A Randomized Study of Intraoperative Autologous Retropubic Urethral Sling on Urinary Control after Robotic Assisted Radical Prostatectomy.

PURPOSE: We evaluated whether placement of a retropubic urethral sling fashioned from autologous vas deferens during robotic assisted radical prostatectomy would improve recovery of continence. MATERIALS AND METHODS: In a phase 2, single blind trial age stratified patients were randomized to undergo robotic assisted radical prostatectomy by multiple surgeons with or without sling placement. The outcomes were complete continence (0 urinary pads of any type) and near continence (0, an occasional or 1 pad per day) at 6 months, which was assessed by the Fisher exact test and logistic regression. The Kaplan-Meier method and the log rank test were used to evaluate time to continence. EPIC-UIN (Expanded Prostate Cancer Index Composite-Urinary Inventory) and I-PSS (International Prostate Symptom Score) 1, 3 and 6 months after catheter removal were evaluated by mixed models for repeated measures. RESULTS: Of 203 patients who were recruited 95 and 100 were randomized to undergo sling and no sling placement, respectively, and completed postoperative interviews. Six months after surgery the proportions reporting complete and near continence (66% and 87%, respectively) and times to complete and near continence were similar in the groups. Younger age was associated with a higher likelihood of complete continence (OR 1.74 per decreasing 5-year interval, 95% CI 1.23-2.48, p <0.01) and near continence (OR 2.18 per decreasing 5-year interval, 95% CI 1.21-3.92, p <0.01) adjusting for clinical, urinary and surgical factors. Adjusted EPIC-UIN and I-PSS scores changed with time but did not differ between the groups. No serious adverse events were observed. CONCLUSIONS: This trial failed to demonstrate a benefit of autologous urethral sling placement at robotic assisted radical prostatectomy on early return of continence at 6 months. Continence was related to patient age in adjusted models.

Associations between circulating carotenoids, genomic instability and the risk of high-grade prostate cancer.

BACKGROUND: Carotenoids are a class of nutrients with antioxidant properties that have been purported to protect against cancer. However, the reported associations between carotenoids and prostate cancer have been heterogeneous and lacking data on interactions with nucleotide sequence variations and genomic biomarkers. OBJECTIVE: To examine the associations between carotenoid levels and the risk of high-grade prostate cancer, also considering antioxidant-related genes and tumor instability. METHODS: We measured plasma levels of carotenoids and genotyped 20 single nucleotide polymorphisms (SNP) in SOD1, SOD2, SOD3, XRCC1, and OGG1 among 559 men with non-metastatic prostate cancer undergoing radical prostatectomy. We performed copy number analysis in a subset of these men (n = 67) to study tumor instability assessed as Fraction of the Genome Altered (FGA). We examined associations between carotenoids, genotypes, tumor instability and risk of high-grade prostate cancer (Gleason grade ≥ 4 + 3) using logistic and linear regression. RESULTS: Circulating carotenoid levels were inversely associated with the risk of high-grade prostate cancer; odds ratios (OR) and 95% confidence intervals (CI) comparing highest versus lowest quartiles were: 0.34 (95% CI: 0.18-0.66) for α-carotene, 0.31 (95% CI: 0.15-0.63) for ß-carotene, 0.55 (0.28-1.08) for lycopene and 0.37 (0.18-0.75) for total carotenoids. SNPs rs25489 in XRCC1, rs699473 in SOD3 and rs1052133 in OGG1 modified these associations for α-carotene, ß-carotene and lycopene, respectively (P ≤ 0.05). The proportion of men with a high degree of FGA increased with Gleason Score (P < 0.001). Among men with Gleason score ≤ 3 + 4, higher lycopene levels were associated with lower FGA (P = 0.04). CONCLUSION: Circulating carotenoids at diagnosis, particularly among men carrying specific somatic variations, were inversely associated with risk of high-grade prostate cancer. In exploratory analyses, higher lycopene level was associated with less genomic instability among men with low-grade disease which is novel and supports the hypothesis that lycopene may inhibit progression of prostate cancer early in its natural history.

Clinical outcome and prognostic factors for central neurocytoma: twenty year institutional experience.

Central neurocytomas are uncommon intraventricular neoplasms whose optimal management remains controversial due to their rarity. We assessed outcomes for a historical cohort of neurocytoma patients and evaluated effects of tumor atypia, size, resection extent, and adjuvant radiotherapy. Progression-free survival (PFS) was measured by Kaplan-Meier and Cox proportional hazards methods. A total of 28 patients (15 males, 13 females) were treated between 1995 and 2014, with a median age at diagnosis of 26 years (range 5-61). Median follow-up was 62.2 months and 3 patients were lost to follow-up postoperatively. Thirteen patients experienced recurrent/progressive disease and 2-year PFS was 75% (95% CI 53-88%). Two-year PFS was 48% for MIB-1 labeling >4% versus 90% for ≤4% (HR 5.4, CI 2.2-27.8, p = 0.0026). Nine patients (32%) had gross total resections (GTR) and 19 (68%) had subtotal resections (STR). PFS for >80% resection was 83 versus 67% for ≤80% resection (HR 0.67, CI 0.23-2.0, p = 0.47). Three STR patients (16%) received adjuvant radiation which significantly improved overall PFS (p = 0.049). Estimated 5-year PFS was 67% for STR with radiotherapy versus 53% for STR without radiotherapy. Salvage therapy regimens were diverse and resulted in stable disease for 54% of patients and additional progression for 38 %. Two patients with neuropathology-confirmed atypical neurocytomas died at 4.3 and 113.4 months after initial surgery. For central neurocytomas, MIB-1 labeling index >4% is predictive of poorer outcome and our data suggest that adjuvant radiotherapy after STR may improve PFS. Most patients requiring salvage therapy will be stabilized and multiple modalities can be effectively utilized.

Detection and characterization of invasive circulating tumor cells derived from men with metastatic castration-resistant prostate cancer.

The Vitatex cell-adhesion matrix (CAM) platform allows for isolation of invasive circulating tumor cells (iCTCs). Here we sought to determine the utility of prostate-specific membrane antigen (PSMA) as a metastatic castration-resistant prostate cancer (mCRPC) iCTC biomarker, to identify solitary cells and clusters of iCTCs expressing either epithelial, mesenchymal, or stem cell markers, and to explore the feasibility of iCTC epigenomic analysis. CTCs were isolated and enumerated simultaneously using the Vitatex and CellSearch platforms in 23 men with mCRPC. CAM-avid iCTCs were identified as nucleated cells capable of CAM uptake, but without detectable expression of hematopoietic lineage (HL) markers including CD45. iCTCs were enumerated immunocytochemically (ICC) and by flow cytometry. Whole-genome methylation status was determined for iCTCs using the Illumina HumanMethylation27 BeadChip. Thirty-four samples were collected for iCTC analysis. A median of 27 (range 0-800) and 23 (range 2-390) iCTCs/mL were detected by ICC and flow, respectively. In a subset of 20 samples, a median of seven CTCs/mL (range 0-85) were detected by the CellSearch platform compared to 26 by the CAM platform. iCTC clusters were observed in 17% of samples. iCTCs expressing PSMA as well as markers of EMT and stemness were detectable. The iCTC methylation profile highly resembled mCRPC. More CTCs were recovered using the CAM platform than the CellSearch platform, and the CAM platform allowed for the detection of iCTC clusters, iCTCs expressing EMT and stem-cell markers, and characterization of the iCTC methylome. Correlation with clinical data in future studies may yield further insight into the functional significance of these findings.

Antioxidant and vitamin E transport genes and risk of high-grade prostate cancer and prostate cancer recurrence.

BACKGROUND: Observational studies suggest an inverse association between vitamin E and risk of prostate cancer, particularly aggressive tumors. However, three large randomized controlled trials have reported conflicting results. Thus, we examined circulating vitamin E and vitamin E-related genes in relation to risk of high-grade prostate cancer and prostate cancer recurrence among men initially diagnosed with clinically organ-confined disease. METHODS: We measured circulating α- and γ-tocopherol and genotyped 30 SNPs in SOD1, SOD2, SOD3, TTPA, and SEC14L2 among 573 men with organ-confined prostate cancer who underwent radical prostatectomy. We examined associations between circulating vitamin E, genotypes, and risk of high-grade prostate cancer (Gleason grade ≥ 8 or 7 with primary score ≥ 4; n = 117) using logistic regression, and risk of recurrence (56 events; 3.7 years median follow-up) using Cox proportional hazards regression. RESULTS: Circulating γ-tocopherol was associated with an increased risk of high-grade prostate cancer (Q4 v. Q1 odds ratio [OR] = 1.87; 95% confidence intervals [CI]: 0.97-3.58; P trend =0.02). The less common allele in SOD3 rs699473 was associated with an increased risk of high-grade disease (T > C: OR = 1.40, 95% CI: 1.04-1.89). Two independent SNPs in SOD1 were inversely associated with prostate cancer recurrence in additive models (rs17884057 hazard ratio [HR] = 0.49, 95%CI: 0.25-0.96; rs9967983 HR = 0.62, 95% CI: 0.40-0.95). CONCLUSIONS: Among men with clinically organ-confined prostate cancer, genetic variation in SOD may be associated with risk of high-grade disease at diagnosis and disease recurrence. Circulating γ-tocopherol levels may also be associated with an increased risk of high-grade disease at diagnosis.

Palliative and oncologic co-management: symptom management for outpatients with cancer.

PURPOSE: Although outpatient palliative care clinics are increasingly common, evidence for their efficacy remains limited. METHODS: We conducted an observational study at the palliative care clinic of an academic cancer center to assess the association between palliative care co-management and symptoms and quality of life. Two hundred sixty-six adult outpatients were seen for a minimum of two palliative care visits within 120 days. A subset of 142 patients was seen for a third visit within 240 days. Patients completed a questionnaire containing validated symptom, quality of life, and spiritual wellbeing questions at each visit. RESULTS: The first follow-up visit was on average 41 days after the initial visit; the second follow-up visit was on average 81 days after the initial visit. Between the initial and first follow-up visits, there was significant improvement in pain (p < 0.001), fatigue (p < 0.001), depression (p < 0.001), anxiety (p < 0.001), quality of life (p = 0.002), and spiritual wellbeing (p < 0.001), but not nausea (p = 0.14). For the subset of patients seen for a second follow-up visit, the improvements in pain, fatigue, depression, anxiety, quality of life, and spiritual wellbeing persisted (p ≤ 0.005 for trend of each symptom). Patients had similar improvement regardless of their gender, age, ethnicity, disease stage, disease progression, and concurrent oncologic treatments. CONCLUSIONS: Palliative care was associated with significant improvement in nearly all the symptoms evaluated. A sustained change in symptoms was observed in the subset of patients seen for a second follow-up visit. Members of all subgroups improved.

A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma.

BACKGROUND: The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma. METHODS: Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined. RESULTS: Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib. CONCLUSIONS: The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma.

Ixabepilone, mitoxantrone, and prednisone for metastatic castration-resistant prostate cancer after docetaxel-based therapy: a phase 2 study of the Department Of Defense Prostate Cancer Clinical Trials Consortium.

BACKGROUND: Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncross- resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination. METHODS: Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m(2) and mitoxantrone 12 mg/m(2) administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity. RESULTS: Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed ≥ 50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed ≥ 30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively. CONCLUSIONS: These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim.

Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer.

BACKGROUND: Nutritional factors are associated with reduced risk of prostate cancer progression, yet mechanisms remain unclear. We examined the effects of lycopene and fish oil supplements versus placebo on the normal prostate microenvironment, among men pursuing active surveillance for low-burden prostate cancer. We hypothesized that lycopene or fish oil supplements would down-regulate insulin-like growth factor-1 (IGF-1) and cyclooxygenase 2 (COX-2) gene expression, respectively, reflecting putative proliferation (IGF-1) and inflammatory (COX-2) pathways relevant to carcinogenesis. METHODS: We conducted a 3-month randomized, double-blinded, clinical trial comparing prostate tissue gene expression profiles (assessed by qRT-PCR) among men with favorable-risk prostate cancer receiving either 30 mg/day lycopene, 3 g/day fish oil (including 1,098 mg eicosapentaenoic and 549 mg docosahexaenoic fatty acids) or placebo. RESULTS: Among 69 men (22 assigned to lycopene, 21 to fish, and 26 to placebo), there was no difference in the change from baseline to the 3 months in IGF-1 expression level between the placebo and lycopene arms (p = 0.93) nor in COX-2 expression between the placebo and fish arms (p = 0.99). CONCLUSION: Compared to placebo, 3-month intervention with lycopene or fish oil did not significantly change IGF-1 and COX-2 gene expression in the normal prostate microenvironment in men with low-burden prostate cancer. Further analysis of global gene expression profiles may shed light on the bioactivity and relevance of these nutrients in prostate cancer.

A pilot study of endorectal magnetic resonance imaging and magnetic resonance spectroscopic imaging changes with dutasteride in patients with low risk prostate cancer.

OBJECTIVE: •To evaluate the effects of dutasteride on treatment-naïve prostate cancer in men using serial magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) in this pilot study. PATIENTS AND METHODS: •This investigator-initiated prospective single-arm study was approved by the institutional committee on human research ethics board. •The target accrual was 10 patients. Newly diagnosed prostate cancer patients with low risk disease either with symptomatic benign prostatic hypertrophy or deemed to require pre-brachytherapy androgen suppression therapy were eligible. In the latter group, dutasteride was used to achieve cytoreduction. •All patients received 6 months of dutasteride 3.5 mg daily and underwent baseline blood work, health-related quality of life indices and MRI/MRSI, which were repeated at 1, 3 and 6 months. •MRSI spectra were examined and scored as healthy or cancerous. The change in cancerous volumes over time was evaluated. RESULTS: •Of the 10 patients enrolled, nine patients completed the entire study. One patient withdrew after 3 months because of drug-related toxicity. •Because a significant decrease in citrate and polyamines on MRSI spectra was noted at 1 month compared with baseline, healthy tissue appeared to be more like cancer and thus created a false impression that the cancer had grown after 1 month. To reduce this bias, comparisons were made between the 1-month and 6-month scans. •The median MR cancer volumes at 6 months and 3 months were 100% and 101% of the 1-month value, respectively. Three of the nine patients had a 30-45% decrease in cancer volume at 6 months relative to 1-month measures. Of the others, two had no change in cancer volume and four had an increase (range 65-167% of the 1-month value). •The median cancer volume (range) at baseline was only 0.5 (0.1-5.6) mL. CONCLUSIONS: •The inclusion of only men with low volume disease may have limited our ability to accurately assess response rates after dutasteride due to the background effects on normal prostate metabolism. Despite this, one-third of patients had a 30-45% reduction in cancer volume at 6 months. •Future studies including men with larger volume disease may enable estimates of response rates to be made more accurately.

Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention.

Epidemiological and prospective studies indicate that comprehensive lifestyle changes may modify the progression of prostate cancer. However, the molecular mechanisms by which improvements in diet and lifestyle might affect the prostate microenvironment are poorly understood. We conducted a pilot study to examine changes in prostate gene expression in a unique population of men with low-risk prostate cancer who declined immediate surgery, hormonal therapy, or radiation and participated in an intensive nutrition and lifestyle intervention while undergoing careful surveillance for tumor progression. Consistent with previous studies, significant improvements in weight, abdominal obesity, blood pressure, and lipid profile were observed (all P < 0.05), and surveillance of low-risk patients was safe. Gene expression profiles were obtained from 30 participants, pairing RNA samples from control prostate needle biopsy taken before intervention to RNA from the same patient's 3-month postintervention biopsy. Quantitative real-time PCR was used to validate array observations for selected transcripts. Two-class paired analysis of global gene expression using significance analysis of microarrays detected 48 up-regulated and 453 down-regulated transcripts after the intervention. Pathway analysis identified significant modulation of biological processes that have critical roles in tumorigenesis, including protein metabolism and modification, intracellular protein traffic, and protein phosphorylation (all P < 0.05). Intensive nutrition and lifestyle changes may modulate gene expression in the prostate. Understanding the prostate molecular response to comprehensive lifestyle changes may strengthen efforts to develop effective prevention and treatment. Larger clinical trials are warranted to confirm the results of this pilot study.

Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis.

Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single cell RNA sequencing using prospectively acquired patient specimens identified interferon response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.

CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4(+) T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4(+) T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4(+) T cells, but also in the number of CD4(+) FoxP3(+) Tregs. Although the effects were dose-dependent, CD4(+) FoxP3(+) regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was seen only at the highest dose level studied. Moreover, these expanded CD4(+) FoxP3(+) regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4(+) FoxP3(+) Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at http://www.clinicaltrials.gov/ct2/show/NCT00064129, registry number NCT00064129.

Perioperative outcomes comparing patient controlled epidural versus intravenous analgesia in gynecologic oncology surgery.

OBJECTIVES: Our aim was to compare perioperative patient controlled epidural analgesia (PCEA) versus patient controlled intravenous analgesia (PCA) after gynecologic oncology laparotomy. METHODS: This was a prospective cohort study where perioperative pain management was decided through patient-centered discussion by anesthesia and surgical teams. The study was designed to accrue 224 patients, to test for equivalence in pain control on postoperative day 1, defined as less than a 10% difference in the proportion of patients with a visual analog scale pain score of <2 (0-10 scale). RESULTS: Two hundred forty patients were enrolled, with 205 patients evaluable for outcomes: 98 received PCA, while 107 received a thoracic level PCEA. Utilization of PCEA was associated with longer anesthesia time pre-op (means: 60 vs. 44 min, p<0.0001), as well as more likely use of pressors during surgery (78% vs. 57%, p=0.002). Pain control was comparable between groups on postoperative day 1 (mean VAS: 2.4 vs. 2.5, p=0.56), but patients with PCEA tended to require more supplemental pain medications. Time to first ambulation was longer in the PCEA patients (means: 49 vs. 36 h post-op, p=0.03), with no difference in time to tolerating regular diet (means: 89 vs. 77 h post-op, 0.17) and no difference in readiness for discharge (means: 144 vs. 145 h post-op, p=0.95). CONCLUSIONS: In this nonrandomized prospective study, selection of a PCEA for perioperative pain management did not improve pain management for patients undergoing gynecologic oncology surgery.

High-dose-rate brachytherapy for localized prostate adenocarcinoma post abdominoperineal resection of the rectum and pelvic irradiation: Technique and experience.

PURPOSE: Treatment options are limited for patients with localized prostate cancer and a prior history of abdominoperineal resection (APR) and pelvic irradiation. We have previously reported on the successful utility of high-dose-rate (HDR) brachytherapy salvage for prostate cancer failing definitive external beam radiation therapy (EBRT). In this report, we describe our technique and early experience with definitive HDR brachytherapy in patients post APR and pelvic EBRT. PATIENTS AND METHODS: Six men with newly diagnosed localized prostate cancer had a prior history of APR and pelvic EBRT. Sixteen to 18 HDR catheters were placed transperineally under transperineal ultrasound-guidance. The critical first two catheters were placed freehand posterior to the inferior rami on both sides of the bulbar urethra under cystoscopic visualization. A template was used for subsequent catheter placement. Using CT-based planning, 5 men received 36Gy in six fractions as monotherapy. One patient initially treated with EBRT to 30Gy, received 24Gy in four fractions. RESULTS: Median age was 67.5 (56-74) years. At a median followup of 26 (14-60) months, all patients are alive and with no evidence of disease per the Phoenix definition of biochemical failure, with a median prostate-specific antigen nadir of 0.19ng/mL. Three men have reported grade 2 late genitourinary toxicity. There has been no report of grade 3-5 toxicity. CONCLUSION: Transperineal ultrasound-guided HDR brachytherapy using the above technique should be considered as definitive therapy for patients with localized prostate cancer and a prior history of APR and pelvic EBRT.

Chemoprevention of colonic polyps with balsalazide: an exploratory, double-blind, placebo-controlled study.

BACKGROUND: A number of agents, including aspirin, nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, folic acid, calcium, and vitamins, have been evaluated for their potential in chemoprevention of sporadic colorectal adenomas or cancer. Preclinical data suggest that 5-aminosalicylates also may have a chemopreventive effect. AIM: To investigate chemoprevention of colonic polyps with balsalazide, a 5-aminosalicylate prodrug. METHODS: In this randomized, double-blind, placebo-controlled study, adults diagnosed with small polyps in the rectosigmoid colon were treated with either balsalazide 3 g/d or placebo for 6 months. Follow-up lower endoscopy was performed, and all polyps were measured and analyzed histologically. The primary endpoint was reduction in mean size of the largest polyp per subject. RESULTS: Among 241 participants screened, 86 were randomized to treatment, with 75 subjects evaluable. Balsalazide 3 g/d (n = 38) did not significantly reduce the mean size of the largest colonic polyp or the number of polyps compared with placebo (n = 37). Although not significant, post-hoc analysis revealed that total adenoma burden per subject, calculated as the sum of the volumes of all adenomas in mm3, increased by 55% in the balsalazide group compared with 95% in the placebo group. CONCLUSIONS: Although balsalazide did not have significant chemopreventive effects on established colonic polyps, these results can aid in designing future prospective studies.

Decreased aortic growth and middle aortic syndrome in patients with neuroblastoma after radiation therapy.

BACKGROUND: Long-term CT follow-up studies are required in pediatric patients who have received intraoperative radiation therapy (IORT) and external beam radiation therapy (EBRT) to assess vascular toxicities and to determine the exact complication rate. OBJECTIVE: To analyze with CT the effects of radiation therapy (RT) on the growth of the aorta in neuroblastoma patients. MATERIALS AND METHODS: Abdominal CT scans of 31 patients with intraabdominal neuroblastoma (stage II-IV), treated with RT (20 IORT+/-EBRT, 11 EBRT alone), were analyzed retrospectively. The diameter of the abdominal aorta was measured before and after RT. These data were compared to normal and predicted normal aortic diameters of children, according to the model of Fitzgerald, Donaldson and Poznanski (aortic diameter in centimeters = 0.844 + 0.0599 x age in years), and to the diameters of a control group of children who had not undergone RT. Statistical analyses for the primary aims were performed using the chi-squared test, t-test, Mann-Whitney test, nonparametric Wilcoxon matched-pairs test and analysis of variance for repeated measures. Clinical files and imaging studies were evaluated for signs of late vascular complications of neuroblastoma patients who had received RT. RESULTS: The mean diameter before and after RT and the growth of the aorta were significantly lower than expected in patients with neuroblastoma (P<0.05 for each) and when compared to the growth in a control group with normal and nonirradiated aortas. Among the patients who had received RT, there was no difference due to the type of RT. Seven patients from the IORT+/-EBRT group developed vascular complications, which included hypertension (five), middle aortic syndrome (two), death due to mesenteric ischemia (one) and critical aortic stenosis, which required aortic bypass surgery (two). CONCLUSION: Patients with neuroblastoma who had received RT showed impaired growth of the abdominal aorta. Significant long-term vascular complications occurred in seven patients who received IORT+/-EBRT. Thus, CT evaluation of patients with neuroblastoma who receive RT should include not only reports of changes in tumor extension, but also documentation of perfusion, and the size and growth of the aorta and its branches over time.

Comparison of dosimetric and biologic effective dose parameters for prostate and urethra using 131 Cs and 125 I for prostate permanent implant brachytherapy.

PURPOSE: To compare the urethral and prostate absolute and biologic effective doses (BEDs) for 131 Cs and 125 I prostate permanent implant brachytherapy (PPI). METHODS AND MATERIALS: Eight previously implanted manually planned 125 I PPI patients were replanned manually with 131 Cs, and re-planned using Inverse Planning Simulated Annealing. 131 Cs activity and the prescribed dose (115 Gy) were determined from that recommended by IsoRay. The BED was calculated for the prostate and urethra using an alpha/beta ratio of 2 and was also calculated for the prostate using an alpha/beta ratio of 6 and a urethral alpha/beta ratio of 2. The primary endpoints of this study were the prostate D90 BED (pD90BED) and urethral D30 BED normalized to the maximal potential prostate D90 BED (nuD30BED). RESULTS: The manual plan comparison (alpha/beta = 2) yielded no significant difference in the prostate D90 BED (median, 192 Gy2 for both isotopes). No significant difference was observed for the nuD30BED (median, 199 Gy2 and 202 Gy2 for 125 I and 131 Cs, respectively). For the inverse planning simulated annealing plan comparisons (alpha/beta = 2), the prostate D90 BED was significantly lower with 131 Cs than with 125 I (median, 177 Gy2 vs. 187 Gy2, respectively; p = 0.01). However, the nuD30BED was significantly greater with 131 Cs than with 125 I (median, 192 Gy2 vs. 189 Gy2, respectively; p = 0.01). Both the manual and the inverse planning simulated annealing plans resulted in a significantly lower prostate D90 BED (p = 0.01) and significantly greater nuD30BED for 131 Cs (p = 0.01), compared with 125 I, when the prostate alpha/beta ratio was 6 and the urethral alpha/beta ratio was 2. CONCLUSION: This report highlights the controversy in comparing the dose to both the prostate and the organs at risk with different radionuclides.

von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma.

PURPOSE: The von Hippel-Lindau (VHL) gene is often inactivated (by mutation or promoter hypermethylation) in renal cell carcinoma but the relation to therapeutic outcome is unclear. MATERIALS AND METHODS: Patients with metastatic clear cell renal cell carcinoma with available baseline tumor samples who received vascular endothelial growth factor targeted therapy were included in analysis. Patient characteristics, VHL gene status and clinical outcome were documented. Our primary end point was to test for response rate in relation to VHL inactivation. Progression-free survival and overall survival in relation to VHL status were investigated as secondary end points. RESULTS: A total of 123 patients were evaluable. Response rate, median progression-free survival and median overall survival were 37% (95% CI 28-46), 10.8 (95% CI 7.7-14.8) and 29.8 (CI not estimable) months, respectively. Patients with VHL inactivation had a response rate of 41% vs 31% for those with wild-type VHL (p = 0.34). Patients with loss of function mutations (frameshift, nonsense, splice and in-frame deletions/insertions) had a 52% response rate vs 31% with wild-type VHL (p = 0.04). On multivariate analysis the presence of a loss of function mutation remained an independent prognostic factor associated with improved response. Progression-free survival and overall survival were not significantly different based on VHL status. CONCLUSIONS: To our knowledge this is the largest analysis investigating the impact of VHL inactivation on the outcome of vascular endothelial growth factor targeted agents in metastatic renal cell carcinoma. We did not find a statistically significant increase in response to vascular endothelial growth factor targeted agents in patients with VHL inactivation. Loss of function mutations identified a population of patients with a greater response. Investigation of downstream markers is under way.

Phase I study of dose escalation to dominant intraprostatic lesions using high-dose-rate brachytherapy.

PURPOSE: Radiation dose escalation for prostate cancer improves biochemical control but is limited by toxicity. Magnetic resonance spectroscopic imaging (MRSI) can define dominant intraprostatic lesions (DIL). This phase I study evaluated dose escalation to MRSI-defined DIL using high-dose-rate (HDR) brachytherapy. MATERIAL AND METHODS: Enrollment was closed early due to low accrual. Ten patients with prostate cancer (T2a-3b, Gleason 6-9, PSA < 20) underwent pre-treatment MRSI, and eight patients had one to three DIL identified. The eight enrolled patients received external beam radiation therapy to 45 Gy and HDR brachytherapy boost to the prostate of 19 Gy in 2 fractions. MRSI images were registered to planning CT images and DIL dose-escalated up to 150% of prescription dose while maintaining normal tissue constraints. The primary endpoint was genitourinary (GU) toxicity. RESULTS: The median total DIL volume was 1.31 ml (range, 0.67-6.33 ml). Median DIL boost was 130% of prescription dose (range, 110-150%). Median urethra V120 was 0.15 ml (range, 0-0.4 ml) and median rectum V75 was 0.74 ml (range, 0.1-1.0 ml). Three patients had acute grade 2 GU toxicity, and two patients had late grade 2 GU toxicity. No patients had grade 2 or higher gastrointestinal toxicity, and no grade 3 or higher toxicities were noted. There were no biochemical failures with median follow-up of 4.9 years (range, 2-8.5 years). CONCLUSIONS: Dose escalation to MRSI-defined DIL is feasible. Toxicity was low but incompletely assessed due to limited patients' enrollment.