bluuebunny/crossref_metadata_2025 huggingface dataset:
Bevacizumab activity in gastric cancer cells with high expression of VEGF.
Authors: Lee Hee Yeon , Shin Jung-Young , Kim Jeong-Oh , Zhang Xiang-Hua , Oh Ji-Eun , Kang Jin Hyoung
Published: February 2017

64

Background: Metastasis of cancer cells is associated with numerous activating molecules, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and tumor necrosis factor (TNF)-α. Excess VEGF production induces hematogenous metastasis in gastric cancer (GC) cells. To understand the anti-metastatic effect of bevacizumab, an anti-VEGF monoclonal antibody developed for selective inhibition of tumor angiogenesis, we investigated VEGF-induced expression of key adhesion molecules in human umbilical vein endothelial cells (HUVECs) and the inhibitory effect of bevacizumab on the adhesion of GC cells expressing high levels of VEGF.

Methods: We measured the soluble VEGF (sVEGF) produced by 7 GC cells by ELISA. We evaluated intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin expression in HUVECs pretreated with SNU-1-conditioned medium (SNU-1 CM) or recombinant VEGF (rhVEGF) at different time points by western blotting.

Results: We identified that SNU-1 cells secreted the highest sVEGF concentration in 7 GC cells. After rhVEGF pretreatment, ICAM-1 and E-selectin expression were highest at 4–6 h and 2 h, respectively, but VCAM-1 expression was unchanged. Bevacizumab cotreatment markedly decreased VCAM-1 and E-selectin expression to basal levels, whereas ICAM-1 expression was unaffected. The SNU-1 adherent cell percentage decreased following bevacizumab cotreatment of SNU-1 CM- or rhVEGF-pretreated HUVECs. Investigation of SNU-1-cell invasiveness through activated HUVECs revealed less than 10 invasive adherent cells, whereas no cells were found after bevacizumab cotreatment.

Conclusions: Our preclinical data suggests that bevacizumab, might contribute to anti-metastasis by inhibiting SNU-1 cell adhesion to HUVECs by reducing E-selectin and VCAM-1 expression.
Therapeutic effect of TAS-102 (A) in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy by the Köhne model (Km).
Authors: Nishina Tomohiro , Yoshino Takayuki , Mizunuma Nobuyuki , Yamazaki Kentaro , Komatsu Yoshito , Baba Hideo , Tsuji Akihito , Yamaguchi Kensei , Muro Kei , Ohtsu Atsushi
Published: February 2017

650

Background: TAS-102 is a novel oral antitumor agent consisting of trifluorothymidine and thymidine phosphorylase inhibitor. In the TAS-102 phase II study, TAS-102 significantly improved overall survival (OS) compared with placebo (P) in pts with mCRC who had 2 or more prior regimens and refractory to fluoropyrimidine, irinotecan and oxaliplatin (A: 112pts; P: 57 pts; median OS, 9.0 vs 6.6 months (M); HR, 0.56; p = 0.0011) [K. Yamazaki et al. JSMO 2011 Abst 10428, Y. Kuboki et al. ECCO 2011 Abst 6005]. Km [Ann Oncol 2002; 13:308-317] suggested predictive prognosis marker and showed 4 parameters to classify pts with mCRC treated 5-FU-based first line chemotherapy into 3 risk groups (low risk group (L), intermediate risk group (IM) and high risk group (H)). We retrospectively evaluated TAS-102 phase II study by Km.

Methods: Classification of pts into each risk group was done as follows: L is ECOG performance status (PS) 0-1, 1 tumor site; IM is (1) PS 0-1, >1 tumor site, ALP <300 IU/L and (2) PS >1, WBC <10×109 /L, 1 tumor site; H is (1) PS 0-1, >1 tumor site, ALP ≥300 IU/L, (2) PS >1, WBC <10×109 /L, >1 tumor site and (3) PS >1, WBC ≥10×109 /L. Progression-free survival (PFS) was assessed by an independent review committee.

Results: Pts were classified as L/ IM/ H in 36/ 31/ 102 pts. The median OS for TAS-102 vs Placebo were in L (not reached vs 10.1M; hazard ratio (HR), 0.62), in IM (9.0 vs 4.9 M; HR, 0.44) and in H (7.6 vs 5.6 M; HR, 0.58). This risk stratified analysis by Km demonstrated that HR of OS and PFS was similar in each risk group (Table).

Conclusions: The OS and PFS of TAS-102 were superior to that of placebo in all risk groups by Km. Further prospective TAS-102 phase III study is necessary to confirm these results.

[Table: see text]
Phase II study of helical tomotherapy in the multidisciplinary treatment of oligometastatic colorectal cancer.
Authors: Engels Benedikt , Gevaert Thierry , Everaert Hendrik , Sermeus Alexandra , Storme Guy , Verellen Dirk , De Ridder Mark
Published: February 2017

653

Background: Complete metastasectomy provides a real chance for long-term survival in patients with oligometastatic colorectal cancer (CRC). For patients who are not amenable for metastasectomy, we demonstrated in a previous study the feasibility of moderately hypofractionated intensity-modulated and image-guided radiotherapy (RT) by helical tomotherapy. Aiming at higher response rates, we evaluated in this study helical tomotherapy delivering 50 Gy in daily fractions of 5 Gy.

Methods: Inoperable CRC patients with ≤ 5 metastases were enrolled. No limitations concerning dimension or localization of the metastases were imposed. Whole body PET-CT was performed at baseline and 3 months after the initiation of RT to evaluate the metabolic response rate according to PERCIST v 1.0. Side effects were scored using the NCI CTC AE v 3.0 scale.

Results: We report the results of the first 22 patients. Thirteen patients (59%) received previous chemotherapy for metastatic disease, displaying residual (n=7) or progressive (n=6) metabolic active metastatic disease at time of inclusion. A total of 51 metastases were treated. Most common sites were the lung, liver and lymphnodes. One patient (5%) experienced grade 3 dysphagia; 2 patients (9%) and 1 patient (5%) grade 2 dysphagia and diarrhea, respectively. Twenty patients were evaluated by post-treatment PET-CT. Five and 6 patients achieved a complete and partial metabolic response, resulting in an overall metabolic response rate of 55%. At a median follow-up of 11 months, 17 patients (77%) developed progressive disease, of which 3 isolated local progression. Five patients (23%) are in remission in all irradiated areas without evidence of distant recurrence. Interestingly, those 5 patients received previous chemotherapy with residual oligometastatic disease at time of inclusion.

Conclusions: Ten fractions of 5 Gy resulted in a promising 55% metabolic response rate with limited toxicity. Helical tomotherapy is an attractive modality in the multidisciplinary approach of oligometastatic CRC, more specifically in the consolidation of residual and inoperable oligometastatic disease in patients previously treated with chemotherapy.
Effect of protons on bone marrow and small-bowel exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer.
Authors: Nichols Romaine Charles , Huh Soon N. , Getman Nataliya , Ho Meng Wei , Li Zuofeng , Awad Ziad , Zaiden Robert Anthony , Mendenhall Nancy Price , Mendenhall William M. , Hoppe Bradford S.
Published: February 2017

669

Background: Determine the potential role for protons in the preoperative treatment of resectable rectal cancer.

Methods: Eight consecutive patients with resectable (T2-T3) rectal cancers underwent 3D conformal photon (3DCRT); intensity-modulated photon (IMRT); and 3D conformal proton (PT) treatment planning. Initial target volumes (PTV1) were contoured using the RTOG anorectal atlas guidelines. Boost target volumes (PTV2) consisted of the gross rectal tumor plus a uniform 2cm expansion. Plans delivered 45Gray (Gy) or Cobalt Gray Equivalent (CGE) to the PTV1 and a 5.4 Gy (CGE) boost to the PTV2. Ninety-five percent of PTVs received 100% of the target dose and 100% of the PTVs received 95% of the target dose. Standard normal tissue constraints were utilized. Wilcoxon paired t-tests were performed to compare various dosimetric points between the 3 plans for each patient.

Results: All plans met all normal-tissue constraints and were isoeffective in terms of PTV coverage. Proton plans offered significantly reduced median normal-tissue exposure over the 3DCRT and IMRT plans with respect to: pelvic bone marrow (PBM) at the V5Gy, V10Gy, V15Gy and V20Gy levels and small bowel (SB) at the V10Gy and V20Gy levels. Proton plans also offered significantly reduced median normal-tissue exposure over the 3DCRT plans with respect to the SB at the V30Gy and V40Gy levels.

Conclusions: 1.) By reducing bone marrow exposure, protons may reduce the acute hematologic toxicity of neoadjuvant chemoradiation and increase the likelihood of uninterrupted chemotherapy delivery. Bone marrow sparing may also facilitate the delivery of salvage chemotherapy for patients who go on to develop hematogenous metastasis. 2.) By reducing small bowel exposure, protons may reduce toxicity and possibly facilitate the use of more aggressive concomitant chemotherapy with radiotherapy.

[Table: see text]
Relationship of myeloid-derived suppressor cells (MDSC) and immune suppression, nutritional impairment, and inflammatory markers in patients with gastrointestinal cancer.
Authors: Shibata Masahiko , Gonda Kenji , Nakamura Izumi , Ohki Shinji , Sakurai Kenichi , Shimura Tatsuo , Takenoshita Seiichi
Published: February 2017

675

Background: A suppression of cell mediated immunity and malnutrition are commonly seen in patients with advanced cancer and it has been reported that chronic inflammation plays a key role in induction of these conditions. MDSC: myeloid-derived suppressor cells, found as a new type of immune suppressor cells that is closely related to chronic inflammation, have reported to be present in blood circulation in patients with cancer. MDSC have been reported to suppress immune function through several pathways.

Methods: Peripheral blood mononuclear cells (PBMC) were collected from 18 normal healthy volunteers, and 53 patients with gastrointestinal cancer including 5 patients with esophageal, 16 with gastric, 26 with colorectal, 3 with bile duct, 1 with pancreatic and 1 with hepatocellular carcinomas, and these cells were used for the detection of MDSC (CD11b+CD14-CD33+) by flow cytometry. PBMC was also used for the PHA-blastogenesis of lymphocytes which is a marker of cell mediated immunity (stimulation indices: SI).

Results: MDSC(%PBMC) of whole patients with gastrointestinal cancer, those with gastric cancer and those with colorectal cancer were higher than those of healthy volunteer (3.76+4.90%, 5.18+1.86%, 4.21+1.43% vs 1.59+1.08%, p<0.05, p<0.05, p<0.10, respectively). MDSC of patients with gastrointestinal cancer were also inversely correlated to the SI (r=−0.271, p<0.05) and to the serum concentrations of total protein (r=−0.490, p<0.005). It also tended to correlate to neutrophil counts (r=0.287, p<0.10) and neutrophil/lymphocyte ratios (NLR, r=0.623, p=0.10), and inversely did to lymphocyte counts (r=−0.251, p<0.10).Thus MDSC was successfully detected in peripheral blood and was significantly higher in patients with gastrointestinal cancer. It was related to the inhibition of cell-mediated immunity, hypoaproteinemia and inflammatory markers such as NLR.

Conclusions: MDSC seemed to work in the mechanisms of suppression of immune reaction and malnutrition, typically seen in cancer cachexia, in patients with gastrointestinal cancer and may be important as a marker of advancement of malignant diseases.
Treatment of rectal cancer with synchronous metastasis at diagnosis: 65 consecutive Italian cases of the Bologna Multidisciplinary Rectal Cancer Group.
Authors: Pinto Carmine , Pini Sara , Di Fabio Francesca , Cuicchi Dajana , Iacopino Bruno , Lecce Ferdinando , Ercolani Giorgio , Rojas Llimpe Fabiola Lorena , Giaquinta Stefania , Martoni Andrea
Published: February 2017

676

Background: Twenty per cent of middle/low rectal cancer pts have synchronous distant metastasis (M1) at diagnosis. At present, the treatment strategy in this pt setting is not well defined. This mono-institutional retrospective analysis evaluates the treatment strategy and clinical outcome of three different pt group.

Methods: Between January 2000-July 2011 the Bologna Multidisciplinary Rectal Group of S. Orsola-Malpighi Hospital evaluated 65 pts with rectal cancer M1 disease. Three different groups were defined: rectal cancer with resectable metastatic disease (Group A); rectal cancer with potentially resectable metastatic disease (Group B); and rectal cancer with unresectable metastatic disease (Group C). Treatment strategy in the different groups entailed an individualized approach.

Results: The distribution per group was: Group A 11 (17%) pts, Group B 28 (43%), and Group C 26 (40%). The pt characteristics were: M 42 (64.6%), F 23 (35.4%); median age 62 years (35-83); median ECOG PS 0 (0-2); cT3 45(69.2%), cT4 20 (30.8%); cN- 10 (15.4%), cN+ 55 (84.6%); M1 sites: liver 32 (49.2%), lung 8 (12.3%), liver + lung 11 (16.9%), ovary/peritoneal carcinosis/abdominal lymph nodes 7 (10.8%), liver + bone 2 (3.1%), >2 sites 5 (7.7%). Forty-three (66.2%) pts underwent to surgery for primary rectal tumor, and 30 (46.2%) pts for metastasis resection (23 liver, 5 lung, 2 liver + lung). Treatments for different groups are shown (Table). Median OS according to the three different groups was: Group A not reached, Group B 32 months (95% CI 24-40), and Group C 16 months (95% CI 7-26). Patients undergoing metastasis resection have higher median OS than those not resected: 44 months (95%CI 12-76) vs 15 months (95% CI 8-23) (p=0.0006).

Conclusions: Treatment strategy in synchronous metastatic rectal cancer must consider the possibility of distant metastasis resection. Long-term survival can be achieved using an integrated approach.

[Table: see text]
Update of AMC 0201 study: A randomized phase III trial comparing mitomycin-C plus short-term doxifluridine (Mf) versus mitomycin-C plus long-term doxifluridine plus cisplatin (MFP) after curative resection of advanced gastric cancer (NCT00296335).
Authors: Ryoo Baek-Yeol , Kang Yoon-Koo , Min Young Joo , Zang Dae Young , Kim Gyu Yeol , Yang Dae Hyun , Jang Se Jin , Yook Jeong Hwan , Oh Sung Tae , Kim Byung Sik
Published: February 2017

76

Background: Despite a continuing debate on the role of adjuvant chemotherapy, several studies have suggested that mitomycin-C (M) plus fluoropyrimidine (f) could improve the outcome of curatively resected advanced gastric cancer (AGC) patients (pts). To improve further the adjuvant Mf chemotherapy, we have prolonged the administration of oral fluoropyrimidine (F) and added cisplatin (P) to Mf (MFP) and performed a phase III randomized trial to determine whether this strategy could improve the 3-year relapse free survival (3yRFS) in curatively resected AGC pts (HR=0.63, α=0.05, β=0.1). Three year follow-up results were reported in 2008 ASCO meeting. Here we report long-term follow-up results for confirmation.

Methods: Three to 6 wks after R0 resection, the pts who had postoperative stage II-IV were randomized to receive either Mf or MFP adjuvant chemotherapy. For Mf group, 20 mg/m2 of M was iv injected and 4 wks later, 460-600 mg/m2/day of doxifluridine was administered orally for 3 months. For MFP group, the administration of doxifluridine was extended for a total of 12 months and 6 shots of monthly 60 mg/m2 of cisplatin were added to Mf.

Results: Between Feb 2002 and Aug 2006, a total of 871 pts were randomized (435 in Mf, 436 in MFP). Sixteen pts were excluded because of ineligibility (11 in Mf, 5 in MFP). Postoperative stages were II in 51.0%, IIIA in 31.1%, IIIB in 9.4%, and IV in 8.5% of pts. With a median follow up of 6.6 yrs in April 2011, a total of 353 events (relapse or death) have been observed. There was no difference in RFS between the two groups (HR, 1.10; 95% C.I. 0.89 – 1.35; p=0.3918; 5yRFS 61.1% in Mf and 57.9% in MFP). Difference in overall survival (OS) was also insignificant (HR, 1.11; 95% C.I. 0.89 – 1.39; p=0.3349; 5yOS 66.5% in Mf and 65.0% in MFP).

Conclusions: Long-term follow-up results of AMC 0201 trial confirmed prolongation of doxifluridine administration and addition of cisplatin to adjuvant chemotherapy with mitomycin-C plus 3 months of doxifluridine did not improve the treatment outcome in curatively resected AGC pts.
ABI-007 in the treatment of unresectable or recurrent gastric cancer refractory to fluoropyrimidine-containing regimen: Updated data from the multicenter phase II study.
Authors: Takiuchi Hiroya , Sasaki Yasutsuna , Nishina Tomohiro , Yasui Hirofumi , Muro Kei , Tsuji Akihito , Koizumi Wasaburo , Toh Yasushi , Hara Takuo , Miyata Yoshinori
Published: February 2017

90

Background: ABI-007 is a novel Cremophor-free nanoparticle albumin-bound paclitaxel. Cremophor-free formulation allows administration using a shorter infusion schedule (30 minutes) and without the need for premedicaion to prevent solvent-based hypersensitivity reactions.This single arm phase II study evaluated the efficacy and safety of ABI-007 given every three weeks to unresectable or recurrent gastric cancer patients (pts) who had received one prior chemotherapy regimen containing fluoropyrimidine and developed disease progression (PD) or recurrence.

Methods: Eligibility include: histologically or cytologically confirmed gastric adenocarcinoma , received one prior regimen containing fluoropyrimidine analogs and developed PD or recurrence, age: 20 - 74, at least one measurable lesion by RECIST(1.0), PS:0-2, adequate organ function and written informed consent. Study duration was until PD or unacceptable toxicity developed. Pts received ABI-007 260 mg/m2, i.v. on day 1 of each 21 day cycle) without premedication. The primary endpoint was overall objective response rate (ORR).

Results: From April 2008 to July 2010, total of 56 pts were enrolled, 55 received the study treatment, and 54 pts were evaluable for response. Median age was 64, Male/Female was 43/12, PS:0/1/2 was 33/22/0 and number of sites of metastasis corresponding was 1/2/≥3:19/21/15. ORR was 27.8% (15/54; 95%CI, 16.5-41.6) and DCR (disease control rate:CR+PR+SD) was 59.3% (32/54, 95%CI, 45.0-72.4) for all evaluable patients. One confirmed CR was observed. Median progression–free survival was 2.9 months (95%CI, 2.4-3.6), and median overall survival was 9.0 months (95%CI, 6.6-11.5). The most common grade 3/4 toxicities were neutropenia (49.1%), leucopenia (20.0%), lymphopenia (10.9%); and peripheral sensory neuropathy (23.6%).

Conclusions: These data demonstrate that ABI-007 showed promising activity with well-tolerated toxicities for previously treated unresectable or recurrent gastric cancer pts.
Outcomes of multivisceral resection of gastric gastrointestinal stromal tumors.
Authors: Ganai Sabha , Posner Mitchell , Prachand Vivek N. , Alverdy John C. , Choi Eugene A. , Waxman Irving , Patti Marco G. , Roggin Kevin K.
Published: February 2017

91

Background: Despite the recent introduction of imatinib and laparoendoscopic techniques to the management of gastric gastrointestinal stromal tumors (GISTs), outcomes remain uncertain in the setting of multivisceral involvement.

Methods: We conducted a retrospective review of 69 consecutive patients who underwent resection of gastric GISTs from October 2002 through August 2011. Median follow-up was 19 months (interquartile range [IQR] 4-37).

Results: Patients were 51% female, with a mean age of 65 ± 13 years and BMI of 30 ± 8 kg/m2. Patients undergoing multivisceral resection (n=13) had a longer interval from diagnosis to surgery (7.4 [IQR 1.9 – 15.0] vs. 1.3 [IQR 0.7-3.5] months, p<0.01), greater use of neoadjuvant imatinib (62% vs. 4%, p<0.001), and greater preoperative tumor size (12 ± 8 vs. 4 ± 3 cm, p<0.001) in comparison to gastric-only resections (n=56). Patients were less likely to be managed laparoscopically (8% vs. 71%, p<0.001), had a longer operative time (286 ± 92 vs. 152 ± 65 min, p<0.001), and were less likely to be R0 (69% vs. 98%, p<0.001). While patients undergoing multivisceral resection were more likely to have a pathological complete response to therapy (23% vs. 0, p<0.01), they were also more likely to have metastatic disease present (31% vs. 0, p<0.01). Hospital length of stay was greater (median 8 [IQR 7-9] vs. 3 [IQR 2-6] days, p<0.001). There were no significant differences in grade or mitotic index between groups, or in the use of adjuvant imatinib (54% vs. 23%). Overall survival was less in patients undergoing multivisceral resection (63% vs. 86% at 3 years, p<0.05), as was disease-free survival (52% vs. 71% at 3 years, p<0.05). Median disease-free survival was 50 and 66 months, respectively (p<0.01). Controlling for tumor size, grade, resection status, and the use of neoadjuvant imatinib, multivisceral resection was an independent predictor of disease-free survival (p<0.05).

Conclusions: Multivisceral involvement is associated with tumors of greater size, and despite an increased use of neoadjuvant imatinib, it is associated with poor outcome for patients with gastric GISTs.
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in men with prostate cancer previously treated with taxane.
Authors: Petrylak Daniel Peter , Kantoff Philip W. , Mega Anthony E. , Dreicer Robert , Frank Richard C. , Shore Neal D. , Morris Stephen , Olson William C. , Israel Robert Joseph
Published: February 2017

107

Background: The abundant expression of prostate specific membrane antigen (PSMA) type II transmembrane glycoprotein on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage and release of free MMAE occur, causing cell cycle arrest and apoptosis. We report results from an ongoing phase 1 dose escalation study of PSMA ADC in patients (pts) with taxane-refractory metastatic castration-resistant prostate cancer (metCRPC).

Methods: Eligibility requirements include metCRPC after taxane-containing regimen and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Adverse events, PK, PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS. Dosing cohorts have ranged from 0.4 mg/kg to 2.2 mg/kg.

Results: 26 pts have enrolled in six dosing cohorts (0.4, 0.7, 1.1, 1.6, 1.8, 2.0 mg/kg). Treatment has to date been generally well tolerated with the most commonly seen adverse event being fatigue and the most common laboratory abnormalities being reversible changes in liver and hematological parameters. Antitumor activity manifested as reductions in PSA, circulating tumor cells and/or bone pain has been observed in the higher dose cohorts and appears to be dose-related. Exposure to PSMA ADC increased with dose and was ∼1,000-fold greater than MMAE exposure. Similar PK metrics were observed after the first and third doses. Dosing at the 2.2 mg/kg cohort is continuing and an MTD has not yet been reached.

Conclusions: In pts with metCRPC previously treated with taxane PSMA ADC has exhibited dose-related antitumor activity. The MTD has not yet been reached and enrollment is ongoing at higher dose levels.
Tumor regression and growth rates determined in two intramural NCI prostate cancer trials: The growth rate constant as an indicator of therapeutic efficacy.
Authors: Adesunloye Bamidele , Stein Wilfred Donald , Wilkerson Julia , Huang Xuan , Karzai Fatima H , Madan Ravi A. , Apolo Andrea Borghese , Figg William Douglas , Dahut William L. , Fojo Tito
Published: February 2017

133

Background: Like ATTP [bevacizumab + thalidomide + docetaxel + prednisone], ARTP [bevacizumab + lenalidomide + docetaxel + prednisone] is active in CRPC and in both the data suggest acquired resistance does not develop, supporting a strategy that continues therapy if tolerable. Discerning amongst new therapies in CRPC would be helped by novel assessment strategies that yield answers from smaller trials and allow comparisons across trials. We have validated a novel assessment method that quantifies tumor regression (d) and growth (g) rate constants using data obtained while pts are treated in a trial. We utilized this method to evaluate a phase II trial of ARTP in CRPC contrasting this with a previous study using thalidomide instead of lenalidomide (ATTP).

Methods: Using PSA values and a two-phase mathematical equation we determined d and g. A three-phase equation was used to determine resistant fractions.

Results: The median log g value with ARTP (-2.84) was statistically similar (p=0.204) to that observed with ATTP (-3.16). Both therapies had similar effects on log d (ARTP=-2.18; ATTP=-2.64; p=0.404). In a subset of pts with robust data both regimen are highly effective with only 3.01% and 5.46% of tumor resistant to ATTP and ARTP, respectively. In individual pt, statistically valid g and d values could be estimated after the fourth PSA value had been obtained, long before PSA increased - providing an early indicator of treatment failure. In most pts receiving prolonged treatment – as long as 700 d – the growth rate constant did not change, despite rising PSA values, indicating acquired resistance did not develop, and that if tolerable, therapy can be continued for longer periods of time.

Conclusions: The substitution of daily thalidomide with lenalidomide 14/21 days in ARTP resulted in a combination statistically as effective as ATTP. As with ATTP majority of pts experienced marked reductions in the tumor’s g, and surprisingly in most, there was no evidence of acquired resistance, g remaining unchanged over prolonged time periods. Given the tolerability of this combination, pts with marked reductions in g may benefit from prolonged ARTP therapy.
Is systematic 10 core prostate needle biopsy enough for treatment determination of localized prostate cancer?
Authors: Kishimoto Ryo , Tanimoto Ryuta , Bekku Kensuke , Kobayashi Yasuyuki , Ebara Shin , Saika Takashi , Nasu Yasutomo , Kumon Hiromi
Published: February 2017

163

Background: To evaluate whether the systematic 10 cores prostate needle biopsy is enough for determination of NCCN risk classification (NRC), we analyzed migration of Gleason score (GS), cancer location, and NRC between pre and postoperative periods in a cohort of patients who underwent radical prostatectomy.

Methods: A total of 197 patients were included in this study. These patients were divided into three groups along the number of biopsy cores: less than 10 (L), 10, and more than 10 (M). We compared between three groups about Gleason score, cancer location and NCCN risk classification change (CC) between prostate biopsy and radical prostatectomy specimen. Statistical analysis were performed with chi-square test, and multiple logistic regression with p<0.05, and Bonferroni correction with p<0.017 considered significant difference.

Results: The rate of CC in L, 10, M was 55.1%, 43.0%, 26.5%, respectively. On chi-square test rates of CC were significantly different between three groups (P=0.035), but rates of Gleason score and cancer location were not. On univariate analysis, PSA (Odds rate (OR) 0.872 p<0.001), preoperative NRC (low vs. intermediate, and poor, OR 0.157 and 0.241, p<0.001), prostate volume (normal vs. mild or moderate, OR 1.989 p=0.025), the number of biopsy cores (L vs. M, OR 0.293 p=0.011), GS (6 vs. 8, OR 2.374 p=0.021) were correlated with CC. On multivariate analysis, the most important independent predictive factors for CC were preoperative NRC (low vs. intermediate, p<0.001, OR 0.198, 95% CI 0.09-0.45) and PSA (p=0.007, OR 0.903, 95%CI 0.83-0.98), but the number of biopsy cores was not associated CC significantly.

Conclusions: Although multivariate analysis showed no significant difference, the more biopsy cores reduced the risk of CC. Systematic 10 core biopsy might be insufficient for accurate diagnosis and treatment decision of prostate cancer.
Tc-99m labeled small-molecule inhibitors of prostate-specific membrane antigen (PSMA): New molecular imaging probes to detect metastatic prostate adenocarcinoma (PC).
Authors: Osborne Joseph , Akhtar Naveed Hassan , Vallabhajosula Shankar , Nikolopoulou Anastasia , Maresca Kevin P. , Hillier Shawn M. , Joyal John L. , Crummet Robert , Armor Thomas , Tagawa Scott T. , Nanus David M. , Goldsmith Stanley J. , Babich John W.
Published: February 2017

173

Background: Sensitive and specific imaging remains a clinically-relevant problem for men with PC. PSMA is a well established target for imaging of PC with therapeutic implications. We have recently developed novel 99mTc-labeled small molecule inhibitors of the enzymatic domain of PSMA based on glutamate-urea-glutamate and glutamate-urea-lysine pharmacophores, and contain a bis-imidazole chelator to complex Tc-99m. Preclinical studies with PSMA positive LNCaP cells and xenografts demonstrate that 99mTc-MIP-1404 and 99mTc-MIP-1405 bind to PSMA with high affinity and localize in tumors rapidly. This study reports the first human data in men with metastatic PC and in healthy male subjects.

Methods: Under an exploratory IND, using a cross-over design, the pharmacokinetics, biodistribution, and tumor uptake of 99mTc-MIP-1404 and 99mTc-MIP-1405 were compared in 6 healthy men and 6 men with radiographic evidence of metastatic PC. Whole body images were obtained at 10 min, 1, 2, 4 and 24 hr. Single photon emission computed tomography (SPECT) was performed between 3–4 hours post injection.

Results: Both agents cleared the blood rapidly with MIP-1404 demonstrating significantly lower urinary activity (7%) compared to MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal and parotid glands. Uptake in liver and kidney was acceptable for imaging at 1-2 hr post injection (PI). In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 hr PI. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone and CT scans, In majority of patients, more lesions including sub-cm lymph nodes were seen with 99mTc-MIP-1404 and 99mTc-MIP-1405. The high contrast images exhibited signal:noise ratios from 3:1 to 28:1 at 4 and 24 hr.

Conclusions: 99mTc-MIP-1404 and 99mTc-MIP-1405 identified a greater number of lesions than bone scans and rapidly detected soft tissue PC lesions including sub-cm lymph nodes. Since 99mTc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high risk clinically-localized PC.
Effect of adding short-term androgen deprivation therapy to dose-escalated radiation therapy on failure-free survival for select men with intermediate-risk prostate cancer.
Authors: Bian Shelly , Kuban Deborah A. , Levy Lawrence B. , Oh Jeong Hoon , Castle Katherine , Pugh Thomas , Choi Seungtaek , McGuire Sean E. , Frank Steven J. , Nguyen Paul Linh , Lee Andrew , Hoffman Karen Elizabeth
Published: February 2017

176

Background: Independently, dose-escalated external beam radiation therapy (DE-EBRT) and short-term androgen deprivation therapy (ADT) improve outcomes for men with intermediate-risk prostate cancer; however, the incremental benefit of adding short-term ADT to DE-EBRT is uncertain. The aim of this study was to determine the effect of adding ADT to DE-EBRT and to identify men most likely to benefit from ADT.

Methods: We reviewed the medical records of 636 men treated for intermediate-risk prostate cancer with DE-EBRT (>75 Gy) from 1995 to 2009. The adult comorbidity evaluation-27 index categorized severity of comorbidity. Recursive partitioning analysis defined unfavorable disease. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT.

Results: Median age was 70 years (interquartile range [IQR] 65–74). Overall, 45% received DE-EBRT alone and 55% DE-EBRT with ADT (median 6 months, IQR 6-8). Median follow up was 4.3 years. On Cox-proportional hazard regression analysis that adjusted for differences in comorbidities and tumor characteristics, administration of ADT improved FFS (adjusted hazard ratio 0.36, 95% confidence interval 0.18–0.72; p=0.004). Recursive partitioning analysis of men without ADT classified Gleason 4+3=7 or ≥ 50% positive cores as unfavorable disease (5-year FFS 96.3% favorable vs. 81.6% unfavorable; p<0.001). The addition of ADT to DE-EBRT improved 5-year FFS for men with unfavorable disease (n=334; 81.6% vs. 92.9%; p=0.009) but did not improve FFS for men with favorable disease (n=302; 96.3% vs. 97.4%; p=0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (p=0.006) but did not improve FFS for men with unfavorable disease and moderate to severe comorbidity (p=0.380).

Conclusions: The addition of ADT to DE-EBRT improves FFS for men with unfavorable intermediate-risk prostate cancer (Gleason 4+3=7 or ≥ 50% positive cores) especially those with no or minimal comorbidity. Men with favorable intermediate-risk disease or with moderate to severe comorbidity may not benefit from the addition of ADT to DE-EBRT.
Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer.
Authors: Sheikh Nadeem A. , Wesley Johnna D. , Perdue Nikole , Stewart Frances P. , Fong Lawrence
Published: February 2017

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Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in subjects with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC).

Methods: Subjects with localized prostate cancer were enrolled in an open-label, Phase 2 study (P07-1; NCT00715104 ) in which they received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to radical prostatectomy. All samples were evaluated for cellular composition and antigen presenting cell (APC) activation pre- and post-culture with PA2024, a fusion protein comprising prostatic acid phosphatase and granulocyte macrophage-colony stimulating factor. Additionally, cytokines within the culture supernatant were assessed, and T and B cell activation were evaluated pre- and post-culture using flow cytometry.

Results: Of the 42 enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T. Consistent with previous trials in mCRPC, CD54 upregulation (APC activation) was greater at the second and third infusions relative to the first. While the percent of CD4+ and CD8+ T cells was unchanged with treatment, the expression of early T cell activation markers (CD134, CD137, CD278 and CD279) was increased in pre-culture cells obtained after the first infusion, and further increased post-culture. Similarly, while the percent of B cells was unchanged, there was a progressive increase in memory B cells (CD20+CD27+IgD−CD86+; pre- and post-culture) and activated mature B cells (CD20+CD27+IgD+CD86+; post-culture) following the first infusion. Activated T cell-associated cytokines were significantly elevated (TNF-α, P < 0.001; IFN-γ, P < 0.001; and IL-2, P < 0.001) in the second and third products.

Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune system activation that included APCs, memory and activated mature B cells, and both CD4+ and CD8+ T cells. The patterns observed at the second and third infusions, relative to the first, are consistent with an immunological prime-boost profile.
Effect of serum testosterone on treatment outcomes in patients with intermediate- to high-grade prostate cancer.
Authors: Jackson Matthew W. , Ramahi Emma , Swanson Gregory P. , Basler Joseph W.
Published: February 2017

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Background: Low serum testosterone (TS) has been suggested to be a potential marker for more aggressive prostate cancer. However, there are conflicting data regarding whether or not patients with low TS have a higher rate of biochemical recurrence following radical prostatectomy (RP). We evaluated the relationship between postoperative TS and treatment outcomes in patients with Gleason 7–10 adenocarcinoma of the prostate.

Methods: Our retrospective study cohort included 462 men diagnosed with Gleason 7–10 prostate cancer who underwent RP between 1998 and 2008 at a single institution. Patients were stratified into five groups on the basis of their postoperative TS percentile within the study cohort (<10th percentile, 10–25, 25–75, 75–90, or >90th percentile). Primary endpoints for comparison were biochemical failure free survival (BFFS) and overall survival (OS). PSA >0.2 ng/dl was used to define biochemical failure.

Results: In the study cohort, mean TS was 345.2 ng/dl ± 125.2 and range 107–872 ng/dl. 44 of the 462 men had TS ≤203 ng/dl. This group had a 5-year BFFS of 43% which was significantly worse than all other TS strata (p=0.0017). Range of 5-year BFFS in all other percentile groups was 61.4 – 68.6%. There was no significant difference noted between patients with TS ≥508 ng/dl (>90th percentile) and all other TS strata (p=0.694). Furthermore, no difference in OS was noted among any of the groups (p=0.842). Groups did not differ significantly with respect to age, BMI, presence of diabetes, or known cardiovascular disease.

Conclusions: Patients with exceedingly low TS are at significantly increased risk for biochemical failure following RP. Further prospective study is warranted to elucidate interventions that might improve biochemical outcomes in these patients.

[Table: see text]
Non-enrichment-based method for analysis of androgen receptor expression in circulating tumor cells (CTCs) in patients with metastatic castrate-resistant prostate cancer.
Authors: Gross Mitchell E. , Lazar Daniel , Cho Edward H , Luttgen Madelyn , Metzner Thomas , Uson Maria Loressa , Torrey Melissa Louise , Kuhn Peter
Published: February 2017

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Background: We have established a fluid phase biopsy approach that identifies CTCs which preserves cytologic features in high-definition (HD) for diagnostic pathology without using immune or surface receptor-based enrichment. HD-CTCs identified with this approach can be used for enumeration and molecular characterization.

Methods: Blood was collected from metastatic prostate cancer patients and normal donors in Cyto-Chex tubes (Streck, Omaha, NE) as part of IRB approved protocols at each site. Following erythrocyte lysis, 3 million nucleated cells were deposited on a glass slide. Samples were incubated with a pan-cytokeratin (CK), CD45, and androgen receptor (AR) antibodies and counter-stained with DAPI. LNCaP cells were spiked into normal blood. Images were obtained with a fluorescent scanning microscope and analyzed with a computer algorithm. Candidate HD-CTCs were subsequently verified by expert readers. Slides were re-imaged for quantitative analysis using at a fixed exposure and gain.

Results: A total of 227 CTCs from ten patients were compared to 20 LNCaP cells. The median (range) HD-CTCs in this cohort was: 9 (1-62) cells/ml. The mean ± standard deviation measurements in HD-CTCs were observed: CK intensity 60.4±154; total cell area 89.0 ± 53.8 µm2; nuclear area 61.1 ± 36.0 µm2. LNCaP cells spiked into normal blood gave the following values: CK intensity 1166+/−306; total cell area 143 ± 48.1 µm2; nuclear area 63.1 ± 18.6 µm2. CTCs were additionally classified as either AR positive (AR+) or AR negative (AR−). 37 of the 227 (16.3%) HD-CTCs were AR+. The average CK intensity was significantly higher in AR+ versus AR− cells at 174.23 and 39.86, respectively (p<0.001). The AR expression intensity in AR+ HD-CTCs and LNCaP cells was comparable at 979.4 and 902.2, respectively (p=0.824).

Conclusions: We find a positive association between AR and CK expression on a per cell basis. Further, we find AR is expressed at comparable levels in CTCs from patients and human prostate cancer cells in culture. The HD-CTC based approach may be used for enumeration and molecular interrogation of CTCs in patients with prostate cancer.
Identifying patients with node-positive prostate cancer who may benefit from adjuvant pelvic radiation following prostatectomy.
Authors: Shukla Monica Erin , Reddy Chandana A. , Stephans Kevin L. , Stephenson Andrew J. , Klein Eric A. , Garcia Jorge A. , Dreicer Robert , Tendulkar Rahul D.
Published: February 2017

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Background: Three PRTs address the role adjuvant radiotherapy (RT) following radical prostatectomy (RP) in men with locally advanced and/or margin positive prostate cancer (PCa), one of which demonstrated an improvement in overall survival by the addition of early RT. Not addressed in these studies is the role of adjuvant RT in lymph node positive (LN+) PCa.

Methods: We reviewed an IRB-approved prospective database at the Cleveland Clinic and identified 84 men with non-metastatic, LN+ PCa treated with RP from 1987-2010. Men receiving neoadjuvant therapy or adjuvant RT were excluded from this analysis. Pelvic failure (PF) was defined as recurrence in the prostate bed or pelvic LN up to the common iliacs. Distant failures (DF) were defined as any LN recurrence beyond the common iliacs, bone, or other solid organ metastases. Kaplan-Meier estimates of pelvic failure (PF), distant failure (DF) and overall survival (OS) were conducted.

Results: Median follow-up was 6 years. The median initial PSA was 10.1 ng/mL, 50% had Gleason 7, 12% had Gleason 8, 31% had Gleason 9 disease. The median number of LNs dissected was 11 (range 1-49) and 36% had >1 LN+. Extracapsular extension was present in 90%, seminal vesicle invasion in 66%, and surgical margins positive in 55%. The 6 week post-operative PSA was undetectable (<0.2 ng/ml) in 58%. Overall, 41% received immediate androgen deprivation therapy (ADT), and 45% received delayed ADT after biochemical or clinical failure, while 23% received salvage RT and 22% received chemotherapy. The 10-year OS was 61%. Clinically documented PF and DF occurred in 14% and 24%, respectively. Gleason score was the factor most predictive of PF, DF, and OS. Comparing Gleason score of ≤7 vs. ≥8, the 5-year PF rate was 3% vs. 24% (p=0.006), the 5-year DF rate was 2% vs. 37% (p<0.0001), and 5-year OS was 97% vs. 74% (p<0.0001), respectively. The number of LN+ was not prognostic.

Conclusions: Men with Gleason score ≥8 LN+ PCa have a high rate of pelvic recurrence, and pelvic radiation may be worthy of prospective investigation.
Androgen receptor and HIF-1α interaction in prostate cancer.
Authors: Reece Kelie M , Troutman Sarah M , Pressler Heather M , Pisle Stephen T , Figg William Douglas
Published: February 2017

197

Background: Prostate cancer is the most common noncutaneous cancer among men in the United States, and its progression is largely controlled by the androgen receptor (AR). Androgen deprivation therapy (ADT) is an initially effective treatment for prostate cancer, but most tumors eventually become castrate resistant. Tumor hypoxia also appears to be associated with a poor prognosis in prostate cancer. HIF-1a regulates the transcription of genes that allow tumor survival and growth in low oxygen conditions. Our laboratory has data showing that in response to castration and anti-androgen therapy in mice, there was a strong transcriptional relationship between HIF-1a and AR, as measured by quantitative RT-PCR, suggesting an interaction between the two proteins. Thus, the purpose of this study was to determine if there is a molecular interaction between HIF-1a and AR in prostate cancer cells.

Methods: We used Western blot analysis to examine the expression levels of HIF-1a and AR in LNCaP prostate cancer cells to determine if they are upregulated together at the protein level. Four experimental conditions were tested: control (no treatment), DHT for induction of AR expression, CoCl2 for induction of HIF-1a, and a combination treatment of DHT and CoCl2. Immunoprecipitation experiments were carried out to determine if there is an association between HIF-1a and AR. In addition, cells were fractionated into nuclear and cellular cells extracts, followed by Western blot analysis to determine where in the cells this interaction occurs.

Results: Western blot analysis of cell lysates showed synergistic upregulation of both HIF-1a and AR expression only under combined CoCl2 and DHT treatment conditions. In addition, immunoprecipitation experiments showed that HIF-1a and AR exist in a complex with one another, and fractionation experiments indicated this complex occurs in the nucleus.

Conclusions: Our results demonstrate that HIF-1a and AR associate with one another in cells. Binding assays are in progress to determine the nature of this interaction. In addition, we are examining the cellular consequences of this protein interaction, as it is possible that upregulation of HIF-1a in response to low androgen contributes to the development of tumor resistance to ADT.
Performance characteristics of PSA in patients undergoing radical prostatectomy.
Authors: Liu Jen-Jane , Brooks James D , Ferrari Michelle , Nolley Rosie , Presti Joseph C.
Published: February 2017

199

Background: The Prostate Cancer Prevention Trial demonstrated that the performance characteristics of PSA are improved for diagnosis of high grade disease. We assessed the performance of PSA for determining total and high grade cancer volume in a radical prostatectomy series.

Methods: We identified 1307 patients from the Stanford Radical Prostatectomy Database with clinical stage T1c (n=658) and T2 (n=549) disease who had surgery between 1988 and 2002 and detailed morphometric mapping by a single pathologist. Patients with T1c and T2 disease were analyzed separately as the indication for biopsy was different in these two populations (elevated PSA versus abnormal DRE). We generated receiver operating characteristic (ROC) curves for PSA based on total tumor volume and volume of Gleason 4 or 5 disease and compared the areas under the curve (AUC) for different cut points of total and high grade cancer volume.

Results: For patients with clinical stage T1c disease, as total and high grade cancer volumes increased, so did the AUC for PSA performance. There was a significant difference in AUC for PSA for total cancer volumes greater than 0.5 cc (AUC=0.62) compared to greater than 2 cc (AUC=0.72, p=0.02), and also between volumes greater than 2 cc (AUC=0.72) and 5 cc (AUC=0.79, p=0.0003, Fig.1). The AUC for PSA performance for volume of high grade disease increased from 0.66, to 0.68, to 0.76 for Gleason 4 or 5 volumes of 0, 0.5, and 3 cc, respectively (Fig. 2). For patients with clinical stage T2 disease, the AUCs for total or high grade cancer volume were not different across cut points, but were overall higher compared to the T1c group.

Conclusions: In T1c patients, PSA performance improved in a stepwise fashion with higher total and high grade cancer volumes as evidenced by improved receiver operating characteristics. In T2 patients, no similar trend was observed, although overall PSA performance was improved compared to T1c patients. Prior studies show that PSA performs better for the detection of high grade disease; here, we show that PSA performs better in predicting volume of high grade disease in radical prostatectomy specimens.