bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors and outcomes for late recurrence of renal cell carcinoma.
Authors: Kim S. P. , Weight C. J. , Leibovich B. C. , Thompson R. H. , Lohse C. M. , Boorjian S. A.
Published: February 2017

348

Background: While the initial natural history after surgical resection for localized renal cell carcinoma (RCC) has been well-characterized, recurrence patterns for patients who experience late recurrence of disease continue to be defined. Here, we evaluated the clinical characteristics and survival of patients who experienced disease recurrence > 5 years following nephrectomy.

Methods: We identified 1,454 patients who were treated with radical nephrectomy (RN) or nephron-sparing surgery (NSS) for unilateral, sporadic pT1-4NxM0 RCC between 1970-2000 and who had remained free of disease for 5 years after surgery. Late (> 5 years) recurrence was then recorded and was classified as renal (ipsilateral/contralateral kidney) recurrence and distant (all other sites) recurrence. The incidence of late recurrence was estimated using the Kaplan Meier method, and clinicopathological variables subsequent disease relapse were analyzed using Cox proportional hazard regression models.

Results: Median follow-up after nephrectomy in the cohort here was 13.9 years (range 5.1-38.9). In total, 63 patients experience a late recurrence in the ipsilateral/contralateral kidney, at a median of 9.3 years (range 5.1-25.3) after surgery. 172 (11.8%) patients developed late distant metastases, at a median of 9.6 years (range: 5.1-26.6). Estimated recurrence-free survival at 10 and 15 years following nephrectomy was 97.3% and 95.2% for renal recurrence and 93.1% and 85.9% for distant recurrence, respectively. Increased tumor size (HR 1.1; p<0.001) was associated with a higher rate of late renal recurrence, while increased tumor size (HR 1.1; p=0.018), clear cell or collecting duct histology (HR 3.7; p<0.001), and tumor stage pT1b (HR 2.8; p<0.001), pT2a (HR 4.5; p<0.001), pT2b (HR 3.4; p=0.007), and pT3/4 (HR 5.1; p<0.001) were predictive of the development of late distant metastasis.

Conclusions: Patients undergoing surgery for localized RCC remain at life-long risk of disease recurrence. Approximately 5% experience renal recurrence and 15% demonstrate distant relapse, during the ensuing 10 years. Continued investigation to identify potential site-specific predictors of late recurrence is necessary to guide postoperative surveillance regimens.

No significant financial relationships to disclose.
C-met as a therapeutic target using ARQ 197 in renal cell carcinoma.
Authors: Gibney G. , Conrad P. , Aziz S. A. , Camp R. L. , Schwartz B. E. , Chen C. , Kelly W. K. , Kluger H. M.
Published: February 2017

360

Background: c-Met is a receptor tyrosine kinase involved in normal cellular growth and vascular development. It has also been identified as a proto-oncogene. Activating c-Met mutations and indirect c-Met activation via von Hippel-Lindau gene silencing have been demonstrated in renal cell carcinoma (RCC) for papillary and clear cell histologic subtypes, respectively. We studied c-Met expression in a large cohort of RCC tumors and investigated in vitro activity of the new selective c-Met inhibitor, ARQ 197.

Methods: Tissue microarrays were performed to analyze c-Met protein expression in situ in 317 RCC tumor specimens using Automated Quantitative Analysis (AQUA). Western blots were performed for c-Met, phospho-c-Met and downstream pathway markers in 6 RCC cell lines (A498, ACHN, Caki-1, Caki-2, 769P, and 786-O). In vitro activity of ARQ 197 was studied by cell viability and clonogenic assays, and by changes in c-Met and down-stream mediators.

Results: c-Met expression is higher in RCC than adjacent normal renal tissue (p < 0.0001) and is expressed in all subtypes of RCC, including clear cell carcinoma; expression is highest in papillary and sarcomatoid subtypes. Greater c-Met expression correlates with higher tumor grade (p = 0.0019) and clinical stage (p = 0.0208), and is an independent predictor of poor overall survival (Multivariate Cox LR 5.7, p = 0.017). c-Met expression correlates to decreased survival in the clear cell subset as well. c-Met protein is activated (phosphorylated) in all 6 RCC cells. ARQ 197 inhibits cell growth in RCC cell lines at nanomolar concentrations (IC50 350-680 nM) and inhibits colony formation at 500 nM. ARQ 197 decreases phosphorylation of c-Met in time- and dose-dependent patterns with dose-dependent decreases in phospho-ERK.

Conclusions: c-Met expression is an independent predictor of survival in RCC, including clear cell subtype, suggesting that it is a potential therapeutic target worthy of further investigation. ARQ 197 effectively inhibits proliferation of clear cell carcinoma cell lines. Further preclinical studies are planned to determine mechanism of cellular arrest and apoptosis and markers of drug sensitivity and resistance.

[Table: see text]
Chromosomal deletions, tumor phenotype, and prognosis in prostate cancer.
Authors: Minner S. , Krohn A. , Burkhardt L. , Tennstedt P. , Simon R. , Sirma H. , Huland H. , Sauter G. , Schlomm T.
Published: February 2017

37

Background: Chromosomal deletions are frequent in prostate cancer (PCa) but target genes and potential clinical significance are often unknown. This project aimed at the identification of frequent and new deletions in PCa and to study their association with tumor phenotype and PSA recurrence.

Methods: Array CGH was performed on 77 advanced PCa. Deletions of interest were subsequently analyzed on a tissue microarray containing more than 2000 PCa with clinical follow-up data using fluorescence in situ hybridization (FISH). The FISH probes used included a break-apart probe for TMPRSS2-ERG and dual-labeling probes for centromere 10/PTEN and centromere 3/3p14.

Results: The most frequent circumscribed deletions found by array CGH were 3p14 (including FOXP1) in 18%, 5q31 in 16%, 5q21 in 14%, 6q13 in 21%, 6q21 in 19%, 6q26 in 14%, 8p11 in 17%, 10q23 (including PTEN) in 18%, 12p13 in 14%, 13q14 in 14%, 16q24 in 22% and 21q (representing TMPRSS2-ERG fusion) in 18%. TMPRSS2-ERG fusions, PTEN and FOXP1 deletions were selected for FISH analysis. A TMPRSS2-ERG fusion was observed in 394 of 947 interpretable cases (41.6%). TMPRSS2-ERG fusion was unrelated to tumor stage, Gleason grade, and PSA recurrence. PTEN deletions were observed in 8.9% of 1844 interpretable cases and were associated with advanced tumor stage (p<0.0001), high Gleason grade (p<0.0001), and early biochemical recurrence (p<0.0001). FOXP1 deletions were seen in 5.0% of 619 cases. FOXP1 deletions were not significantly linked to tumor phenotype and outcome. Both PTEN and FOXP1 deletions were strongly linked to TMPRSS2-ERG fusions. TMPRSS2-ERG fusion positive tumors had PTEN deletions in 15.4% and FOXP1 deletions in 10.7%, while TMPRSS2-ERG fusion negative cancers had PTEN deletions in only 5.8% and FOXP1 deletions in only 2.0% of cases (p<0.0001 each).

Conclusions: The TMPRSS2-ERG fusion determines a genetically distinct subgroup of prostate cancers. Our data provide no evidence for a particular clinical behaviour of TMPRSS2-ERG fusion positive cancers in radically operated patients. PTEN and FOXP1 alterations are preferentially found in TMPRSS2-ERG fusion positive cancers. Both genes may potentially be involved in pathway dysregulation in these cancers.

No significant financial relationships to disclose.
An underinvestigated toxicity of sunitinib: Red cell macrocytosis.
Authors: Hands D. J. , Eccles B. , Geldart T. R.
Published: February 2017

371

Background: Sunitinib, a multitargeted receptor tyrosine kinase inhibitor represents a standard firstline therapy for advanced renal cell carcinoma. Red blood cell (RBC) macrocytosis (with or without anaemia) is a recognized haematological toxicity but its aetiology remains uncertain.

Methods: The medical records of 73 patients (55 male, 18 female) patients treated with sunitinib between 2007 and 2010 at Poole and Bournemouth NHS Trusts, UK were reviewed. Patient demographics, length of treatment, response, RBC mean cell volume (MCV) indices, and known causes of macrocytosis including B12 and folate deficiency and hypothyroidism were examined.

Results: Median duration of treatment was 6 months (range 0-30). 38 (51%) have died. 24 (32%) received 2 or less cycles of treatment with the majority stopping due to early progression or death. 30 patients (41%) developed macrocytosis on treatment, but a trend to macrocytosis was identified in most patients positively correlating to time on treatment. 26 (87%) had a macrocytic anaemia. Median time to onset of macrocytosis was 4 months (range 1-11 months). Of the 30 macrocytic patients; 5 were hypothyroid, 7 had untreated borderline hypothyroidism and 13 were euthryoid throughout. Of patients tested to date 1 patient was found to be serum folate deficient at 2.5 ug/L (3-17). Supplementation corrected the macrocytosis. 1 patient was found to be serum B12 deficient; 53 ng/L (180-900) without any obvious comorbid cause. Further retrospective evaluation of other parameters such as red cell folate and reticulocyte count are currently being carried out.

Conclusions: A significant proportion of patients on sunitinib (41%) develop macrocytosis. On the basis of this case series, the largest to date, underlying causes of macrocytosis (with or without anaemia) appear multifactorial. Biochemical hypothyrodism is common following sunitinib treatment and is likely to represent one of several possible contributing factors. B12 and folate deficiency should not be forgotten as a potentially reversible cause of macrocytosis secondary to sunitinib. C-kit inhibition by sunitinib is a potential mechanism, paralleling the potential C-kit mediated macrocytosis commonly recognised in imatinib therapy.

No significant financial relationships to disclose.
Survival outcomes in metastatic renal carcinoma based on histological subtypes: SEER database analysis.
Authors: Didwaniya N. , Edmonds R. J. , Fang X. , Silberstein P. T. , Subbiah S.
Published: February 2017

381

Background: Renal cell cancer (RCC) represents a heterogeneous group of tumors with distinct histopathologic, genetic, and clinical features. This study was conducted to evaluate the prognostic value of histology in RCCs.

Methods: 3,062 patients with metastatic RCC from year 1998-2007 were identified from Surveillance Epidemiology and End Results (SEER) database. Data regarding their age, sex, race, treatment modality utilized and cancer specific survival was extracted and analyzed.

Results: Clear cell, sarcomatoid, adenocarcinoma NOS, papillary, collecting duct, chromophobe and cyst associated renal carcinoma accounted for 2,166 (70%), 433 (14%), 216 (7%), 160 (52%), 47 (1.5%), 35 (1.14%), and 5 (0.01%) respectively. The mean age of presentation was 63.5 in clear cell RCC and 62.7 years in non-clear cell RCC. Surgery was performed in 57.23% of all clear cell cancers and 50.84% in non-clear cell-RCC group. 27.34% of all clear cell cancer patients received radiation in contrast to 34.53% in the other group. Both clear cell RCC (64.54%) and non-clear cell RCC (69.52%) occurred commonly in males. Incidence of clear cell RCC was 4.67% in Asians, 7.01% in Blacks, 88.32% in Whites. The incidence of non-clear cell RCC was 3.81% in Asians, 14.78% in Blacks, and 81.41% in Whites. Cancer-specific survival was calculated in all histologic subtypes. Median survival for clear cell RCC was 8 months, 3 months for adenocarcinoma NOS, 7 months for cyst associated renal carcinoma, 8 months for papillary carcinoma, 7 months for chromophobe type, 4 months for sarcomatoid and 4 months for collecting duct RCC. Median overall survival was significantly better for clear cell cancer as compared to non-clear cell RCCs (8 months vs. 4 months; p< 0.0001).

Conclusions: Non-clear histology RCCs represent 30% of metastatic RCC and are associated with poor prognosis when compared to clear cell RCC.While development of novel targeted therapies has improved survival in clear cell RCC, it has not made a impact in survival of non-clear RCCs. An indepth understanding of the genetic and molecular changes associated with non-clear cell RCCs is important to improve their prognosis.

No significant financial relationships to disclose.
Pheochromocytoma (PC)/paraganglioma (PG) and sunitinib: Review of reported cases and literature and case report contribution.
Authors: Dettino A. A. , Guimaraes G. C. , Formiga M. , Rinck J. , Ribeiro A. G. , Alves M. S. , Rameri C. , Serrano S. C. , Pagano T. , Fanelli M. F.
Published: February 2017

406

Background: Pheochromocytomas/paragangliomas (PC/PG) are rare diseases, but may be responsible for lower quality of life to patients,if progressive or metastatic when malignant. Recently, some benefit has been reported with the use of palliative tyrosine-kinase inhibitors (TKI),such as sunitinib, already approved for kidney cancer.

Methods: Review of litearure with a Medline search for PC/PG and suninitib, due to the need to treat a patient with progressive advanced malignant PC, refractory to chemotherapy (CT). Our plan is to contribute reporting safety and efficacy in an additional PC patient.

Results: We expose the data found in a table below,with most relevant features related to PC/PG treatments and TKI.

Conclusions: Sunitinib as a treatment option to refractory PC/PG may be active and should be further evaluated in this context. A phase II trial is under way (SNIPP; NTC00843037). Other therapies may be evaluated, such as sorafenib, bevacizumab, temozolomide, temsirolimus, thalidomide, and other potential molecular strategies, also with other small molecules, target therapies, and antiangiogenic factors. We plan to follow the reported PC patient and show additional data in the near future.

[Table: see text]

No significant financial relationships to disclose.
Parafibromin as a new immunohistochemistry staining to improve pathologic diagnosis of renal oncocytoma: Analysis of 225 renal tumors.
Authors: Albiges L. , Couturier J. , Allory Y. , Camparo P. , Sibony M. , Vieillefond A. , Teh B. T. , Escudier B. J. , Molinie V. ,   GELU
Published: February 2017

408

Background: Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma (Onc) are two distinct but closely related entities with strong morphologic and genetic similarities. While chRCC is a malignant tumor, Onc is usually considered as a benign entity. Recently, gene expression profiling applied on chRCC and Onc identified new potential markers that may effectively discriminate the 2 pathologic entities, including parafibromin. This work aims at evaluating the diagnostic value of Parafibromin (Pf) immuno staining on a large number of renal tumor samples.

Methods: Sixty-three renal clear cell carcinoma (ccRCC), 47 papillary (Pap), 40 chRCC, and 75 Onc were immunostained for parafibromin antibody (1/200; Santacruz Biotechnology), on a tissue micro array.

Results: Parafibromin was positive in 38.6% of Onc, vs 5% of chRCC (p < 0.001), with a 95% specificity, and the positive predictive value observed for parafibromin was 94%. For other tumor types, a positive staining for parafibromin was observed in 7.9% and 8.5% in ccRCC and Pap respectively.

Conclusions: Parafibromin is a recently identified protein which seems to be specific for oncocytoma, and highly discriminant for other histologic renal cell tumor subtypes, especially for chromophobe. IHC may help to optimize therapeutics strategy for small renal mass and avoid surgical resection of benign lesions in some patients.Validation of this staining on renal tumor biopsies is on going.The value of the combination of this new immunostaining associated with the three standard IHC staining (CK7, CD117, E Cad) will be provided at the meeting.

[Table: see text]

No significant financial relationships to disclose.
Do urologists and radiation oncologists agree on adjuvant radiation therapy for prostate cancer? A web-based patterns-of-care survey.
Authors: Showalter T. N. , Teti K. A. , Foley K. A. , Keith S. W. , Trabulsi E. J. , Dicker A. , Lallas C. D. , Pizzi L. , Gomella L. G.
Published: February 2017

76

Background: Three randomized trials support adjuvant radiation therapy (ART) over observation after radical prostatectomy (RP) for prostate cancer (PC) patients with adverse pathologic features (APFs), but many clinicians instead favor early salvage RT (SRT) for a rising PSA. We conducted a web-based survey of U.S. radiation oncologists (RO) and urologists (U) regarding ART and SRT.

Methods: We designed a web-based survey to evaluate beliefs about post-RP RT and treatment policies. Survey invitations were e-mailed to SUO members and a list of 926 RO ASTRO members with an interest in PC. One email was sent to limit message burden. Only those responses at least 50% complete were included in the analysis. Differences in ART recommendation rates were evaluated by chi square test.

Results: Responses were received from 231 RO and 101 U, resulting in 302 analyzable responses (88 U, 214 RO). 79% of U and 32% of RO respondents were academic physicians. ART was recommended based on APF alone (78% RO, 44% U), based on APF plus Gleason score or PSA (14% RO, 35% U), only for detectable PSA (7% RO, 14% U), or never (2% RO, 7% U). When asked the effect of ART on outcomes, most respondents replied “improves survival” (71% RO, 63% U) or “improves biochemical control but not survival” (29% RO, 30% U), but 9% of U replied “delays PSA recurrence, but no durable benefit” or “no improvement in any outcomes” (versus 0% RO). A recommendation for ART based on APFs alone was made for: seminal vesicle invasion (SVI) (76% RO, 59% U; p=0.003), extracapsular extension (ECE) (70% RO, 32% U; p<0.001), positive surgical margin (PSM) (91% RO, 48% U; p<0.002). For patients with Gleason score 8-10 PC, ART was recommended for: SVI (75% RO, 56% U; p=0.001), ECE (73% RO, 45% U; p<0.001), PSM (93% RO, 74% U; p<0.001). Reported PSA threshold for SRT was: any detectable (36% RO, 23% U), 0.2-0.3 (50% RO, 36% U), 0.4-0.5 (9% RO, 30% U), 0.6-0.8 (3% RO, 10% U) ng/mL, or higher (1% RO, 1% U).

Conclusions: Despite similar rates of belief that ART improves survival or biochemical control, U were less likely than RO to recommend ART based solely on APFs after RP. Upcoming results of clinical trials of ART versus SRT may provide consensus for decisions in this setting.

No significant financial relationships to disclose.
Correlation of radiotherapy with cause-specific and overall survival in clinically node-positive prostate cancer.
Authors: Tward J. D. , Shrieve D. C.
Published: February 2017

9

Background: Clinically staged node-positive prostate adenocarcinoma is a rare entity. We evaluated the role of definitive radiotherapy (RT) in clinical N1 prostate cancer patients who did not undergo prostatectomy and compared their cause-specific (CSS) and overall (OS) survival to men who did not undergo any definitive therapy.

Methods: Subjects were identified using the NCI's Surveillance, Epidemiology and End Results (SEER) Program diagnosed between the years 1988 and 2006 with adenocarcinoma of the prostate. Subjects included in the analysis were men with clinically staged node-positive disease, who were otherwise non-metastatic. Descriptive statistics were performed, and CSS and OS was estimated using the methods of Kaplan and Meier. Statistical comparisons of treatment modalities were analyzed using univariate and multivariate Cox regression.

Results: A total of 1,100 subjects were identified. The median age was 69 yrs (range 41-95) and median f/u time was 90 months (range 1-255 months). The 5, 10 and 15 yr CSS for men who had no definitive therapy was 71.1%, 50.3% and 35.1% respectively. The 5, 10 and 15 yr CSS for men who had external beam RT was 78.1%, 62.9% and 51.4% respectively. This was significantly different favoring RT on univariate cox regression (Hazard Ratio (HR) =0.66, 95% CI=0.54 to 0.82, P = 0.0002). The 5, 10 and 15 yr OS for men who had no definitive therapy was 56.2%, 29.1% and 14.86% respectively. The 5, 10 and 15 yr OS for men who had external beam RT was 67.8%, 44.2% and 20.4% respectively. This difference was also significant favoring RT on univariate cox regression (HR =0.70, 95% CI 0.59 to 0.81, P < 0.0001). On multivariate Cox regression analysis taking into account age at diagnosis, Gleason sum 2-4, 5-7, and 8-10, year of diagnosis, and presence or absence of definitive RT, RT (HR=0.69, 95% CI=0.56 to 0.86, P = 0.0008), earlier year of diagnosis (HR=0.94, 95% CI=0.92 to 0.97, P < 0.0001), and GS 7 or less was correlated with improved CSS.

Conclusions: RT for node-positive subjects is correlated with both clinically and statistically improved cause-specific and overall survival. Patients with clinical N1 prostate adenocarcinoma should be strongly considered for RT.

No significant financial relationships to disclose.
Dose to regions within the prostate during the learning curve phase in low dose rate (LDR) brachytherapy: Sector analysis of 71 consecutive patients at Princess Margaret Hospital.
Authors: Saibishkumar E. P. , Iupati D. , Borg J. , Fernandes K.
Published: February 2017

91

Background: It is important to evaluate the dose distribution within the prostate in highly conformal and operator dependent treatment like brachytherapy, especially in the learning curve phase when technical skill is evolving. We report detailed dosimetric analysis of prostate sectors in the initial 71 consecutive implants performed by a physician in the first year of practice.

Methods: Implants were done based on a pre plan but intra-operative adjustments were made to account for actual seed positions and addition of seeds and the final dose distribution to the prostate was documented as Intra-operative (IO) plan. Post-implant assessment was at 1 month using fused MRI/CT scans. Twelve prostate sectors were generated by division into 4 quadrants (anterior, posterior, laterals) and 3 segments (base, middle and apex). IO and post-implant (PI) V100 and D90 for sectors and whole prostate were recorded. Comparative (Wilcoxon Rank Sum) and association (Spearman's rank correlation) testing was performed for univariate analysis. Optimal dosimetry values for the entire prostate and sectors were defined as D90 >90% and V100 >85%.

Results: Seventy implants were optimal (out of 71) with mean prostate PI V100 and D90 of 95.5% and 117.1%. Only 1 sector had suboptimal mean PI V100 and D90 (70.3% and 85.9%), significantly lower than IO (p<0.001), contributing to lower PI V100 for the base (88%) and anterior sectors (86.9%). The mean IO D90 of apical sectors (126%) was lower than base and mid gland (131% and 132% respectively) and lateral sectors was (134%) higher than anterior and posterior sectors (123% and 126%) consistent with a modified peripheral loading approach. D90 decreased from IO to PI plan in anterior (123% vs 106%, p<0.001) and base sectors (132% vs 108%, p<0.001) while increase was noted in apical (126% vs 133%, p<0.001) and posterior sectors (126% vs 131%, p=0.006).

Conclusions: Results are encouraging with optimal dosimetry in 11/12 sectors in most patients, and sector analysis provided insight into planning factors and provided useful data for refinement in practice. Further study correlating sector analysis with clinical outcomes is required.

No significant financial relationships to disclose.
Optimized response prediction in esophagogastric junction adenocarcinomas (EGJAc) with combination of molecular biomarkers and FDG-PET.
Authors: Petty Russell David , Bain Gillian H , Murray Graeme I , Gilbert Fiona Jane , Denison Alan , Mckiddie Fergus , Ahearns Trevor , Leeds John , Phull Perminder , Park Ken , Nanthakumaran Shayanthan , Welch Andy , Schweiger Lutz , Collie-Duguid Eliana
Published: February 2017

1

Background: Predictive biomarkers (BMs) for EGJAc would optimise treatment selection and avoid ineffective therapy. Metabolic response (MR) defined as >35% decrease in tumour FDG Standardized Uptake Value (SUV) between day 0 & 14 after starting chemotherapy has a high negative predictive value (95%) for response, but limited positive predictive value (50%). Combining molecular BMs with FDG-PET may optimise response prediction. We used global gene expression profiling (GEP) to identify molecular BMs that when combined with FDG-PET would improve predictive accuracy.

Methods: 28 patients with locally advanced or metastatic EGJAc received platinum based chemotherapy (PBC). FDG PET CT scans were at day 0 and day 14 and GEP (Affymetrix ST1.0 Exon Genechips) on day 0 tumour biopsies. A tissue microarray comprising an independent set of 154 OGJAc who underwent surgery +/− neoadjuvant PBC was used with immunohistochemistry (IHC) for qualification of GEP results. Radiological response was assessed after 3/ 4 cycles of PBC by RECISTv1.1.

Results: We identified a gene expression signature (86 genes) that separated FDG PET MR patients(>35% fall SUV day 0 to14) into those that do and do not go on to have a RECIST response. In cross validation, this signature correctly predicted response in 28/28. Pathway analysis on GEP data identified potential novel mechanisms of response, including the Leptin pathway. Leptin mRNA was higher in FDG metabolic responders who did not have a RECIST response compared to those that did. In the independent set, high Leptin protein by IHC was strongly associated with lack of histopathologic response to neoadjuvant PBC (n=64, p=0.002). High Leptin expression also had a therapy independent prognostic effect with longer survival in the absence of histopathologic response or with no neoadjuvant PBC and in low Leptin patients poor survival was mitigated to a certain extent by neoadjuvant PBC (n=154, Kaplan-Mieier, log rank p=0.041 & Cox MVA p=0.040).

Conclusions: Molecular biomarkers (Leptin in particular) combine with FDG PET to optimise response prediction in EGJAc. Further investigation of this combined molecular and imaging approach is warranted.
Regional differences in patient (pt) characteristics of AVAGAST: An exploratory comparison in chemotherapy plus placebo (PL) arm between Japanese (JPN) and the rest of the world (ROW) pts.
Authors: Nishina Tomohira , Sawaki Akira , Yamaguchi Kensei , Doi Toshihiko , Yamada Yasuhide , Chin Keisho , Satoh Taroh , Boku Narikazu , Omuro Yasushi , Komatsu Yoshito , Takiuchi Hiroya , Hamamoto Yasuo , Koizumi Wasaburo , Saji Shigehira , Shah Manish A. , Van Cutsem Eric , Kang Yoon-Koo , Ohtsu Atsushi
Published: February 2017

100

Background: AVAGAST study showed regional differences in efficacy, including notable differences in progression free survival (PFS) and overall survival in the PL arm. In Japan, there is a certain number of pts with minimal peritoneal metastasis (PM) diagnosed only by laparoscopy or open surgery, which seems unusual in Western as well as in other Asian countries, and it might have led the differences. Therefore, an exploratory analysis was conducted among the PL arm to examine pt characteristics including PM associated with differences in outcome between JPN and ROW.

Methods: We compared PFS of PL arm between pts enrolled from JPN and those from ROW. Hazard ratio (HR) and its 95% confidence interval (95%CI) between JPN and ROW were calculated using Cox’s proportional hazard model for each major covariates (disease status, performance status, prior gastrectomy, prior (neo)adjuvant chemotherapy, age, sex, primary site, liver metastasis (mets), number of metastatic sites, disease measurability, histologic type, maximum of tumor size, sum of tumor size, bone mets, PM and only PM)

Results: 188 pts from 14 sites were enrolled from JPN, of which 94 pts were randomized to PL arm. Compared with 293 pts from ROW in PL arm, PFS tend to be favorable in JPN. Subgroups of JPN without liver mets, with diffuse or mixed type gastric cancer (GC), with PM and with only PM were clearly favorable than that of ROW. The difference in subgroup with PM was especially large with lower confidence limit of 1.21. When the pts with only PM were excluded, the difference of PFS in PL arm between JPN and ROW became smaller ( Table ).

Conclusions: In this exploratory analysis, pts with PM in JPN had a better prognosis than ROW pts. Understanding this unique pt population may provide insight to the regional differences in outcome noted on this study.

[Table: see text]
Comparison of adjuvant chemoradiation to peri-operative chemotherapy for the treatment of resected gastric and gastroesophageal junction adenocarincoma.
Authors: Kim Haerin , Kollmannsberger Christian K. , Schellenberg Devin , Cheung Winson Y. , Lim Howard John
Published: February 2017

103

Background: Currently there are several accepted peri-operative treatment modalities for the resected gastric (GC) and gastroesophageal junction (GEJ) adenocarcinoma. In the 2008, peri-operative chemotherapy (CRT) using the MAGIC was adopted as the preferred approach to adjuvant chemoradiation with the MacDonald protocol (cXRT) in the British Columbia. An era to era comparison was performed to determine if there were differences in outcomes.

Methods: Data from the pharmacy records of patients (pts) referred to 1 of 5 cancer treatment in BC were analyzed from 2001- July 2010. Pts that underwent curative resection for GC or GEJ were only included. cXRT cohort was defined from Jan 2001-Dec 2007, prior to the CRT era. CRT cohort started from Jan 2008-July 2010. Descriptive statistics were used to compare the groups. Survival analysis was performed using Kaplan Meier methods.

Results: The Table summarizes the patient characteristics. In the CRT arm, there were more males, less pts with a LN ratio >0.2 and shorter median follow-up. 92.1% completed the pre-op chemotherapy and 44.7% completed post-op chemotherapy whereas 73.3% of pts completed cXRT (p<0.05). 1 yr survival was similar between the 2 cohorts. Median overall survival was not reached in the CRT arm and was 64.1 months in the cXRT arm.

Conclusions: Delivery of CRT was similar to that in the MAGIC trial. Outcomes of CRT compared to cXRT appears to be similar in this cohort to cohort study with similar 1 yr survival. Pre-operative CRT results in less pts with a LN ratio > 0.2. Further follow-up is needed with respect to relapse and overall survival. Either modality can be considered for peri-operative management of GC or GEJ adenocarcinoma.

[Table: see text]
Processes of care in curative therapy for gastric cancer: A RAND/UCLA appropriateness study.
Authors: Brar Savtaj Singh , Law Calvin , McLeod Robin S. , Paszat Lawrence Frank , Helyer Lucy K. , Seevaratnam Rajini , Cardoso Roberta , Mahar Alyson L. , Yohanathan Lavanya , Bocicariu Alina , Coburn Natalie G. ,   Gastric Cancer Processes of Care Expert Panel
Published: February 2017

104

Background: Processes of care in curative therapy for gastric cancer are ill-defined, have significant variations and may impact patient outcomes.

Methods: A multi-disciplinary expert panel (16 physicians, 6 countries) scored 595 scenarios using the RAND/UCLA Appropriateness Methodology. Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores from 1-3 were considered inappropriate, 4-6 uncertain, and 7-9 appropriate. Agreement was reached when 11 of 16 panelists scored the statement similarly. If a statement was agreed to be appropriate, it was given a necessity score in the same manner.

Results: Open gastrectomy was considered appropriate for all patients and necessary for patients with N2-3 disease, while laparoscopic gastrectomy was appropriate for patients with T1-2 N0 disease. D1 lymph node dissection (LND) was considered appropriate for T1 N0 disease. For all others, D2 LND was considered appropriate and necessary. It was appropriate to assess at least 15 LN. Intraoperative pathologic assessment of the proximal margin was considered appropriate for gross margins <5 cm or T3/T4 lesions. If the margin was positive on frozen section, re-resection of the stomach or abdominal esophagus was considered appropriate for N1-3 disease and necessary for N0 disease. Curative resection was appropriate if a patient presented with perforation. Neoadjuvant chemotherapy was considered appropriate for patients who presented with T1-2 N2-3 or T3-4 N0-3 disease with minor symptoms but not with major symptoms. Adjuvant chemoradiotherapy was considered appropriate and necessary for patients with T1-2 N1-3 or T3-4 N0-3 disease. No adjuvant therapy was considered appropriate for patients with T1N0 disease.

Conclusions: The above criteria have been found to be appropriate and necessary for the curative treatment of patients with gastric cancer and may be used to improve processes and quality of care.
Role of repeat staging laparoscopy in locoregionally advanced gastric cancer after completion of neoadjuvant therapy.
Authors: Cardona Kenneth , Zhou Qin , Gönen Mithat , Strong Vivian E. , Brennan Murray F. , Coit Daniel G.
Published: February 2017

11

Background: Staging laparoscopy (SL) can identify occult, subradiographic metastatic disease, either visible or cytologic, defining patients with stage IV gastric cancer who are unlikely to benefit from gastrectomy. The purpose of this study was to characterize the yield of repeat SL performed immediately prior to gastrectomy following administration of neoadjuvant therapy for locoregionally advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

Methods: Retrospective review of a prospective database identified patients with locoregionally advanced G/GEJ adenocarcinoma (T3−4Nany or TanyN+) that underwent pretreatment SL with negative peritoneal cytology followed by neoadjuvant chemotherapy or chemoradiation. After neoadjuvant therapy, patients underwent repeat SL. The yield of repeat SL to identify metastatic disease (M1) was determined and outcome data were analyzed.

Results: From 1994−2010, 164 patients with locoregionally advanced G/GEJ adenocarcinoma were identified who underwent repeat SL immediately prior to gastrectomy. Occult M1 disease was identified in 12 patients (7.3%). Of these 12 patients, M1 disease was identified at laparoscopy in 9 patients (5.5%)—8 patients had visible disease and 1 patient had peritoneal cytology−only M1 disease. M1 disease not identified by SL was discovered at laparotomy in the other 3 patients (1.8%). There were no complications associated with patients who only underwent SL. Median follow-up was 30 months with a median survival of 18 months for patients with M1 disease and 47 months for patients resected with curative intent without M1 disease (p<0.001).

Conclusions: Repeat staging laparoscopy following neoadjuvant therapy for locoregionally advanced G/GEJ adenocarcinoma identifies 5−6% of patients with clinically occult, subradiographic M1 disease. The majority of M1 disease is identified at repeat SL rather than at laparotomy and the majority is visible as opposed to cytology−only M1. These patients with occult M1 disease have a poor prognosis, are unlikely to benefit from gastrectomy, and repeat SL can avert the morbidity of a non−therapeutic laparotomy in this patient population.
Multicenter phase II study of triplet combination chemotherapy with paclitaxel, cisplatin, and S-1 for advanced gastric cancer (OGSG 0703).
Authors: Fujitani Kazumasa , Kimura Yutaka , Imamura Hiroshi , Gotoh Masahiro , Iijima Shohei , Ueda Shugo , Imano Motohiro , Oshita Masahide , Kurokawa Yukinori , Shimokawa Toshio , Takiuchi Hiroya , Tsujinaka Toshimasa , Furukawa Hiroshi ,   Osaka Gastrointestinal Cancer Study Group
Published: February 2017

124

Background: Docetaxel combined with cisplatin and 5-fluorouracil is active in advanced gastric cancer, but not generally accepted because of its substantial toxicities. We conducted a multicenter phase II study of triplet combination using paclitaxel, cisplatin and S-1 (PCS) as first-line treatment for advanced gastric cancer.

Methods: Patients with previously untreated, locally advanced or metastatic measurable gastric cancer, a performance status < 2, age of 20-75 years, and adequate organ functions were given intravenous paclitaxel at 70 mg/m2 and cisplatin at 30 mg/m2 on days 1 and 15, plus oral S-1 at 40 mg/m2 b.i.d. on days 1 to 21, followed by 2-week rest, repeated every 5 weeks. Treatment was continued until disease progression or unacceptable toxicity occurred, or the patient refused the therapy. Study endpoints included overall response rate (ORR) as primary, progression free survival (PFS), overall survival (OS), and toxicity. Sample size of 40 patients was determined to reject the ORR of 55% under the expectation of 75% with a power of 80% and a one-sided α of 5%.

Results: A total of 52 patients were enrolled in this study, among whom 49 were assessable for efficacy and 51 assessable for toxicity. ORR was 46.9% (95% CI: 32.5-61.7%). The median PFS and median OS were 5.4 months (95% CI: 4.1-7.0) and 11.5 months (95% CI: 7.3-16.1), respectively. Frequent grade 3/4 toxicities were neutropenia (51%), leucopenia (25%), anemia (20%), hyponatremia (16%), anorexia (14%), diarrhea (8%) and fatigue (8%). There was no treatment-related death.

Conclusions: Triplet combination chemotherapy with PCS demonstrated superior feasibility with promising antitumor activity, though which did not meet the statistical hypothesis, for advanced gastric cancer.
Body weight loss after surgery as an independent risk factor for continuation of S-1 adjuvant chemotherapy for gastric cancer.
Authors: Yoshikawa Takaki , Aoyama Toru , Kuwabara Hiroshi , Mikayama Yo , Ogata Takashi , Cho Haruhiko , Tsuburaya Akira
Published: February 2017

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Background: S-1 adjuvant chemotherapy improves survival of stage II/III gastric cancer, however, the compliance is not high. The aim of the present study is to clarify risk factors for continuation of S-1 after gastrectomy.

Methods: Patients were retrospectively selected according to the following criteria; (1) patients underwent curative D2 gastrectomy for gastric cancer during 2002 and 2010, (2) pathological stage II/III, (3) creatinine clearance more than 60 ml/min, and (4) S-1 was initiated at a dose of 80mg/m2 within 6 weeks after surgery. Clinical factors when starting S-1 chemotherapy were examined by uni- and multi-variate analyses.

Results: Seventy-five patients were eligible. Median age was 62 years (range: 36-80). Performance status was 0 in 65 patients and 1 in 10. Serum albumin level was >4.0 g/dl in 34 patients and <4.0 g/dl in 39. Operative procedure was total gastrectomy (TG) in 46 patients and distal one in 29. Median percentile of body weight loss to preoperative state (%BW loss) was 9.3 (range 0-21.1). Stage was II in 22 patients and III in 53. When %BW loss was classified to two groups; LOW (<15%, n=64) and HIGH (>15%, n=11), S-1 continuation rates were 82.8% in the LOW and 54.6% in the HIGH at 3 months and 73.2% in the LOW and 45.5% in the HIGH at 6 months, which were statistically significant (p=0.025). Among age, performance status, type of gastrectomy, %BW loss, serum albumin, and stage, only %BW loss was a significant independent risk factor for S-1continuation with hazard ratio of 2.437 by multi-variate Cox proportional hazard analyses (p=0.039).

Conclusions: To improve drug compliance which leads to survival, it is a key to maintain BW before starting adjuvant chemotherapy. Peri-operative nutritional therapy should be developed and be focused on chronic inflammatory phase after surgery and on starvation after gastrectomy. A randomized phase III trial is on-going to show efficacy of peri-operative nutritional support including eicosapentaenoic acid (EPA).
Quality of life following laparoscopic distal gastrectomy with modified billroth II reconstruction.
Authors: Le Maithao N. , Ellenhorn Jacob , Kim Joseph , Trisal Vijay , Ellenhorn Joshua D. I.
Published: February 2017

140

Background: Laparoscopic gastrectomy has been proposed as a procedure to reduce the morbidity of gastric cancer surgery. Modified Billroth II (BII) reconstruction with a side to side loop gastrojejunostomy is technically straightforward to accomplish laparoscopically. To determine the long term morbidity of this reconstruction technique, we performed a quality of life (QOL) analysis of patients undergoing laparoscopic distal gastrectomy with modified BII reconstruction.

Methods: Between June 2005 and May 2011, 64 patients underwent laparoscopic distal gastrectomy with modified BII reconstruction at City of Hope Medical Center (COH). Patients alive with no evidence of disease were recruited to participate in the QOL study. The study was approved by the Institutional Research Board of COH. Research subjects completed the EORTC QOL-STO22 instrument which queried patients for post gastrectomy symptoms. Comparison between groups was done using the Student-t test.

Results: 33 of 64 patients met the criteria for participation in our QOL study. Of these, 23 patients consented to participate and completed the EORTC QOL-STO22 instrument. Overall, 81% categorized symptoms as occurring “not-at-all” or “a-little” while 19% reported symptoms occurring “quite-a-bit” or “very-much”. Since symptoms could be worse in patients with small gastric pouches, we divided our cohort into two groups, one having at least 70% of the stomach resected (12 patients) and the other having less than 70% of the stomach resected (11 patients). The two groups were compared with respect to symptoms. There was no difference between the groups with respect to dysphasia (p=0.80), pain (p=0.98), reflux (p=0.93), and eating restriction (p=0.33). Overall 78% of patients with a small gastric pouch and 83% of patients with a larger gastric pouch reported these symptoms as occurring “not-at-all” or “a-little”.

Conclusions: Laparoscopic distal gastrectomy with modified BII reconstruction resulted in an acceptable morbidity rate with few patients experiencing severe symptoms. Gastric pouch size did not predict symptoms and most patients with a small gastric pouch report excellent QOL.
SBRT as an alternative to RFA for the treatment of primary and metastatic liver tumors.
Authors: Liu Erqi , Stenmark Matthew H. , Lee Oliver E , Schipper Matthew J , Caoili Elaine M , Ben-Josef Edgar , Lawrence Theodore Steven , Feng Mary Uan-Sian
Published: February 2017

158

Background: Radiofrequency ablation (RFA) is a widely used local therapy for small, unresectable liver tumors (LT). Stereotactic body radiotherapy (SBRT) has been used for similar patients, and has the advantage that it can be used when lesions are adjacent to blood vessels, are difficult to reach and cannot be imaged on ultrasound. We examined RFA and SBRT outcomes for treating primary and metastatic LT at our institution and identified predictive factors for local control.

Methods: This study included 62 patients (pts) with 106 LT (69 metastatic, 37 primary) treated with SBRT and 127 pts with 206 LT (80 metastatic, 126 primary) treated with RFA from 2000 to 2010. 42 lesions were ablated intra-operatively while 164 were ablated percutaneously. Mean tumor size by maximum diameter was 2.2 cm (0.4-11) and 2.3 cm (0.6-6.2) for RFA- and SBRT-treated LT, respectively. Freedom from local progression (FFLP) for SBRT was defined as absence of progressive LT within or at the PTV margin while FFLP for RFA was defined as recurrence within or immediately adjacent to the ablation zone.

Results: With a median follow-up of 29.4 months (0.46 to 120.8), 1- and 2-yr FFLP rates for all SBRT- vs RFA-treated LT were 93% and 84% vs 86% and 83%. There were 14 cases of residual LT after RFA, 6 of which were re-ablated; these were not counted as RFA failures. Significantly more pts in the SBRT group had received prior systemic therapy (54% vs 31%, p=0.0001) and had active extrahepatic disease at treatment start (36% vs 23%, p=0.01). For SBRT, neither LT size nor dose predicted for FFLP. For RFA, tumor size ≥3 cm had worse FFLP (HR: 5.3, p<0.0001) but an intraoperative approach had better FFLP (HR: −2.2, p=0.01). For tumors >3cm, SBRT had significantly better FFLP than percutaneous RFA (HR: 0.32, p=0.018). In the RFA group, there were 9 complications, including pneumothorax, hemothorax, and small bowel injury, 2 of which resulted in death. In the SBRT group, there was 1 case of radiation-induced liver disease in a Child-Pugh Class B pt but no other significant toxicities.

Conclusions: SBRT is a safe alternative to RFA, can be used in a wider variety of patients, and may be more effective than percutaneous RFA at locally controlling larger liver tumors.
Diagnostic microRNA serum profile in pancreatic cancer.
Authors: Schultz Nicolai Aagaard , Dehlendorff Christian , Werner Jens , Nielsen Thor Schutt Svane , Calatayud Dan , Giese Nathalia , Vittrup Benny , Nielsen Kaspar , Johansen Julia S. , Andersen Klaus Kaae
Published: February 2017

160

Background: MicroRNAs (miRs) regulate genes with important roles in oncogenesis, angiogenesis and tissue differentiation. MiRs have high tissue-specific expression patterns and are interesting new biomarkers with a potential for earlier diagnosis of pancreatic cancer (PC). The aim was: 1) to identify a panel of diagnostic miRs in serum that can separate patients with PC from patients with chronic pancreatitis (CP) and healthy subjects (HS); and 2) to use statistical methods that make the analysis of the miR panel less sensitive to known methodological day-to-day variation.

Methods: RNA was purified from serum according to SOP in pretreatment samples stored at −80°C from two prospective studies of 139 patients with PC (101 were operated and 38 had locally or metastatic PC), 17 patients with CP and 50 healthy subjects from 4 University Hospitals. MiR expression was measured using TaqMan Array Human MicroRNA A and B cards (v3.0 Applied Biosystems) profiling 768 miR. Raw miR expression values were checked for outliers. In a univariate selection method the rank of each miR (miRs were ranked for each subject) was related to PC using logistic regression. MiRs with p-values below 0.000001 were tested in a multivariate analysis.

Results: Serum samples from 206 patients had acceptable miR. After exclusion of miRs that was undetermined in ≥20% of samples 85 miRs were considered in the univariate analysis and 12 of these subsequently included in the multivariate model. Seven miRs were significantly associated with PC. For all miRs in the diagnostic panel decreased expression is associated with PC.

Conclusions: We present a diagnostic panel of 7 miRs in serum that discriminates samples from patients with PC from patients with CP and HS. The 7 miRs were selected with a rank-based method, which is a novel non-parametric method for data processing in miRNA array studies.

[Table: see text]