERIALS AND METHODS: We analyzed data from 1,268 patients who underwent radical prostatectomy for clinically localized prostate cancer at our center between 1992 and 2008, and did not receive any neoadjuvant or adjuvant treatment. We examined the relation of age, pretreatment prostate specific antigen, pathological T stage, radical prostatectomy Gleason score, disease risk group and surgical margin status to biochemical progression-free survival. RESULTS: The overall positive surgical margin rate was 20.8% and median followup was 79 months. The impact of positive surgical margins was dependent on risk group. Biochemical progression-free survival was 99.6% for the negative surgical margin group vs 94.9% for the positive surgical margin group in low risk disease (log rank p = 0.53), 93.5% for the negative surgical margin group vs 83% for the positive surgical margin group in intermediate risk disease (log rank p <0.001) and 78.5% for the negative surgical margin group vs 57.1% for the positive surgical margin group in high risk disease (log rank p = 0.003). These differences remained significant in a multivariate Cox regression model adjusting for other clinicopathological features. CONCLUSIONS: Positive surgical margins are an independent predictor of biochemical progression in patients with intermediate and high risk prostate cancer. Patients with low risk disease have a favorable long-term outcome regardless of margin status and may be candidates for expectant management even with positive surgical margins, sparing them the side effects and costs of treatment.