bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a real-time multiplex PCR assay for the detection of FGFR3 mutations in urine.
Authors: Millholland J. , Patel S. G. , Fernandez C. A. , Shuber A. P.
Published: February 2017

271

Background: We have recently reported the development of a Multi-Analyte Diagnostic Readout (MADR) non-invasive assay using urinary matrix metalloproteinases (MMPs) and FGFR3 as triage monitors in high-risk bladder cancer populations. This concept combines the marker performance characteristics of protein and DNA biomarkers into one assay for optimal performance. Eight common FGFR3 mutations in 3 exons have been associated with bladder cancer. Analysis of mutational status for each single mutation required 8 amplification steps, which were costly and time consuming. We have now developed a real-time multiplexed FGFR3 assay, generating a cost-effective, clinically applicable assay for the detection of FGFR3 mutations in urine.

Methods: Our approach involves a two-step PCR amplification process. The initial round generates exon specific PCR products, which are then used as template for real-time PCR mutation detection utilizing locked nucleic acid (LNA) oligonucleotides. The LNA suppress wild-type DNA amplification. To convert our existing FGFR3 assay to a multiplex format, primary amplifications of exons 7, 10, and 15 were combined into a single real-time PCR assay for exon specific amplification and DNA quantitation. The LNA-mediated mutation detection was then converted from 4 reactions to 2 duplex amplifications. All multiplex assays were carried out on the Roche LC 480 real-time PCR platform.

Results: To validate the new multiplex format, FGFR3 multiplex analysis was performed on DNA isolated from 50 Ta stage bladder tumors. FGFR3 mutations were detected in 90% (48/50) of the tumors. To directly compare performance with single mutation analysis, 40 urine samples previously analyzed using the singleplex format were again tested using the multiplex FGFR3 assay. 100% concordance was seen between the two assay formats.

Conclusions: By multiplexing the FGFR3 mutation analysis we reduced the number of amplification steps, improving assay turnaround time and throughput, without compromising assay performance. The FGFR3 multiplex analysis provides a robust, cost-effective DNA assay that in combination with MMP protein analysis delivers a clinically applicable assay with optimal performance.

[Table: see text]
A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with PSA progression after radical therapy: NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013.
Authors: Klotz L. , O'Callaghan C. J. , Ding K. , Dearnaley D. P. , Higano C. S. , Horwitz E. M. , Malone S. , Goldenberg S. L. , Gospodarowicz M. K. , Crook J. M.
Published: February 2017

3

Background: In men with PSA recurrence after radical radiotherapy (RRT), intermittent androgen suppression (IAS) has been suggested by phase II trials to improve quality of life (QoL) but effects on survival are unknown. In this Intergroup randomized phase III trial, we compared IAS vs continuous androgen deprivation (CAD) to test for non-inferiority of IAS with respect to overall survival (OS).

Methods: Eligible men had rising PSA > 3.0 ng/ml >1 year post RRT, either initial or salvage, for localized prostate cancer. Patients could receive up to 1 year of neo/adjuvant androgen deprivation therapy (ADT) completed >1 year prior. Stratification factors were time since RRT (>1-3 vs >3 years), initial PSA (<15 vs >15), prior radical prostatectomy and prior ADT. IAS was delivered for 8 months in each cycle with restart when PSA reached >10 ng/ml off treatment. Primary endpoint was OS; secondary endpoints included time to hormone refractory state (HR), QoL, cholesterol/HDL/LDL, duration of treatment/non-treatment intervals, time to testosterone and potency recovery. The independent DSMC recommended halting the trial after a planned interim analysis demonstrated that a pre-specified stopping boundary for non-inferiority was crossed.

Results: 1,386 patients were randomized to IAS (690) or CAD (696) arms. Arms were balanced for important baseline factors. Median follow up was 6.9 years. IAS patients completed a median of 2 x 8 month cycles (range: 1-9). 524 deaths were observed (268 on IAS vs 256 on CAD). Median OS was 8.8 vs 9.1 years on IAS and CAD arms, respectively (HR 1.02, 95%CI 0.86-1.21; p for non-inferiority [HR IAS vs CAD ≥ 1.25] = 0.009). The IAS arm had more disease related (122 vs 97) and fewer unrelated (134 vs 146) deaths. Time to HR was statistically significantly improved on the IAS arm (HR 0.80, 95%CI 0.67-0.98; p = 0.024). IAS patients had reduced hot flashes, but otherwise there was no evidence of differences in AEs, including myocardial events or osteoporotic fractures.

Conclusions: In men with PSA recurrence after RRT IAS, given as described herein, is non-inferior to CAD with respect to OS.

No significant financial relationships to disclose.
Association of genetic markers in angiogenesis- or exposure-related genes with overall survival in pazopanib (P) treated patients (Pts) with advanced renal cell carcinoma.
Authors: Xu C. , Ball H. A. , Bing N. , Sternberg C. N. , Xue Z. , McCann L. , King K. , Spraggs C. F. , Mooser V. E. , Pandite L. N.
Published: February 2017

303

Background: Pazopanib, an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit, has been approved for the treatment of advanced renal cell cancer (RCC). Interindividual variability in response and survival is observed among advanced RCC pts treated with P. Our previous analyses showed that germline variants in angiogenesis (IL8, HIF1A, VEGFA)- and exposure (NR1IR)-related genes may predict progression free survival and/or response rate to P monotherapy (ASCO 2010 abstract 4520). This study sought to test the hypothesis that differences in overall survival (OS) can be explained, at least in part, by germline genetic variants in angiogenesis- and/or exposure-related genes.

Methods: Twenty-seven functional polymorphisms within 13 genes were evaluated in 241 P treated pts with advanced RCC from a phase III study (ESMO 2010 abstract LBA22) and a single arm Phase II study. Genetic association with OS was analyzed using the Cox proportional hazards model.

Results: Six polymorphisms in IL8, FGFR2, VEGFA, FLT4, and NR1I2 showed nominally significant association with OS (p≤0.05). A median OS of 29.6 months was observed in pts carrying wild-type IL8 2767 AA genotype (n=68, 31%), compared to 14.8 months in those with the TT variant genotype (n=36, 16%) (HR (95%CI) = 2.3 (1.4, 3.9) for TT vs. AA, p=0.002]. The median OS for pts who were heterozygous for this IL8 polymorphism was 23.9 months (n=119, 53%). The FGFR2 IVS2 + 906C>T variant TT genotype was associated with inferior OS compared with the wild-type CC genotype (median OS, 21.4 vs. 28.0 months, HR (95%CI) = 2.0 (1.2, 3.2), p=0.009). Similarly, shorter OS was observed for the VEGFA −1154G>A variant AA genotype compared with the wild-type GG genotype [median OS, 16.7 vs. 25.3 months, HR (95%CI) = 2.2 (1.3, 3.6), p=0.004]. The variant genotypes of the NR1IR (−25385C>T) and FLT4 (1480A>G) polymorphisms were also associated with reduced OS (p<0.05).

Conclusions: Germline variants in angiogenesis- and exposure-related genes may be associated with survival outcome for P monotherapy in pts with advanced RCC. These associations are considered exploratory and require confirmation in an independent dataset.

[Table: see text]
AMG 386 in combination with sorafenib in patients (pts) with metastatic renal cell cancer (mRCC): A randomized, double-blind, placebo-controlled, phase II study.
Authors: Rini B. I. , Szczylik C. , Tannir N. M. , Koralewski P. , Tomczak P. , Deptala A. , Kracht K. , Sun Y. , Puhlmann M. , Escudier B.
Published: February 2017

309

Background: AMG 386 inhibits angiogenesis by sequestering angiopoietin-1 and -2, thus preventing their interaction with the Tie2 receptor on endothelial cells. Combination with VEGF receptor inhibition has demonstrated additive effects in vivo. The efficacy and tolerability of sorafenib plus AMG 386, an investigational peptide-Fc fusion protein, were evaluated in mRCC pts.

Methods: Treatment-naive pts with clear cell mRCC were randomized 1:1:1 to sorafenib 400 mgPO BID plus AMG 386 10 mg/kg (Arm A) or 3 mg/kg (Arm B) QW; or placebo (Arm C) IV QW. Endpoints were progression-free survival (PFS; primary); and (secondary) objective response rate (ORR), change in tumor burden, adverse events (AEs) and pharmacokinetics. Tumor assessment was performed at baseline and every 8 weeks thereafter.

Results: 152 pts were randomized: Arms A/B/C, n=50/51/51. 60/61/61% of pts had intermediate and 40/39/37% had low MSKCC risk at baseline. PFS was similar in all 3 arms, whereas ORR was higher in the AMG 386 arms ( Table ). In Arms A/B/C the incidence of grade ≥ 3 AEs was 66/73/86% and serious AEs 36/49/28%. The most common AEs included diarrhea (70/67/56%; grade ≥3 8/10/8%), hand- foot syndrome (52/47/54%; grade ≥3 12/16/28%), alopecia (50/45/50%; grade ≥3 0/0/2%), and hypertension (42/49/46%; grade ≥3 18/20/14%). Median steady-state Cmax and Cmin for AMG 386 were similar to those reported previously. Sorafenib coadministration did not markedly affect AMG 386 exposure.

Conclusions: Sorafenib plus AMG 386 was tolerable but did not improve PFS compared with sorafenib plus placebo. Increased ORR and the observed reduction in tumor burden are suggestive of an antitumor effect of AMG 386 in mRCC.

[Table: see text]

[Table: see text]
A phase III, randomized, controlled study to compare tivozanib with sorafenib in patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Motzer R. J. , Bhargava P. , Esteves B. , Al-Adhami M. , Slichenmyer W. , Nosov D. , Eisen T. , Sternberg C. N. , Hutson T. E.
Published: February 2017

310

Background: Drugs that block vascular endothelial growth factor (VEGF) pathway signaling, such as the tyrosine kinase inhibitor sorafenib, have become standard treatment for pts with RCC. Tivozanib (AV-951) is a potent, selective small-molecule pan-VEGF receptor (VEGFR) inhibitor, with activity against the VEGFR-1, -2, and -3 kinases at subnanomolar concentrations. Preliminary results from a phase II randomized discontinuation trial of tivozanib (1.5 mg/d; 3 wks on, 1 wk off) in pts with RCC demonstrated an objective response rate (ORR) of 27% and a median progression-free survival (PFS) of 11.8 mo by independent radiology review, with a favorable safety profile. Patients with clear cell RCC who had undergone nephrectomy had an ORR of 32% and median PFS of 14.8 mo (Bhargava, et al. ASCO 2010. Abstract 4599). Based on this antitumor activity a phase III, randomized, controlled, global, multicenter trial is currently in progress to compare tivozanib with sorafenib in pts with advanced RCC.

Methods: Approximately 500 adults with clear cell RCC who have undergone nephrectomy and received ≤ 1 prior systemic treatment (no prior VEGF-targeted therapy) were randomized 1:1 to treatment with tivozanib or sorafenib. Pts are receiving 1.5 mg/d tivozanib orally in 4-week cycles (3 wks on, 1 wk off) or continuous 400 mg sorafenib orally twice daily. The primary endpoint will be PFS by independent radiology review; secondary endpoints will include overall survival, ORR, and duration of response. Safety is being monitored through adverse event reporting and laboratory analyses; toxicities are graded using the NCI Common Terminology Criteria for Adverse Events, version 3.0. The effect of therapy on health-related quality of life will be compared between arms using kidney cancer-specific (FKSI-DRS), oncology (FACT-G), and general (EQ-5D) assessments. Pharmacokinetics and biomarker analyses will be performed.

Results: Pending.

Conclusions: Enrollment completed in August 2010. An ongoing extension study will allow access to tivozanib for pts who demonstrate progressive disease on sorafenib, as well as long-term treatment with tivozanib or sorafenib for pts who demonstrate clinical benefit.

[Table: see text]
A phase I study to evaluate safety and antitumor activity of biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in patients with RCC and other advanced refractory malignancies.
Authors: McDermott D. F. , Drake C. G. , Sznol M. , Sosman J. A. , Smith D. C. , Powderly J. D. , Feltquate D. M. , Kollia G. , Gupta A. K. , Wigginton J.
Published: February 2017

331

Background: Programmed death-1 (PD-1), a T-cell inhibitory receptor, may suppress antitumor immunity. BMS-936558, a fully human PD-1 blocking antibody, has shown antitumor activity and manageable toxicity after biweekly dosing (Sznol, ASCO 2010, #2506). This report provides an update on safety and antitumor activity with special emphasis on RCC.

Methods: An open-label phase I dose escalation study of BMS-936558 was conducted in patients (pts) with treatment refractory metastatic clear-cell renal cell carcinoma (RCC), castrate-resistant prostate cancer (CRPC), melanoma (MEL), non-small cell lung cancer, or colorectal cancer (CRC). Dose escalation continued to 10 mg/kg when an expansion cohort for pts (16) with each tumor type was opened for additional safety and efficacy information. Tumor response (RECIST) was evaluated every 8 weeks. Clinically stable pts with early PD could continue until further PD or clinical deterioration.

Results: 126 pts (18 RCC) were treated with 1, 3, or 10 mg/kg. MTD was not reached. Across all doses, the most common AEs (Any/grade 3-4) were fatigue (45.2%/6.3%) and diarrhea (30.2%/0.8%) while the most common drug-related AEs (Any/grade 3-4) were fatigue (20.6%/0.8%), rash (11.9%/0%), pruritus (11.3%/0%), and diarrhea (10.3%/0.8%). There was no apparent relationship between dose and frequency of AEs. One pt died with sepsis while being treated for drug-related grade 4 pneumonitis. The median number of prior treatment regimens in the RCC cohort was 2 (range 1-6). Of the 18 RCC pts, 16 were treated with 10 mg/kg. The median duration of treatment was 7.6+mo. ORR was 5/16 (31.2%) and SD>4mo was 6/16 (37.5%). The median duration of response was 4.0+ mo (3.7-7.4+ mo). Of the 2 RCC pts treated with 1 mg/kg, 1 obtained a CR (12+ mo) and 1 had SD (21+ mo). For evaluable CRPC pts, 1/15 pts (6.7%) obtained a PR (2+ mo) and 3/15 (20%) had SD>4mo.

Conclusions: BMS-936558 administered biweekly is tolerable and has encouraging antitumor activity in a previously treated patients with RCC. Data on baseline characteristics, long-term toxicity and response duration will be updated at the meeting.

[Table: see text]
Plasma cytokine and angiogenic factors (CAFs) predictive of clinical benefit and prognosis in patients (Pts) with advanced or metastatic renal cell cancer (mRCC) treated in phase III trials of pazopanib (PAZO).
Authors: Liu Y. , Tran H. T. , Lin Y. , Martin A. , Zurita A. J. , Sternberg C. N. , Amado R. G. , Pandite L. N. , Heymach J. ,   VEG105192 Team
Published: February 2017

334

Background: PAZO is a multikinase inhibitor approved for the treatment of mRCC. From phase II study of PAZO in mRCC (VEG102616), plasma CAF analysis from 3 different platforms (cross platform correlation r >0.70) revealed several candidate CAFs including HGF, IL-6, IL-8, TIMP-1, VEGF, E-Selectin and OPN were found to be significantly correlated with clinical benefit (Tran ASCO 2010, #4522). To validate these findings, plasma were analyzed for CAFs from mRCC pts enrolled in phase III randomized, placebo controlled trial with PAZO where progression-free survival (PFS) of 9.2 months of PAZO and 4.2 months of placebo (hazard ratio:0.46 p<.0001) and overall response rate 30% was observed (Sternberg, JCO, 2010).

Methods: Plasma samples (n=344) from phase III randomized, placebo-controlled trial (VEG105192) were analyzed for candidate CAFs by a CLIA-certified laboratory (Aushon Biosystems, MA). These markers of PAZO and placebo arms were correlated with PFS by Cox regression and plotted in Kaplan Meier by using median concentration of each marker as a cutoff.

Results: Higher levels of IL-8 (p<0.006), HGF (p<0.01), OPN (p<0.001) and TIMP-1 (p<0.006) were associated with shorter PFS in PAZO treated pts. Higher levels of all these markers except HGF were also associated with shorter PFS in the placebo arm (IL-8 (p<0.002), OPN (p<0.001), IL-6 (<0.001), TIMP-1 borderline at p= 0.052) and were therefore prognostic. Only IL-6 was predictive of PFS benefit; pts with high IL-6 had a greater relative benefit from PAZO compared to placebo with a HR of 0.32 in the high IL-6 group and 0.57 in the low IL-6 group (p value for interaction 0.009).

Conclusions: This study validated HGF, IL-8, OPN, and TIMP-1 as markers associated with clinical benefit with PAZO treatment. IL-8 and OPN were confirmed as prognostic markers in the placebo arm and IL-6 was both a prognostic marker and predictive marker for pazopanib therapy.

[Table: see text]
Adjusted indirect comparison of everolimus and sorafenib in sunitinib-refractory mRCC patients using a robust matching technique.
Authors: Di Lorenzo G. , Casciano R. , Malangone E. , Buonerba C. , Sherman S. , Wang J. , Liu Z. , De Placido S.
Published: February 2017

378

Background: Vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFr-TKIs) sunitinib (SU) and sorafenib (SO) are approved for first- and second-line (after cytokines) use in metastatic renal cell carcinoma (mRCC). Because most patients progress after first-line VEGFr-TKI, the need for an effective second-line treatment is compelling. Although SO is frequently considered after SU failure, no randomized controlled trials have established clinical benefit in this scenario. Results from the RECORD-1 phase III trial suggest that second-line everolimus (EVE) therapy leads to improved overall survival (OS) vs. placebo. No trial data exist comparing treatment outcomes for EVE vs SO in the second-line setting. Thus, the current analysis provides a robust estimate from an indirect comparison examining the OS benefit of EVE and SO as second-line treatment options after SU failure.

Methods: The single-arm SO study was selected as a basis by which to match an EVE SU-refractory subpopulation of the RECORD-1 trial. Patients were limited to those with clear cell histology. An adjusted matching approach was taken in which 1,000 repeated random samples matched to the SO population on risk score distribution were produced. These data were used to generate a distribution of survival outcomes and infer a 95% CI around the mean of all sampled median OS estimates.

Results: After adjusted matching, the estimated median OS benefit, based on SO patients with clear cell histology (n = 45) and 1000 random samples of n = 41 from the 127 SU-refractory EVE patients, was 82 weeks (95% CI: 78, 86) and 32 weeks (95% CI: 22, 64) for EVE and SO, respectively.

Conclusions: These indirect comparison results suggest that SU-refractory mRCC patients treated with EVE may experience significantly improved OS outcomes compared with patients treated with SO.

[Table: see text]
Unexpected hyperparathyroidism in metastatic renal cell carcinoma patients treated with sunitinib.
Authors: Mazzanti R.
Published: February 2017

380

Background: Sunitinib malate is a tyrosine kinase inhibitor, active against tyrosine kinase receptors involved in tumour growth and angiogenesis, and is a potent substrate of p-glycoprotein. This study was conducted to assess whether sunitinib could affect phospho-calcium metabolism. This because both sunitinib and parathyroid hormone have been suggested to be substrates of p-glycoprotein. Here we report the incidence of newly onset hyperparathyroidism in a cohort of patients affected by metastatic renal cell carcinoma (mRCC), treated with sunitinib.

Methods: Parathyroid and calcium metabolism function tests were prospectively evaluated in patients receiving a daily 50 mg sunitinib for mRCC according to classic 6-week schedule. Between July 2008 and July 2010, 25 patients received a sunitinib treatment at our institution and resulted eligible for evaluation. Median patients age was 64.3 years old (range 48-79). Parathyroid hormone (PTH), serum and urinary phosphate and calcium, were measured at the beginning of treatment and at the end of each sunitinib ON period.

Results: During sunitinib therapy, 17 patients (68%) developed elevated serum parathyroid hormone, with low-to-normal serum calcium and phosphate. On average patients presented an elevation of PTH after 3 sunitinib cycles (range 1-5). Those presenting elevated PTH showed low or undetectable urinary calcium levels.

Conclusions: Hyperparathyroidism develops in a high percentage of patients undergoing sunitinib. A similar observation was reported among patients on imatinib, due to an inhibition of PDGF receptor both on osteoclasts and osteoblasts. In these patients, a temporary decrease of serum ionized calcium was supposed as the pathogenetic mechanism of hyperparathyroidism. As sunitinib inhibits PDGF receptors', similar events could be hypothesized. This observation suggests that abnormalities in bone metabolism are a common feature of tyrosine kinases inhibitors targeting PDGF receptors. Routine monitoring of bone metabolism during sunitinib therapy is therefore recommended.

No significant financial relationships to disclose.
Use of quantitative gene expression in primary and highest Gleason pattern cancers to identify genes associated with clinical recurrence after radical prostatectomy.
Authors: Klein E. A. , Falzarano S. M. , Maddala T. , Millward C. , Novotny W. F. , Pelham R. J. , Magi-Galluzzi C.
Published: February 2017

39

Background: Prostate biopsy may not adequately sample small, secondary or tertiary Gleason pattern tumors which can drive clinical outcome. We conducted a study to determine whether tumor-derived gene expression profiling could identify a distinct underlying biology associated with clinical recurrence (cR) after radical prostatectomy (RP) across both the primary and highest Gleason pattern (GP) samples.

Methods: All patients (pts) with clinical stage T1/T2 prostate cancer treated with RP at Cleveland Clinic from 1987 to 2004 were identified (n∼f2,600). A cohort sampling design was used to select 127 patients with cR and 374 patients without cR after RP. Each patient had two spatially distinct tumor specimens sampled that included the primary GP and the highest GP. Surgical GS and clinical data were centrally reviewed. RNA was extracted from 6 manually dissected 10 μ m fixed paraffin embedded tissue sections obtained from the RP tumor specimens and expression of 732 cancer-related and reference genes was quantified using RT-PCR. Clinical recurrence-free interval (cRFI) was analyzed using Cox PH regression.

Results: Blocks from 441 patients were evaluable. Median F/U was 5.8 years. Pts were mostly Caucasian (83%), clinical stage T1 (66%), had baseline PSA <10 ng/mL (82%), and had surgical GS ≤7 (87%). As expected, surgical GP, biopsy GP, path T- stage, clin T-stage, baseline PSA, and year of surgery (p<0.05, unadj) were associated with cRFI. In the primary and highest GP specimens respectively, 295 and 297 genes were significantly associated (unadj. p<0.05) with cRFI. 235 genes were associated with cRFI in both specimens, well in excess of the number expected by chance. In a multivariate model adjusted for AUA risk group and allowing a 10% false discovery rate, 289 genes remained significantly and strongly associated with cRFI.

Conclusions: Gene expression analysis using quantitative RT-PCR identified a large number of genes, and underlying biology, that are strongly associated with clinical recurrence in both the primary and highest GP. This information can be used to develop a biopsy-based assay that distinguishes indolent versus aggressive disease.

[Table: see text]
Is there a role for targeted therapies in the collecting ducts of Bellini carcinoma?
Authors: Procopio G. , Verzoni E. , Iacovelli R. , Guadalupi V. , Nicolai N. , Torelli T. , Biasoni D. , Colecchia M. , Salvioni R.
Published: February 2017

396

Background: Carcinoma of Bellini collecting ducts (CDC) is very uncommon but it is one of the most aggressive urological entities. For this tumor, originating from the epithelium of Bellini ducts in the distal tubule and preferentially occurring in young populations, no standard effective therapy has been so far established. Results of previous clinical experiences with chemo- or immunotherapy have been disappointing. We report our experience in 7 cases of CDC treated with targeted therapies.

Methods: From December 2004 to May 2010, 333 patients with advanced renal cell carcinoma have been treated with targeted therapies at Istituto Nazionale Tumori of Milan. From the global database analysis, seven cases with histological subtype of CDC have been identified. All patients had advanced disease and received a targeted therapy as first-line treatment. Six of them underwent previous nephrectomy, all had nodal involvement, and three had two or more sites of disease including lung, liver, and adrenal glands. Four patients received sorafenib as first-line treatment, two sunitinib, and one temsirolimus. After sorafenib failure, two patients received a second-line treatment consisting of both sunitinib and temsirolimus.

Results: Five patients developed early progression of disease with a very short 4-month survival. One patient had a long term partial response of 33 months with sorafenib, he underwent second-line sunitinib and had no progression for further 10 months. The last patient reached a progression-free survival of 6 months with temsirolimus; when progressed, he achieved a disease control for further 9 months during sunitinib therapy. Both patients are alive after 50 and 15 months of treatment, respectively. The most common adverse events, low or moderate in severity, consisted of fatigue, hand-foot skin reaction, diarrhea, hypertension, and anemia.

Conclusions: Prognosis of advanced CDC remains unfavorable. New target agents may be active in this disease and need further prospective phase II studies.

[Table: see text]
Three-dimensional ultrasound-based spectroscopic imaging for detection of prostate cancer in men.
Authors: Chung H. T. , Sofroni E. , Papanicolau N. , Sugar L. , Morton G. , Yaffe M. , Nam R. , Czarnota G. J.
Published: February 2017

57

Background: The objective of this translational research was to investigate the use of real-time novel three-dimension, quantitative ultrasound-based spectroscopic imaging of the prostate as a means of cancer detection.

Methods: Ten patients with T2-3 prostate cancer underwent a 6-9 MHz trans-rectal ultrasound scan of the prostate prior to radical prostatectomy. Equally spaced axial ultrasound images (0.5 cm separation) corresponding elasticity and spectroscopy data were collected in each patient. Colour-coded spectroscopic parametric maps of 0-Mhz intercept (0-Mhz), mid-band fit (MBF) and slope of line of best fit (slope) were generated indicating where the disease in the prostate gland is hypothetically located. Quantitative data (% volume of cancer over the prostate gland) were compared to whole-mount radical prostatectomy histopathology maps to determine the sensitivity and accuracy in parametrically delineating prostate cancer.

Results: Representative data indicate spectral changes were associated with the presence of co-incident disease as located on correlative histopathology whole mount sections. Of the 10 patients enrolled, 7 have been analyzed and presented here. The mean % difference between 0-MHz and MBF, with H&E, was 14% (SD 38%) and 21% (SD 24%), respectively. Gross areas of disease were readily visualized in ultrasound parametric maps and corresponded to a maximum 10dB decrease in 0-MHz or MBF. Parametric maps generated from the spectral slope offered no discrimination of disease.

Conclusions: Initial results suggest that there is good correlation between spectroscopic maps with disease on whole-mount specimens. This method may ultimately permit ultrasound-guided targeted biopsies to improve detection rates and non-invasive assessment of disease for radiotherapy planning.

No significant financial relationships to disclose.
Elective nodal irradiation for prostate cancer patients: Comparison of available dynamic techniques.
Authors: Urbanczyk H. , Hawrylewicz L. , Kulik R. , Szczepanik K. , Ciechowicz J. , Tarnawski R.
Published: February 2017

96

Background: The few recent studies showed that regional lymph node metastases of prostate cancer (PCa) could be successfully treated. It means that role of pelvic nodes (PN) irradiation could increase in next period. A problem is rectal and bladder toxicities of this treatment. Intensity modulated dynamic irradiation techniques (DT) may potentially help to reduce treatment related side effects. The aim of study is to compare three different radiotherapy techniques: conformal (CRT), static field intensity modulated (SF IMRT) and rapid arc (RA) for elective pelvic lymph nodes irradiation.

Methods: We analyzed CRT, IMRT and RA plans of irradiation PN for ten patients. PTVs included PN iliac, iliac external upper then acetabulum, iliac internal and obturatory. Prescribed doses were 44 Gy/22 fractions. We compared the doses delivered to PTV rectum and bladder using dose volume histograms. The U Mann-Whitney, W Shapiro-Wilk and ANOVA rang Kruskal-Wallis tests were used for statistical analysis.

Results: The median PTV doses were not statistically different in analyzed plans. The minimum doses for PTV were significantly lower in IMRT and RA plans but the differences were not clinically significant. Maximum doses were significantly higher for CRT plans. The doses calculated for rectum and bladder were statistically significantly lower for dynamic techniques in whole range of volumes and doses. SF IMRT is the most efficient technique in reducing the dose to bladder. The doses observed in half of the rectum and bladder volumes bladder were also statistically significant different (p=0.002 for rectum and 0.001 for bladder). The median doses for rectum were 43.6 Gy for CRT plans, 33.5 Gy for IMRT and 37.9 Gy for RA, median doses calculated for bladder were 44 Gy for CRT, 35.6 Gy for IMRT and 39.6 Gy for RA.

Conclusions: CRT does not allow to reduce the dose to organs at risk. Both DT reduce the doses to bladder and rectum while maintaining the high homogenous dose to PTV. SF IMRT is more efficient in reducing the dose to bladder than RA. SF IMRT technique seems to be better than Rapid Arc for PN irradiation. It is probably because the nodal PTVs are large and their structures are complicated.

No significant financial relationships to disclose.
Randomized controlled phase II study of alternate-day S-1 as adjuvant chemotherapy for gastric cancer.
Authors: Nakamura Seiichi , Tatebe Shigeru , Shimizu Tetsu , Yamane Nariyuki , Nishidoi Hideaki , Kurisu Yasuro , Kanayama Hirotomo , Ogawa Haruaki , Tsujitani Shunichi , Ikeguchi Masahide ,   San-in Clinical Oncology Group
Published: February 2017

114

Background: Based on the results of ACTS-GC, oral administration of S-1 for 1 year is considered standard postoperative adjuvant chemotherapy for gastric cancer in Japan. However, the 1-year treatment completion rate was only 65.8%, and completion of the treatment is a problem to be solved. On the other hand, we experienced in clinical practice that the alternate-day administration of S-1 reduced adverse effects and was tolerable for advanced gastric cancer patients unwilling to continue the standard daily administration. We therefore conducted a multi-center cooperative prospective study to compare daily with alternate-day administration of S-1 as postoperative adjuvant therapy for gastric cancer.

Methods: Patients with Stage II or III gastric cancer who underwent curative surgery were randomly assigned to receive standard daily administration (group A: S-1 80-120 mg/day according to BSA, days 1 to 28, every 6weeks, for 1 year) or alternate-day administration of S-1 (group B: S-1 80-120 mg/day according to BSA, every other day, for 15 months). The primary endpoints were treatment completion rate and relative dose intensity. Secondary endpoints were safety, overall survival, and relapse-free survival.

Results: A total of 73 patients were enrolled. As of August 30, 2011 analysis of the compliance data of 62 cases had been completed. The results showed a treatment completion rate of 74.2% in group A and 93.5% in group B and relative dose intensity of 72.1% in group A and 85.6% in group B, and compliance tended to be better in group B. Assessment of survival time showed a median follow-up time of 545 days, a 1-year survival rate of 93.8% in group A and 96.9% in group B and 1-year relapse-free survival rate of 79.5% in group A and 90.7% in group B. Digestive system adverse events were less frequent in group B than in group A.

Conclusions: We will report the data from the final analysis at this meeting. The current data show improved compliance and mitigation of adverse effects with alternate-day administration of S-1, and it appears to be a more sustainable option for adjuvant chemotherapy for Stage II and III gastric cancer.
Downstaging capacity of neoadjuvant chemotherapy in distal versus proximal gastric carcinoma: Preliminary data from a regional tumor registry.
Authors: Garlipp Benjamin , Meyer Frank , Burger Elke , Adolf Daniela , Stuebs Patrick , Bernarding Johannes , Gademann Guenther F.E. , Lippert Hans
Published: February 2017

120

Background: Following the results of 3 randomized controlled trials, neoadjuvant chemotherapy has become standard of care for locally advanced gastric cancer in Europe. All of these trials included patients with cancers located in the gastric corpus, antrum, and pylorus (distal gastric cancers, DGC) as well as cancers of the esophagogastric junction and fundus (proximal gastric cancers, PGC). However, data suggest that DGC and PGC may be two distinct tumor entities. The aim of our study was to investigate if the capacity of neoadjuvant chemotherapy to downstage gastric cancers is different for DGC and PGC.

Methods: We used data from the clinical regional tumor registry of Magdeburg which covers the northern section of the federal district of Saxony-Anhalt, Germany, to compare pretherapeutic (clinical) and postoperative (histopathological) UICC tumor stages in patients with DGC and PGC treated with neoadjuvant chemotherapy followed by surgery.

Results: Of 2,460 gastric cancer patients entered into the registry between January 1993 and September 2010, 189 (7.7%) received neoadjuvant chemotherapy. Of these, 149 underwent surgery with curative intent. Pretherapeutic and postoperative UICC stages were not available for 34 of these patients. A further 42 patients had UICC stage IV documented at laparotomy; since this was likely due to peritoneal carcinomatosis which may have gone unnoticed at the start of neoadjuvant chemotherapy and thus does not reliably indicate upstaging, these patients were excluded from analysis. Of the 73 evaluable patients, 33 (45.2%) had DGC and 40 (54.8%) had PGC. UICC tumor stage decreased during therapy in 55.1% and 75.0%, remained unchanged in 16.3% and 20.8%, and increased in 28.6% and 4.2% of DGC and PGC patients, respectively (p=0.039, Fisher’s exact test).

Conclusions: Despite the limited statistical power, these preliminary data suggest that DGC and PGC may differ in their response to neoadjuvant chemotherapy. With more widespread use of neoadjuvant chemotherapy in gastric cancer in recent years, we expect a steep increase in evaluable patients in the tumor registry which will allow for future multivariate analyses regarding this issue.
Feasibility study of neoadjuvant chemoradiotherapy with cisplatin plus 5-fluorouracil and elective nodal irradiation for stage II/III esophageal squamous cell carcinoma.
Authors: Kojima Takashi , Hashimoto Jun , Kato Ken , Ito Yoshinori , Igaki Hiroyasu , Daiko Hiroyuki , Onozawa Masakatsu , Hamamoto Yasuo , Shimizu Hideaki , Katano Susumu , Hara Hiroki , Tanaka Yoichi , Saito Yoshihiro
Published: February 2017

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Background: Based on the JCOG 9907 trial results, neoadjuvant chemotherapy with cisplatin (CDDP) plus 5-fluorouracil (5-FU) is considered a standard treatment for stage II/III esophageal squamous cell carcinoma (ESCC) in Japan. However, patient survival remains unsatisfactory. We conducted a feasibility study of neoadjuvant chemoradiotherapy (NeoCRT) with CDDP plus 5-FU and elective nodal irradiation for stage II/III ESCC.

Methods: Eligibility criteria included clinical stage II/III (UICC 6th, non-T4) ESCC, PS 0-1, and age 20–75 years. Chemotherapy consisted of 2 courses of 5-FU infusion (1000 mg/m2, days 1–4) and a 2-h CDDP infusion (75 mg/m2, day 1), with a 4-week interval. Radiotherapy was concurrently administered to a total 41.4 Gy in 23 fractions for primary tumor, metastatic lymph nodes and regional lymph nodes. After completion of CRT, transthoracic esophagectomy with extensive lymphadenectomy (>D2) was performed. The primary endpoint was the completion rate of NeoCRT and R0 resection.

Results: From July 2010 to June 2011, 33 patients were enrolled, including 2 ineligibles. In 31 eligible patients, the median age was 63 years (range, 40–73); male/female: 28/3; PS0/1: 19/12; cStage IIA/IIB/III: 2/10/19. During CRT, the most common grade 3 or 4 toxicities were leukopenia (65%), neutropenia (65%), anemia (13%), thrombocytopenia (13%), febrile neutropenia (13%), anorexia (16%), esophagitis (16%), and hyponatremia (16%). In total, 31 patients (100%) underwent CRT and 25 (81%) underwent surgery; 1 patient (3%) did not undergo surgery due to disease progression, and the other 5 patients (16%) are scheduled for surgery. Among patients who underwent surgery, there was 1 treatment-related death, and the incidence of operative morbidity was similar to that in previous studies. According to RECIST, the overall response rate was 63% after CRT completion. Pathological complete response was achieved in 11 patients (44%) who underwent esophagectomy.

Conclusions: NeoCRT was well tolerated and appears to be highly promising. The randomized controlled trial compared with neoadjuvant chemotherapy is needed and will be started.
Use of optical biomarkers from nondysplastic metaplastic cells on the detection of high-grade dysplasia and adenocarcinoma from Barrett’s esophagus.
Authors: Brand Randall , Rizvi Sumera , Davison Jon M. , Bista Rajan , Staton Kevin , Hartman Douglas , Fasanella Kenneth , McGrath Kevin , Liu Yang
Published: February 2017

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Background: Patients with Barrett’s esophagus (BE), defined as presence of intestinal metaplasia (IM) in the esophagus, require surveillance due to an increased risk of developing esophageal adenocarcinoma (EAC). The biggest challenge in the current surveillance methodology (i.e., Seattle protocol) is random sampling with the inability to identify those patients with non-dysplastic BE on surveillance who have occult high grade dysplasia (HGD) or will eventually progress to HGD or EAC. We propose a novel approach based on the concept of field effect to detect HGD or EAC through the analysis of non-dysplastic IM, thus identifying a high risk BE population. Our group uses a unique microscope – spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to detect changes in nuclear structure as small as 0.9 nm, a scale 1000 times smaller than what conventional microscopy detects. We hypothesize that the SL-QPM-derived optical biomarkers of non-dysplastic IM would distinguish BE patients with EAC/HGD from those without neoplasia.

Methods: We performed a retrospective study of 60 BE patients who underwent Seattle protocol biopsies: 33 BE patients with IM only and 27 BE patients with HGD or EAC (21 HGD, 6 EAC). H&E stained slides with non-dysplastic IM on review by an expert pathologist were used. The distance between the selected IM biopsy and HGD/EAC was 1 to 4 cm. Forty to 60 columnar cells from each case were analyzed.

Results: We identified three optical biomarkers (nuclear optical path length, intra-nuclear uniformity, entropy) that can distinguish non-dysplastic BE from patients with HGD and EAC with statistical significance (P < 0.01). A prediction model combining all three optical biomarkers can distinguish BE patients with HGD/EAC from those with IM only at 89% sensitivity and 76% specificity (accuracy = 0.87).

Conclusions: The accurate assessment of nanoscale optical biomarkers by SL-QPM is a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium from non-dysplastic IM. This approach could potentially simplify BE surveillance by identifying a subset of high-risk BE patients that warrant intensive surveillance.
Phase II feasibility study of adjuvant S-1 plus CPT-11 for stage III gastric cancer patients after curative D2 gastrectomy (OGSG 0801).
Authors: Kimura Yutaka , Fujitani Kazumasa , Ueda Shugo , Taniguchi Hirokazu , Imamura Hiroshi , Gofuku Junji , Tamura Shigeyuki , Kurokawa Yukinori , Takiuchi Hiroya , Furukawa Hiroshi ,   Osaka Clinical Study Supporting Organization (OGSG)
Published: February 2017

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Background: An adjuvant chemotherapy with S-1 has become the standard treatment for patients (pts) with stage II/III gastric cancer (GC) in Japan. But, it is assumed that the survival benefit for stage III pts who received S-1 is modest. S-1 plus CPT-11 has not shown the superiority in median overall survival (OS), but shown the well response rate (56%) and tolerability in Phase III trial (TOP-002 study). The aims of this phase II study were to evaluate the feasibility and safety of adjuvant S-1 plus CPT-11 in pts with stage III GC who underwent D2 surgery.

Methods: Pts with pathological stage IIIA and IIIB GC who underwent gastrectomy D2 dissection, age 20-75 years, performance status < 1, and informed consent received oral S-1 (80 mg/m2/day) administration for consecutive 3 weeks and intravenous CPT-11 (80 mg/m2) on day 1, 15, repeated every 5 weeks (1 cycle). The treatment was repeated for 4 cycles, followed by S-1 administration until 1 year after surgery. The primary endpoint was feasibility of the 4 cycles administration of S-1 plus CPT-11.

Results: We enrolled forty-five pts, 22 males and 23 females with a median age of 61 years, between December 2008 and April 2010. Pathological stages included IIIA in 25 pts and IIIB in 20 pts. The feasibility of planned 4 cycles of treatment was 62.2% (95% CI 46.5-76.2%, p=0.068) with 28 pts out of 45 pts. Non-hematological toxicities of grade 3 or more involved diarrhea in 13%, anorexia in 16%, nausea in 7% and vomiting in 4%. No Grade 4 toxicities were observed.

Conclusions: Adjuvant S-1 plus CPT-11 therapy had moderate hematological toxicities, but observed several severe non-hematological toxicities. Therefore, predicted feasibility was not achieved. Although the follow-up period is too short to evaluate OS and feasibility of S-1 administration, it is hoped that this regimen will be a candidate for future phase III trial seeking for the optimal adjuvant chemotherapy for stage III GC pts after D2 dissection if OS will be improved.
Multivariate analysis including biomarkers in the phase III RADIANT-2 study of octreotide LAR plus everolimus (E+O) or placebo (P+O) among patients with advanced neuroendocrine tumors (NET).
Authors: Yao James C. , Hainsworth John D. , Wolin Edward M. , Pavel Marianne E. , Baudin Eric , Gross David , Ruszniewski Philippe , Tomassetti Paola , Panneerselvam Ashok , Saletan Stephen , Klimovsky Judith
Published: February 2017

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Background: In this large phase III trial, median progression-free survival (PFS) improved by 5.1 mo with E+O compared to P+O in patients (pts) with NET associated with carcinoid syndrome. Randomization imbalances including WHO performance status (PS), and primary site favoring P+O confounded primary analysis. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are important biomarkers in NET. Analyses were performed to identify prognostic factors and adjust for randomization imbalances.

Methods: Pts were randomized to E+O (n=216) or P+O (n=213). Potential prognostic factors including baseline CgA (≤2×ULN vs >2×ULN), baseline 5-HIAA (≤median vs >median), age (<65 vs ≥65), gender, race, WHO PS (0 vs 1, 2), primary site (lung vs other), prior somatostatin analog use (yes vs no), duration from diagnosis (<6 mo, 6-24 mo, 2-5 yr, >5 yr), and organs involved (liver, bone) were assessed in univariate analysis using the log rank test and a stepwise regression using Cox proportional hazards model.

Results: Randomization resulted in significant imbalance in baseline CgA (median [ng/mL], 251 E+O vs 137 P+O). Median PFS (mo) was significantly longer for pts with nonelevated CgA (27 vs 11; P<.001) and nonelevated 5-HIAA (17 vs 11; P<.001). Analyses also indicated age (14 vs 12; P=.01), WHO PS (17 vs 11; P=.004), liver involvement (14 vs not reached; P=.02), bone metastases (8 vs 15; P<.001), and lung as primary site (11 vs 14; P=.06) as potentially prognostic. Multivariate analysis indicated that significant prognostic factors for PFS included baseline CgA (HR, 0.47; CI, 0.34-0.65; P<.001), WHO PS (HR, 0.69; CI, 0.52-0.90; P=.006), bone involvement (HR, 1.52; CI, 1.06-2.18; P=.02), and lung as primary site (HR, 1.55; CI, 1.01-2.36; P=.04). Adjusted for covariates, a 38% reduction in risk of progression was observed for E+O (HR, 0.62; 95% CI, 0.51-0.87; P=.003).

Conclusions: In the phase III RADIANT-2 trial, baseline CgA levels, WHO PS, lung as primary site, and bone involvement were important prognostic factors. Exploratory analysis adjusted for these prognostic factors indicated significant benefit for everolimus therapy.
Evaluation of combination treatment benefits of nab-paclitaxel in experimental pancreatic cancer.
Authors: Awasthi Niranjan , Ostapoff Katherine , Zhang Changhua , Schwarz Margaret A. , Schwarz Roderich
Published: February 2017

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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers and is characterized by early tissue invasion, metastasis and high resistance to systemic therapies. Gemcitabine, a standard cytotoxic therapy for pancreatic cancer, has shown limited clinical benefits. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel), an approved treatment for breast cancer, has shown efficacy as mono- and combination therapy in multiple tumor types including pancreatic, lung and ovarian cancer. We evaluated combination treatment benefits of nab-paclitaxel with gemcitabine in experimental pancreatic cancer.

Methods: In vitro cell proliferation was evaluated by WST-1 assay in human PDAC cells. Animal survival studies were performed in murine xenografts.

Results: Nab-paclitaxel inhibited in vitro proliferation of PDAC cell lines with IC50 levels of 7.6 mM, 208 nM, 519 nM and 526 nM for AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells. Nab-paclitaxel combination with gemcitabine had significant additive effect on inhibition of PDAC cell proliferation; 72-hour incubation demonstrated that nab-paclitaxel addition caused a 2.5, 2.5, 8.9 and 2.2-fold decrease in IC50 of gemcitabine in AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells, respectively. In an intraperitoneal murine xenograft model, 2-week therapy demonstrated that compared to controls (median survival: 23 days), animal survival increased after gemcitabine (27 days, p=0.05) and nab-paclitaxel monotherapy (35 days, p=0.0005). In a separate 3-week therapy experiment, animal survival was significantly longer in the nab-paclitaxel treated group (41 days, p<0.002 versus control and Gem) compared with gemcitabine (32 days, p=0.005 versus control), docetaxel (32 days, p=0.005) and controls (20 days). Animal survival in nab-paclitaxel / gemcitabine and docetaxel / gemcitabine sequential treatment group was 43 and 40 days, respectively.

Conclusions: Nab-paclitaxel has significant antitumor activity as a single agent in experimental pancreatic cancer and can also enhance gemcitabine effects in combination. These findings provide a strong rationale for testing nab-paclitaxel in patients with pancreatic cancer.