Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer trial study protocol: a randomised clinical trial of fibre-rich legumes targeting the gut microbiome, metabolome and gut transit time of overweight and obese patients with a history of noncancerous adenomatous polyps.

INTRODUCTION: Recently published studies support the beneficial effects of consuming fibre-rich legumes, such as cooked dry beans, to improve metabolic health and reduce cancer risk. In participants with overweight/obesity and a history of colorectal polyps, the Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer randomised clinical trial will test whether a high-fibre diet featuring legumes will simultaneously facilitate weight reduction and suppress colonic mucosal biomarkers of colorectal cancer (CRC). METHODS/DESIGN: This study is designed to characterise changes in (1) body weight; (2) biomarkers of insulin resistance and systemic inflammation; (3) compositional and functional profiles of the faecal microbiome and metabolome; (4) mucosal biomarkers of CRC risk and (5) gut transit. Approximately 60 overweight or obese adults with a history of noncancerous adenomatous polyps within the previous 3 years will be recruited and randomised to one of two weight-loss diets. Following a 1-week run-in, participants in the intervention arm will receive preportioned high-fibre legume-rich entrées for two meals/day in months 1-3 and one meal/day in months 4-6. In the control arm, entrées will replace legumes with lean protein sources (eg, chicken). Both groups will receive in-person and written guidance to include nutritionally balanced sides with energy intake to lose 1-2 pounds per week. ETHICS AND DISSEMINATION: The National Institutes of Health fund this ongoing 5-year study through a National Cancer Institute grant (5R01CA245063) awarded to Emory University with a subaward to the University of Pittsburgh. The study protocol was approved by the Emory Institutional Review Board (IRB approval number: 00000563). TRIAL REGISTRATION NUMBER: NCT04780477.

Long-term Outcome of Per-oral Endoscopic Myotomy Performed in the Endoscopy Unit With Trainees.

INTRODUCTION: Per-oral endoscopic myotomy (POEM) has been widely adopted for the treatment of achalasia as it provides a precise, tailored myotomy in a minimally invasive endoscopic procedure. Several short-term studies and a few long-term studies have confirmed that POEM is a safe and effective treatment for achalasia. However, the long-term outcome of POEM performed by trainees is unknown. MATERIALS AND METHODS: We conducted a retrospective study of all patients who underwent POEM for achalasia at our tertiary care center during December 2012 and January 2019. All procedures performed with trainees were included. The primary outcome was the clinical response to POEM, defined as an Eckardt score of <3 after POEM. Trainees were trained in performing mucosotomy and submucosal dissection, creating a submucosal tunnel, identifying gastroesophageal junction, and performing myotomy and closure of mucosal incision in a step-by-step fashion. Trainees' performance was evaluated by the mentor based on several key points in each step. RESULTS: A total of 153 consecutive patients with a median age of 57±18 years were analyzed in this study. Of the total patients, 69 (45%) were male. The median length of follow-up after POEM was 32 months (range: 7 to 77 mo). A clinically significant response to POEM was achieved in 95% of patients at year 1, 84% at year 2, 80% at year 3, 79% at year 4, 78% at year 5, and 78% at year 6 and above. All trainees obtained competence within 6 cases for each step and could perform the procedure alone after 20 supervised cases. CONCLUSIONS: Overall, 78% of patients maintained positive clinical response at 6 years following POEM procedure. The recurrence rate of symptoms following POEM was 22% at a 6-year follow-up. This long-term outcome of POEM performed with trainees was comparable to those without trainees in other studies. To our knowledge, this is the longest follow-up and the largest number of patients after the POEM procedure performed with trainees.

Long-term Outcome of Gastric Per-Oral Endoscopic Pyloromyotomy in Treatment of Gastroparesis.

BACKGROUND & AIMS: Gastric per oral endoscopic pyloromyotomy (GPOEM) is a promising treatment for gastroparesis. There are few data on the long-term outcomes of this procedure. We investigated long-term outcomes of GPOEM treatment of patients with refractory gastroparesis. METHODS: We conducted a retrospective case-series study of all patients who underwent GPOEM for refractory gastroparesis at a single center (n = 97), from June 2015 through March 2019; 90 patients had more than 3 months follow-up data and were included in our final analysis. We collected data on gastroparesis cardinal symptom index (GCSI) scores (measurements of postprandial fullness or early satiety, nausea and vomiting, and bloating) and SF-36 questionnaire scores (measures quality of life). The primary outcome was clinical response to GPOEM, defined as a decrease of at least 1 point in the average total GCSI score with more than a 25% decrease in at least 2 subscales of cardinal symptoms. Recurrence was defined as a return to baseline GCSI or GCSI scores of 3 or more for at least 2 months after an initial complete response. The secondary outcome was the factors that predict GPOEM failure (no response or gastroparesis recurrence within 6 months). RESULTS: At initial follow-up (3 to 6 months after GPOEM), 73 patients (81.1%) had a clinical response and significant increases in SF-36 questionnaire scores (indicating increased quality of life) whereas 17 patients (18.9%) had no response. Six months after GPOEM, 7.1% had recurrence. At 12 months, 8.3% of patients remaining in the study had recurrence. At 24 months, 4.8% of patients remaining in the study had a recurrence. At 36 months, 14.3% of patients remaining in the study had recurrence. For patients who experienced an initial clinical response, the rate of loss of that response per year was 12.9%. In the univariate and multivariate regression analysis, a longer duration of gastroparesis reduced the odds of response to GPOEM (odds ratio [OR], 0.092; 95% CI, 1.04-1.3; P = .001). On multivariate logistic regression, patients with high BMIs had increased odds of GPOEM failure (OR, 1.097; 95% CI, 1.022-1.176; P = .010) and patients receiving psychiatric medications had a higher risk of GPOEM failure (OR, 1.33; 95% CI, 0.110-1.008; P = .052). CONCLUSIONS: In retrospective analysis of 90 patients who underwent GPOEM for refractory gastroparesis, 81.1% had a clinical response at initial follow-up of their procedure. 1 year after GPOEM, 69.1% of all patients had a clinical response and 85.2% of initial responders maintained a clinical response. Patients maintained a clinical response and improved quality of life for as long as 3 years after the procedure. High BMI and long duration gastroparesis were associated with failure of GPOEM.

Association between duration or etiology of gastroparesis and clinical response after gastric per-oral endoscopic pyloromyotomy.

BACKGROUND AND AIMS: Gastric per-oral endoscopic pyloromyotomy (GPOEM) is a novel procedure with promising potential for the treatment of gastroparesis but with limited data regarding predictors of clinical response. This study aims to evaluate the safety and efficacy of the procedure and explore the impact of duration and etiology (diabetic vs nondiabetic) of gastroparesis on clinical outcome as measured by the Gastroparesis Cardinal Symptom Index (GCSI). METHODS: A single-center retrospective longitudinal study at a tertiary care hospital was performed over an 18-month period. Forty patients with refractory gastroparesis (25 nondiabetic and 15 diabetic patients) were included. RESULTS: GCSI significantly improved throughout the study period (F[2.176, 17.405] = 10.152, P = .001). The nausea/vomiting subscale showed sustained improvement through 18 months (F[2.213, 17.704] = 15.863, P < .00001). There was no significant improvement in bloating (F[2.099, 16.791] = 1.576, P = .236). Gastric scintigraphy retention was significantly reduced by 41.7% (t = -7.90; P < .00001). Multivariate linear regression modeling revealed a significant correlation between the duration of disease and a GCSI improvement at 12 months (P = .02), with a longer duration of disease associated with a poorer long-term response. The etiology of gastroparesis was not associated with clinical improvement (P = .16). Adverse events (7.5%) included 1 capnoperitoneum, 1 periprocedure chronic obstructive pulmonary disease exacerbation, and 1 mucosotomy closure site disruption. CONCLUSIONS: GPOEM appears to be a safe and effective minimally invasive therapy for refractory gastroparesis, especially for patients with predominant nausea/vomiting and shorter duration of disease, regardless of the etiology. We propose the clinical criteria for undergoing GPOEM should be a GCSI of at least 2.0 and a gastric retention of greater than 20%.

Gastric Peroral Endoscopic Pyloromyotomy Reduces Symptoms, Increases Quality of Life, and Reduces Health Care Use For Patients With Gastroparesis.

BACKGROUND & AIMS: Gastric peroral endoscopic pyloromyotomy (GPOEM) is becoming a promising treatment option for patients with refractory gastroparesis. We aimed to systematically assess the efficacy of GPOEM and its effects on health care use. METHODS: We performed a retrospective study on 30 patients with refractory gastroparesis who underwent GPOEM from June 2015 through July 2017 at a tertiary center. We compared outcomes with those of 7 patients with refractory gastroparesis who did not undergo the procedure (controls). The primary outcomes were patient-reported reductions in symptoms, based on the gastroparesis cardinal symptom index (GCSI), and increases in 8 aspects of quality of life, based on Short Form 36 (SF-36) scores. Data were collected on the day of the procedure (baseline) and at 1 month, 6 months, 12 months, and 18 months afterward. Secondary outcomes included visits to the emergency department or hospitalization for gastroparesis-related symptoms. RESULTS: GPOEM was technically successful in all patients and significantly reduced GCSI scores in repeated-measure analysis of variance (F2.044, 38.838 = 22.319; P < .0005). The mean score at baseline was 3.5 ± 0.6, at 1 month after GPOEM was 1.8 ± 1.0 (P < .0005), at 6 months after was 1.9 ± 1.2 (P < .0005), at 12 months after was 2.6 ± 1.5 (P < .026), and at 18 months after was 2.1 ± 1.3 (P < .016). GPOEM was associated with improved quality of life: 77.8%, 76.5%, and 70% of patients had significant increases in SF-36 scores, compared with baseline, at 1 month, 6 months, and 12 months after GPOEM, respectively (F1.71,18.83 = 14.16; P < .0005). Compared with controls, patients who underwent GPOEM had significant reductions in GCSI, after we controlled for baseline score and duration of the disease (F1,31 = 9.001; P = .005). Patients who received GPOEM had significant reductions in number of emergency department visits (from 2.2 ± 3.1 times/mo at baseline to 0.3 ± 0.8 times/mo; P = .003) and hospitalizations (from 1.7 ± 2 times/mo at baseline to 0.2 ± 0.4 times/mo; P = .0002). CONCLUSIONS: In a retrospective study of patients who underwent GPOEM for refractory gastroparesis, we found the procedure significantly improved symptoms, increased quality of life, and reduced health care use related to gastroparesis.

Outcomes and quality-of-life assessment after gastric per-oral endoscopic pyloromyotomy (with video).

BACKGROUND AND AIM: Gastric per-oral endoscopic pyloromyotomy (GPOEM) is emerging as a promising option for the treatment of gastroparesis. This study assessed outcomes and quality of life after GPOEM for gastroparesis, performed in an endoscopy unit at a major tertiary referral center. METHODS: We performed a retrospective review of patients who had undergone GPOEM from June 2015 to July 2016. Data were collected from electronic medical records and included patient demographics, endoscopy records, hospitalization records, clinic visits, and electronic messages. Scores for the Short Form 36 (SF36) and Gastroparesis Cardinal Symptom Index (GCSI) were obtained pre-procedure (16 patients), at 1 month (16 patients), at 6 months (13 patients), and at 12 months (6 patients) after the GPOEM procedure was performed. RESULTS: Sixteen consecutive patients, 13 women and 3 men (mean age, 44.76 ± 14.8 years), who underwent GPOEM were enrolled. GPOEM was technically successful in all cases. Thirteen of 16 (81%) patients had a significant improvement in the mean GCSI after GPOEM: 3.40 ± 0.50 before the procedure (16 patients) to 1.48 ± 0.95 (P = .0001) at 1 month (16 patients), 1.36 ± 0.9 (P < .01) at 6 months (13 patients), and 1.46 ± 1.4 (P < .01) at 12 months (6 patients) follow-up. Mean duration of the procedure was 49.7 ± 22.1 minutes. Mean myotomy length was 2.94 ± 0.1 cm. Mean length of hospital stay was 2.46 ± 0.7 days. No adverse events occurred with GPOEM. The SF36 questionnaire demonstrated a significant improvement in quality of life in several domains that was sustained through 6-months' follow-up. Mean 4-hour gastric retention on gastric emptying scans decreased from 62.9% ± 24.3% to 17.6% ± 16.7% (P = .007) after GPOEM. CONCLUSIONS: GPOEM results in improvement in the overall symptoms of gastroparesis measured by GCSI, objective assessment of improvement in gastric emptying, and improvement in multiple domains on validated quality-of-life inventories in SF36 over a follow-up period of 6 months.

Efficacy of laparoscopic pyloroplasty for the treatment of gastroparesis.

BACKGROUND: The modest results of nonoperative modalities for the treatment of gastroparesis necessitate greater consideration of surgical therapies. However, the role of surgery is not well defined. The aim of this study is to present our experience with laparoscopic pyloroplasty as early treatment for gastroparesis. STUDY DESIGN: Fifty patients with refractory gastroparesis underwent laparoscopic pyloroplasty (hand-sewn Heineke-Mikulicz configuration) from 2006 to 2013 at our institution. Preoperative and postoperative symptom data, gastric emptying scintigraphy, and technical outcomes of the procedure were reviewed. A single-factor ANOVA was performed for the comparison of continuous variables. Results are reported as mean ± SD or median absolute deviation. RESULTS: Thirty-four of 50 (68%) patients had previous foregut procedures and/or cholecystectomy. Thirty-two of 50 (64%) patients underwent concomitant procedures (ie, paraesophageal hernia repair and gastrostomy takedown) along with the pyloroplasty. Operative time, including combined procedures, blood loss, and length of stay were 175 ± 56 minutes, 64 ± 50 mL, 2.5 ± 2.7 days, respectively. There were no conversions to open technique or intraoperative complications. There were no suture-line leaks. The readmission rate was 14%. All patients had symptom follow-up and 33 (66%) had postoperative gastric emptying scintigraphy. Postoperative symptom improvement was reported by 82% of the patients (p < 0.001). Median preoperative T1/2 was 180 ± 73 minutes and postoperative T1/2 was 60 ± 23 minutes (p < 0.001). Five patients (10%), who had normalized postoperative T1/2 times, required other gastric emptying procedures; distal gastrectomy (n = 2), duodenojejunostomy (n = 2), and gastric stimulator placement (n = 1). CONCLUSIONS: Laparoscopic pyloroplasty is an effective early-treatment modality for selected cases of gastroparesis, with substantial improvement in objective gastric emptying times and low morbidity. The laparoscopic approach does not preclude subsequent procedures when necessary.

Conditional protein splicing of α-sarcin in live cells.

Protein splicing technology harnesses the ability of inteins to ligate protein fragments, forming a mature protein. This report describes our effort to engineer rapamycin-dependent protein splicing of a ribotoxin, called α-sarcin. Engineering this system required the investigation of important splicing parameters, including extein context and splicing temperature. We show α-sarcin splicing is dependent on rapamycin, is inducible with rapid kinetics, and triggers apoptosis in HeLa cells. These findings establish a proof-of-concept for a conditional cell ablation strategy.

Toxicity after (125)I prostate brachytherapy in patients with inflammatory bowel disease.

PURPOSE: To determine gastrointestinal (GI) toxicity after (125)I prostate brachytherapy in patients with inflammatory bowel disease (IBD). METHODS AND MATERIALS: We retrospectively reviewed 13 patients diagnosed with IBD from a cohort of over 3200 patients with low- to intermediate-risk prostate cancer treated with (125)I brachytherapy (144Gy). Acute (i.e. <12 months) and late lower GI toxicity after brachytherapy using the Radiation Therapy Oncology Group (RTOG) grading system was assessed. Possible factors (e.g. patient, treatment, dosimetry, and characteristics of IBD) influencing GI toxicity were assessed. RESULTS: Median followup was 4.2 years. Ten patients had ulcerative colitis (UC) and 3 had Crohn's disease. Seven patients with UC had known involvement of the rectum. Acute RTOG GI Grade 0, 1, 2, 3, 4 toxicity was seen in 7, 1, 2, 2, 1 patients, respectively. The corresponding late RTOG GI toxicity was seen in 7, 1, 3, 1, 1 patients, respectively. Two patients required major surgery. All patients with severe GI toxicity (i.e., Grade ≥3) had UC with disease involving the rectum and underwent endoscopic biopsies of the rectum within 3 months after the implant. There was no clear association with other factors with toxicity. CONCLUSIONS: Twenty-three percent and 15% patients with IBD experienced Grade 3 or higher acute and late GI toxicity, respectively, after brachytherapy. Prostate brachytherapy should be used with great caution or avoided, particularly for men with active IBD involving the rectum. Biopsies of the rectum after brachytherapy should be avoided as it may lead to ulceration.

Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight.

Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.

Limited M1 disease: a significant prognostic factor for stage IV breast cancer.

PURPOSE: The prognosis of patients with breast cancer presenting with distant metastasis can vary depending on disease extent. This study evaluates a definition of limited M1 disease in association with survival in a cohort of women presenting with metastatic breast cancer. METHODS: The study cohort comprised 692 women referred to the BC Cancer Agency between 1996 and 2005 with M1 breast cancer at presentation. Limited M1 disease was defined as <5 metastatic lesions confined to one anatomic subsite. Extensive M1 disease was defined as ≥ 5 lesions or disease in more than one subsite. Clinicopathologic and treatment characteristics and overall survival (OS) were compared between subjects with limited (n = 233) versus extensive (n = 459) M1 disease. Multivariable analysis was performed by Cox regression modeling. RESULTS: Median follow-up time was 1.9 years. Five-year Kaplan-Meier OS was significantly higher in patients with limited compared to extensive M1 disease (29.7 vs. 13.1 %, p < 0.001). In the multivariable Cox regression analysis, limited M1 disease was significantly associated with OS (hazard ratio 0.51, 95 % confidence interval 0.40-0.66, p < 0.001). The only patient subsets with limited M1 disease with poor 5-year OS <15 % were patients with Eastern Cooperative Oncology Group performance status of ≥ 2 or estrogen receptor-negative status. CONCLUSIONS: Limited M1 disease, defined as <5 metastatic lesions confined to one anatomic subsite, is a relevant favorable prognostic factor in patients with stage IV breast cancer. This definition may be used in conjunction with other clinicopathologic factors to select patients for more aggressive systemic and locoregional treatments.

Can locoregional treatment of the primary tumor improve outcomes for women with stage IV breast cancer at diagnosis?

PURPOSE: To examine the effect of locoregional treatment (LRT) of the primary tumor on survival in patients with Stage IV breast cancer at diagnosis. METHODS AND MATERIALS: The study cohort comprised 733 women referred to the British Columbia Cancer Agency between 1996 and 2005 with newly diagnosed clinical or pathologic M1 breast cancer. Tumor and treatment characteristics, overall survival (OS), and locoregional progression-free survival were compared between patients treated with (n = 378) and without (n = 355) LRT of the primary disease. Multivariable analysis was performed with Cox regression modeling. RESULTS: The median follow-up time was 1.9 years. LRT consisted of surgery alone in 67% of patients, radiotherapy alone in 22%, and both in 11%. LRT was used more commonly in women with age <50 years, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, Stage T1-2 tumors, N0-1 disease, limited M1 burden, and asymptomatic M1 disease (all p < 0.05). Systemic therapy was used in 92% of patients who underwent LRT and 85% of patients who did not. In patients treated with LRT compared with those without LRT, the 5-year OS rates were 21% vs. 14% (p < 0.001), and the rates of locoregional progression-free survival were 72% vs. 46% (p < 0.001). Among 378 patients treated with LRT, the rates of 5-year OS were higher in patients with age <50, ECOG performance status 0-1, estrogen receptor-positive disease, clear surgical margins, single subsite, bone-only metastasis, and one to four metastatic lesions (all p < 0.003). On multivariable analysis, LRT was associated with improved OS (hazard ratio, 0.78; 95% confidence interval, 0.64-0.94, p = 0.009). CONCLUSION: Locoregional treatment of the primary disease is associated with improved survival in some women with Stage IV breast cancer at diagnosis. Among those treated with LRT, the most favorable rates of survival were observed in subsets with young age, good performance status, estrogen receptor-positive disease, clear margins, and distant disease limited to one subsite, bone-only involvement, or fewer than five metastatic lesions.

Effect of comorbid conditions on adherence to colorectal cancer screening.

Potential barriers to colorectal cancer (CRC) screening include preexisting medical conditions (comorbidities), physician recommendation, psychosocial factors, and screening preparedness. This study's purpose was to investigate the impact of comorbid conditions on CRC screening among African Americans. A stage-matched randomized clinical trial was performed. Asymptomatic African Americans over age 50, with a primary care physician, and eligible for CRC screening were recruited at The Mount Sinai Hospital from 2005 to 2008. One hundred sixty-one patients were assessed for referral for, and completion of, CRC screening, comorbid conditions, "readiness to change," and number of physician visits within the observation period. Data was compared to a pretrial index to predict the likely effect of comorbid conditions on CRC screening. One hundred fifty-nine patients completed the study; 108 (68.9%) were referred for and 34 (21.2%) completed CRC screening. No demographic characteristics were associated with CRC screening completion. CRC screening referrals were similar for all patients, regardless of comorbidities or clinical visits. Comorbidities rated as having extreme influence on CRC screening showed a trend toward lower screening rates. There was a significant increase in screening rates among participants in advanced stages of readiness at enrollment. These data suggest that while comorbidities did not predict colonoscopy completion, they may play a role in concert with other factors. This is the only study to assess the effect of screening colonoscopy in an African American primary care setting. We must continue to explore interventions to narrow the disparate gap in screening and mortality rates.

Homo sapiens systemic RNA interference-defective-1 transmembrane family member 1 (SIDT1) protein mediates contact-dependent small RNA transfer and microRNA-21-driven chemoresistance.

Locally initiated RNA interference (RNAi) has the potential for spatial propagation, inducing posttranscriptional gene silencing in distant cells. In Caenorhabditis elegans, systemic RNAi requires a phylogenetically conserved transmembrane channel, SID-1. Here, we show that a human SID-1 orthologue, SIDT1, facilitates rapid, contact-dependent, bidirectional small RNA transfer between human cells, resulting in target-specific non-cell-autonomous RNAi. Intercellular small RNA transfer can be both homotypic and heterotypic. We show SIDT1-mediated intercellular transfer of microRNA-21 to be a driver of resistance to the nucleoside analog gemcitabine in human adenocarcinoma cells. Documentation of a SIDT1-dependent small RNA transfer mechanism and the associated phenotypic effects on chemoresistance in human cancer cells raises the possibility that conserved systemic RNAi pathways contribute to the acquisition of drug resistance. Mediators of non-cell-autonomous RNAi may be tractable targets for novel therapies aimed at improving the efficacy of current cytotoxic agents.

Extreme-risk prostate adenocarcinoma presenting with prostate-specific antigen (PSA)>40 ng/ml: prognostic significance of the preradiation PSA nadir.

PURPOSE: To examine the impact of patient, disease, and treatment characteristics on survival outcomes in patients treated with neoadjuvant androgen deprivation therapy (ADT) and radical external-beam radiotherapy (RT) for clinically localized, extreme-risk prostate adenocarcinoma with a presenting prostate-specific antigen (PSA) concentration of >40 ng/ml. METHODS AND MATERIALS: A retrospective chart review was conducted of 64 patients treated at a single institution between 1991 and 2000 with ADT and RT for prostate cancer with a presenting PSA level of >40 ng/ml. The effects of patient age, tumor (presenting PSA level, Gleason score, and T stage), and treatment (total ADT duration and pre-RT PSA level) characteristics on rates of biochemical disease-free survival (bDFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were examined. RESULTS: Median follow-up time was 6.45 years (range, 0.09-15.19 years). Actuarial bDFS, PCSS, and OS rates at 5 years were 39%, 87%, and 78%, respectively, and 17%, 64%, and 45%, respectively, at 10 years. On multivariate analysis, the pre-RT PSA level (≤0.1 versus >0.1 ng/ml) was the single most significant prognostic factor for bDFS (p=0.033) and OS (p=0.018) rates, whereas age, T stage, Gleason score, and ADT duration (≤6 versus >6 months) were not predictive of outcomes. CONCLUSION: In prostate cancer patients with high presenting PSA levels, >40 ng/ml, treated with combined modality, neoadjuvant ADT, and RT, the pre-RT PSA nadir, rather than ADT duration, was significantly associated with improved survival. This observation supports the use of neoadjuvant ADT to drive PSA levels to below 0.1 ng/ml before initiation of RT, to optimize outcomes for patients with extreme-risk disease.

Primary sarcoma of the mediastinum: a report of 16 cases referred to the British Columbia Cancer Agency.

BACKGROUND: Sarcoma arising in the mediastinum is a rare entity. This study evaluates treatment and survival in a cohort of patients with primary mediastinal sarcoma. METHODS: Between 1990 and 2006, 16 patients were referred to the British Columbia Cancer Agency with histologically confirmed sarcoma of mediastinal origin. Outcomes examined were disease-free survival (DFS) and overall survival (OS). RESULTS: There were nine male and seven female patients. The median age at diagnosis was 56 years (range 21-70 years). Thirteen (81%) patients had localized disease, and three (19%) patients had distant metastasis at diagnosis. Surgical resection was performed in 8 of 13 patients with localized disease. At a median follow-up of 18 months, 12 patients have died of disease, three were alive with disease, and one was alive with no evidence of disease. In the entire cohort, median DFS was 12 months (range 0-107 months), and median OS was 18 months (range 1-193 months). Patients who underwent surgery experienced improved DFS (p = 0.054) and OS (p = 0.034). Eastern Cooperative Oncology Group performance status 0 to 1 was associated with improved DFS (p = 0.038) and OS (p = 0.007). The histologic subtype with the longest survival was well-differentiated liposarcoma. Age, gender, tumor location, T and N stage, tumor size, location, and grade were not associated with significant survival differences. CONCLUSION: Surgical resection was associated with more favorable survival in patients with mediastinal sarcoma. However, the high rates of progression and mortality underscore the need for more effective adjuvant treatments.

Mass spectrometric detection of candidate protein biomarkers of cancer cachexia in human urine.

Increased membrane permeability and myofibrillar protein breakdown are established features of cancer cachexia. Proteins released from cachectic muscle may be excreted in urine to act as biomarkers of the cachectic process. One-dimensional SDS polyacrylamide gel electrophoresis followed by matrix-assisted laser desorption/ionisation or liquid chromatography tandem mass spectrometry was used to compare the protein content of urine from cachectic (>10% weight loss) (n=8) and weight-stable (n=8) gastro-oesophageal cancer patients and healthy controls (n=8). Plasma creatine kinase concentration was used as a marker of gross muscle breakdown. The number of protein species identified in cachectic samples (median 42; range 28-61; total 199) was greater than that identified in weight-stable cancer (median 15; range 9-28; total 79) and control samples (median 12.5; range 5-18; total 49) (P<0.001). Many of the proteins identified have not been reported previously in the urine of cancer patients. Proteins identified specifically in cachectic samples included muscle (myosin species), cytoskeletal (alpha-spectrin; nischarin) and microtubule-associated proteins (microtubule-actin crosslinking factor; microtubule-associated protein-1B; bullous pemphigoid antigen 1), whereas immunoglobulin kappa-light chain and zinc alpha-2 glycoprotein appeared to represent markers of cancer. The presence of myosin in urine (without an increase in plasma creatine kinase) is consistent with a specific loss of myosin as part of the cachectic process. Urinary proteomics using mass spectrometry can identify muscle-specific and non-muscle-specific candidate biomarkers of cancer cachexia.