bluuebunny/crossref_metadata_2025 huggingface dataset:
Trimodality treatment for advanced esophageal cancer: Impact of minimally invasive esophagectomy.
Authors: Williams D. G. , Carpenter S. , Ross H. J. , Paripati H. , Ashman J. B. , Callister M. D. , Harold K. L. , Jaroszewski D. E.
Published: February 2017

125

Background: Esophageal cancer is best managed by multimodality therapy, frequently with chemotherapy (C) or chemo- radiotherapy (CRT) preceding resection. Minimally invasive esophagectomy (MIE) is increasingly accepted, but studies of MIE in advanced esophageal and gastroesophageal junction cancer after induction CRT are lacking. This report presents the data on MIE as part of tri-modality therapy for esophageal cancer at Mayo Clinic in Arizona (MCA).

Methods: Patients (pts) who underwent CRT before or after MIE for cancer at MCA between November 2006 and May of 2010 were reviewed retrospectively.

Results: 46 pts (40 males, and 6 females) met study criteria and were reviewed. Median age was 62 years (41-88 years). 45 pts (98%) had adenocarcinoma and one pt had squamous carcinoma. Initial clinical stage was IIA in 10 pts (22%), IIB in 3 pts (7%), III in 26 pts (55%), and IVA in 7 pts (15%) with positive celiac nodes. 43 pts (93%) underwent preoperative CRT with additional intra-operative radiotherapy in 4 pts. Median operating time was 354 min (range 211-567 min), median blood loss was 225 ml (range 50-1,400 ml), and median hospital stay was 8 days (range 5-48 days). 19 pts (41%), including the 3 who did not undergo preoperative CRT, received postoperative C or CRT due to either residual disease at resection or to local recurrence. 30 of 43 pts undergoing MIE after CRT were down staged (11 CR [25.6%], 10 near CR [23.3%]) demonstrating a major response to neoadjuvant therapy in 48.9% of pts. One pt died in hospital (from ARDS and sepsis subsequent to aspiration pneumonia) and two pts died within 30 days of surgery (one from pulmonary embolism, and the other from unknown causes) for a 30 day surgical mortality of 6.5%. 29 pts (63%) had a complication of surgery including 11 (24%) minor and 18 (39%) major complications. After a median follow-up of 13 months (range 0.9-43 months) 16 pts were diagnosed with recurrent disease and 10 of these pts have died of their disease.

Conclusions: CRT with MIE is associated with an acceptable morbidity and mortality level for pts with locally advanced esophageal cancer. These results compare favorably with morbidity, mortality, and recurrence rates in open esophagectomy pts.

No significant financial relationships to disclose.
The clinical values of methylation status of P16 and APC genes in bile in diagnosis of malignant obstructive jaundice.
Authors: Yin X. , Yan G. , Peng J. , Liang L.
Published: February 2017

171

Background: Preoperative definitive diagnosis of malignant obstructive jaundice caused by biliary and pancreatic carcinomas still remains a major challenge. Hypermethylation of tumor suppressor genes have been implied in carcinogenesis of biliary and pancreatic malignancies. The diagnostic values of methylation status of tumor suppressor genes in bile in malignant obstructive jaundice have not been well-documented.

Methods: Bile was prospectively collected from 70 patients with obstructive jaundice treated at our hospital between November 2008 and Sepetember 2009. Forty-eight of them were proved to be malignant obstructive jaundice (biliary carcinoma in 36, pancreatic carcinoma in 8 and duodenal carcinoma in 4) by pathological examination, and 22 were benign obstructive jaundice caused by cholelithiasis. DNA was extracted from bile and modified by sodium bisulfite. Methylation-specific PCR was run to detect methylation status of P16 and APC gene promoters. Their diagnostic values in malignant obstructive jaundice were assessed.

Results: Hypermethylation of P16 promoter was presented in 72.9% (35/48) malignant obstructive jaundice, and 9% (2/22) bengin obstructive jaundice (p<0.05). Hypermethylation of APC promoter was presented in 56.2% (27/48) malignant obstructive jaundice, and 9% (2/22) bengin obstructive jaundice (p<0.05). With respect to their diagnostic values in malignant obstructive jaundice, sensitivity, specificity, positive predictivity and negative predictivity were 72.9%, 90.9%, 94.6% and 60.6%, respectively, for P16 gene; 56.2%, 90.9%, 93.1%, 48.8%, respectively, for APC gene.

Conclusions: Methylation status of P16 and APC gene promoters in bile was valuable in diagnosis of malignant obstructive jaundice, with an excellent specificity. P16 gene had a higher sensitivity than APC gene.

No significant financial relationships to disclose.
Clinical benefits TH-302, a tumor-selective, hypoxia-activated prodrug, and gemcitabine in first-line pancreatic cancer (PanC).
Authors: Borad M. J. , Chiorean E. G. , Molina J. R. , Mita A. C. , Infante J. R. , Schelman W. R. , Traynor A. M. , Vlahovic G. , Mendelson D. S. , Reddy S. G.
Published: February 2017

265

Background: Gemcitabine (G) is the standard treatment for first- line PanC. PanC is one of the most hypoxic solid tumors. TH-302 is an inert prodrug of brominated isophosphoramide mustard and undergoes selective activation in deep hypoxia. As a single agent, tumor responses were reported in patients (pts) with metastatic melanoma, SCLC, and head/neck cancer at TH-302 weekly doses of 480-575 mg/m2.

Methods: Eligible pts for the PanC expansion of this phase I/II study ( NCT00743379 ) had ECOG <1, locally advanced or metastatic PanC previously untreated with systemic chemotherapy other than adjuvant G, 5FU, and/or radiation. IV TH-302 was dosed at 240-575 mg/m2 (240 or 340 in expansion) with standard dose G (1000 mg/m2) on days 1, 8 and 15 of a 28-day cycle. Serum protein and microRNA hypoxia biomarkers were analyzed at baseline, start of cycle 3 and end of study.

Results: 46 PanC subjects (12 locally advanced, 34 distant mets); median age: 63 (range 41-83); 24 male; ECOG 0/1 in 29/17 pts; RECIST response rate (RR) of 21%, median PFS of 6.1 mo (95%CI 4.8, 7.7) and median survival of 11.4 mo (95%CI 6.0, not reached) were observed. RR was 23% with median survival of 7.4 mo in pts with distant mets. 52% of pts had a >50% decrease in CA19-9. Common adverse events were skin or mucosal toxicity, nausea, fatigue and vomiting; most grade 1/2. Grade 3/4 neutropenia, thrombocytopenia and anemia in 68%, 64%, and 20% of pts respectively. The dose intensities at 240 mg/m2 and 340 mg/m2 were similar and related to hematologic toxicities. Skin toxicities were less common at 240 mg/m2. A TH-302 dose response was present with higher RR and PFS at 340 mg/m2. Initial serum hypoxia biomarkers did not identify a preferential pt population.

Conclusions: The activity and clinical benefits of the combination of TH-302 with G in first line PanC are promising as compared to previous studies of G alone. TH-302 adds to the hematologic toxicity of G, but the regimen is well tolerated. The safety and activity provided rationale for comparing TH-302 plus G versus G alone in a randomized phase II trial ( NCT01144455 ) and indicate TH-302 may complement G by penetrating into the hypoxic regions of the PanC tumors where activation induces cytotoxicity.

No significant financial relationships to disclose.
A phase I study of AVE1642, a human monoclonal antibody–blocking insulin-like growth factor-1 receptor (IGF-1R), given as a single agent and in combination with sorafenib as first-line therapy in patients with advanced hepatocellular carcinoma (HCC).
Authors: Faivre S. J. , Fartoux L. , Bouattour M. , Bumsel F. , Dreyer C. , Raymond E. , Rosmorduc O.
Published: February 2017

270

Background: AVE1642 blocks IGF-1R signaling. Previous phase I studies recommended AVE1642 doses ranged from 3 to 6 mg/kg in solid tumors. AVE1642 alone and in combination has shown in vitro and in vivo antitumor activity warranting further investigations in HCC.

Methods: Dose-escalation was performed using a 3+3 design in patients with advanced HCC. AVE1642 doses were 1 mg/kg (DL1) 3 mg/kg (DL2), 6 mg/kg (DL3) given IV for 30 min every 3 weeks (w). AVE1642 was given alone for 3 w and every 3 w thereafter in combination with sorafenib (400 mg bid/day). Dose-limiting toxicities (DLT) were assessed during the first two cycles. Safety, pharmacokinetic (PK), pharmacodynamic (PD), tumor response (RECIST) were evaluated.

Results: Thirteen patients (median age: 70y, M/F: 10/3, Child-Pugh A: 13/13) received 83 cycles (range 3-13) of AVE1642: 3 patients at DL1 (31 cycles), 7 patients at DL2 (38 cycles), 3 patients at DL3 (14 cycles) All patients were evaluable for safety and PK/PD. HCC was located in liver in 11 patients and was metastatic in 2. At cycle 1, exposure to AVE1642 alone led to grade 2-3 anemia in 1 patient at DL2, non febrile neutropenia in 1 at DL3. Other adverse events were grade 1-2 gastrointestinal disorders in 1 patient at DL1, in 3 at DL2 and hyperglycemia in only 1 at DL2. No liver function failure or haemorrhagic complications were observed. The frequency of sorafenib induced adverse events was not increased under combination. AVE1642 was eliminated slowly from the serum (t1/2: 5 to 6.7 days). There was no apparent effect of the dose on the systemic clearance of AVE1642, no effect of sorafenib treatment on the PK of AVE1642. IGF1 and IGFBP3 plasma concentrations (not of IGF2) were increased following AVE1642 administration. Most patients (11/13) presented tumor stabilization during a mean time of 13.3 w (ranging 6 to 27 w).

Conclusions: AVE1642 can be safely combined with active doses of sorafenib. PK of both AVE1642 and sorafenib were not modified at these relevant concentrations. Interesting long-lasting disease stabilizations were observed in these patients with progressive disease.

No significant financial relationships to disclose.
Surgery in pancreatic cancer (PC): Identifying potential barriers.
Authors: Beg M. S. , Olowokure O. O. , Atiq M. , Ahmad S. A.
Published: February 2017

290

Background: Due to lack of effective systemic therapy, surgical resection remains the mainstay of treatment of PC and the only potential for cure. Even though mortality of PC surgery has decreased in recent years, surgical rates remain lower than for other cancer types. We performed an analysis of early-stage PC to determine factors that may prevent patients from undergoing surgery.

Methods: PC cases diagnosed between 1996 and 2008 were identified from the Veteran's Affairs Central Cancer Registry. Patients with early stage disease, defined as AJCC clinical stage group 1-3, were included. Data were analyzed using biostatistical software SPSS. Chi-square analysis was performed for categorical variables comparing those who underwent surgery (SUR) and those in which surgery was not performed (SNP). Kaplan-Meier analysis was used for estimates of overall survival.

Results: Of 1,306 cases identified, 97.7% were male, 78% where white. Surgery was performed in 251 (19.2%) cases. Surgery was not recommended in 739 (56.6%) and contraindicated due to patient related factors in 198 (15.2%) cases. Surgery was recommended but not performed due to unknown reasons in 59 (4.5%); patient refusal in 43 (3.3%) and “other reasons” in 16 (1.2%) cases. Mean age in SUR vs. SNP was 64.1 vs. 67.5 years. Median survival was 11.1 months in SUR vs. 5.5 months SNP (p<0.001). On univariate analysis, patients with diabetes had less surgery (10.5%) compared to other comorbidities (p<0.001). Tumors in the body of the pancreas had less surgery (4.8%) compared to the head or tail (19.9%, 23.6%, p<0.001). Sex, race, alcohol, and tobacco use did not significantly impact surgery rates (p>0.05). On multivariable analysis including race, sex, primary site, comorbidity, chemotherapy, radiation, alcohol, and tobacco use, only comorbidity was independently associated with less surgery.

Conclusions: In this registry-based, retrospective analysis of early stage PC, although SUR patients had better survival than SNP, surgery was not recommended as a treatment option for most patients by their providers. Whereas comorbid conditions do seem to influence this decision, race and patient refusal was not a major factor.

No significant financial relationships to disclose.
The significance of p53 and Ki-67 expression rate in adenoma and adenocarcinoma of the stomach.
Authors: Baek I.
Published: February 2017

32

Background: Endoscopic submucosal dissection (ESD) is used for the treatment of gastric adenoma as well as early gastric cancer. Gastric adenoma is a well-known precursor of gastric cancer. The aim of this study is to investigate the expression degree of p53 and Ki-67 in gastric adenoma can predict progression to gastric cancer.

Methods: We analyzed p53 and Ki-67 expression degree in the tumor tissue of 16 gastric adenoma patients treated by ESD and 11 early gastric cancer patients treated by subtotal gastrectomy at Kangnam Sacred Heart Hospital of Hallym University between November 2008 and May 2009. According to the fraction of stained nuclei in tumor tissue, expression degree was classified as < 10% = negative, 10%∼33% = 1+, 34%∼66% = 2+, > 66% = 3+.

Results: Mean age was 65.1 ± 11.5 years and mean tumor size was 33.7 ± 20.2mm. Among 16 gastric adenoma patients, low-grade dysplasia were 11 and high grade dysplasia were 5. p53 positivity was not different between gastric adenoma and gastric cancer, but Ki-67 positivity was significantly different between adenoma and cancer (p < 0.05). In addition, Ki-67 positivity was increasing tendency as the pathology progress from low grade dysplasia to cancer.

Conclusions: Ki-67 positivity grade seems to be correlated with malignancy. High Ki-67 positivity in gastric adenoma can predict progression to gastric cancer. Even if endoscopic biopsy showed low grade dysplasia, additional ESD should be preferentially considered in lesions with high Ki-67 positivity.

No significant financial relationships to disclose.
A single-center experience of small-bowel adenocarcinomas.
Authors: Khan N. A. , Conway W. , Fuloria J.
Published: February 2017

337

Background: The age-adjusted incidence of small-bowel adenocarcinomas was reported as 1.9 per 100,000 per year (SEER 2003-2007). Even early-stage small bowel tumors are associated with a high risk of recurrence. We performed a retrospective chart review to analyze location, stage at presentation, and recurrence rate of early-stage small-bowel adenocarcinomas at our institution.

Methods: Institutional (Ochsner Clinic) tumor registry database was used to identify patients with small-bowel adenocarcinoma from 1983 onward. Medical records were reviewed for pertinent patient information.

Results: 44 patients (24 males, 20 females) were identified. 25 (56.8%) patients had a duodenal primary, 8 (18.1%) jejunal, 4 (9.0%) ileal, and 7 (15.9%) patients did not have a documented site of origin. Mean age at presentation was 64 yrs (range 31-84 yrs). The most common presenting symptoms were abdominal pain (40%), melena (25%), and small-bowel obstruction (16%). Histological grade II or III accounted for 64% of all tumors. Almost half of the patients (43.2%) presented with stage IV disease, which was associated with a median survival of 11.5 months. All patients staged as I, II, and III had a curative resection including 33% who underwent a Whipple's surgery. Four patients were not seen in follow-up at our institution and 6 patients died in the postoperative period from various complications. No stage I patient received adjuvant chemotherapy. All available stage II and III patients received adjuvant 5-FU based chemotherapy. The chemotherapy received was as follows: Stage II (two 5-FU, two FOLFOX); Stage III (four 5-FU, one capecitabine/irinotecan, one FOLFOX). The recurrence for each stage is shown in the Table.

Conclusions: Although our numbers are small, stage I adenocarcinomas of the small bowel had a significant risk of recurrence. This warrants a multi institutional review of patient data to better quantify the risk of recurrence for this rare tumor and the implications for treatment trials.

[Table: see text]

No significant financial relationships to disclose.
Independent validation of a prognostic genomic profile (ColoPrint) for stage II colon cancer (CC) patients.
Authors: Rosenberg R. , Maak M. , Simon I. , Nitsche U. , Schuster T. , Kuenzli B. , Bender R. A. , Janssen K. , Friess H.
Published: February 2017

358

Background: Adjuvant therapy is not routinely recommended for stage II CC patients but may be considered for high-risk patients. In this study we aim to independently validate a genomic profile that was developed to identify high-risk patients and can assist in treatment decisions.

Methods: An 18-gene profile had been developed using gene expression data from whole genome Agilent 44K oligonucleotide arrays and was validated in samples from an independent cohort of 206 CC patients and in in-silico datasets (Salazar et al. JCO 2010 in press). The profile was translated into a robust diagnostic test (ColoPrint) using customized 8-pack arrays. For this study, 233 patients who underwent curative resection (R0) for colon cancer stages II or III at the Klinikum rechts der Isar from 1987 to 2003 were selected. Fresh frozen tissues, clinical parameters and follow-up data for all patients were available. The samples were hybridized and the ColoPrint index was determined for all samples blinded from the clinical data.

Results: Patients in this study had a median age of 64 years and median follow-up of 97 months. The median number of resected lymph nodes was 21, giving an indirect measure of the quality of surgery. In the 135 stage II patients, ColoPrint identified most patients (73%) as low risk. The 5-year distant-metastasis free survival was 95% for low-risk patients and 80% for high-risk patients. In the univariate analysis, ColoPrint was the only significant parameter to predict the development of distant metastasis with a HR of 4.1 (95% CI 1.31-13.01, p=0.009). Using clinical parameters from the ASCO recommendation (T4, perforation, less than 12 LN assessed and/ or high grade) for the identification of high-risk patients was not significant (HR 2.3; 95% CI 0.68-7.53, p=0.18) and did not add power to the ColoPrint classification. These results are in good agreement with results from the first independent validation.

Conclusions: ColoPrint is able to predict the development of distant metastasis of stage II colon cancer patients and facilitates the identification of patients who may be safely managed without chemotherapy.

[Table: see text]
A method to assess KRAS/BRAF genotype in patients with metastatic colorectal cancer (mCRC) elligible for anti-EGFR therapies.
Authors: Lamy A. , Labourier E. , Prigneau O. , Di Fiore F. , Sesboüá R. , Sabourin J.
Published: February 2017

383

Background: KRAS/BRAF mutation screening is a new diagnostic tool since activating mutations, especially for KRAS, are strong negative predictive factors for anti-EGFR monoclonal antibody therapies. Therefore, standardized, reliable, and rapid mutation detection methods are needed. The goal of the present study is to evaluate the concordance between a clinically validated laboratory-developed KRAS/BRAF SNaPshot test and a novel research use assay, the Signature KRAS/BRAF Mutations kit (Asuragen Inc.), in representative clinical specimens.

Methods: Genomic DNA from FFPE mCRC specimens previously tested with the SNaPshot assay were analyzed using the Signature KRAS/BRAF mutations assay. The Signature assay consists of multiplex PCR followed by multiplex hybridization to fluorescent beads coupled to capture probes and detection on the Luminex analyzer. The qualitative assay detects 12 mutations in KRAS codons 12/13 and BRAF V600E based on the median fluorescence intensity (MFI) generated by each bead above (positive) or below (negative) a fixed cut off.

Results: To date, KRAS/BRAF mutational status was successfully assessed with the signature assay in 248 samples. After initial testing, signature and SNaPshot assays were in qualitative agreement for 232 samples (93.5%): 166 positive for KRAS, 46 positive for BRAF, and 20 double negative. 16 samples (6%) presented discrepant results: (i) 11 false negative samples with fluorescence signals for the expected mutations above the average assay background signal but below the 450 MFI positive cut off preselected for this study (330-431 MFI), (ii) 3 samples positive for both KRAS and BRAF and (iii) 2 false positive samples. 7 discrepant samples have been retested to date resulting in an overall agreement of 99.6% (239/240). However, different KRAS mutations were identified by the SNaPshot and signature assays in 3 positive samples.

Conclusions: The signature KRAS/BRAF mutations assay is an attractive method, easy to use, less time consuming than the SNaPshot assay, and potentially adaptable to routine clinical testing. Further analysis will establish and validate cut offs to be used in routine diagnostic procedures.

No significant financial relationships to disclose.
Evaluation of BRAF mutation as a powerful prognostic factor in advanced and recurrent colorectal cancer.
Authors: Yokota T. , Ura T. , Shibata N. , Takahari D. , Shitara K. , Nomura M. , Kondo C. , Mizota A. , Yatabe Y. , Muro K.
Published: February 2017

413

Background: Alterations in the RAS/RAF/ERK signaling pathways frequently occur in colorectal cancer (CRC). KRAS mutations preclude responsiveness to EGFR-targeted therapies for CRC patients. However, prognostic significance of KRAS mutation is still controversial. The aim of this study is to investigate clinicopathological features of KRAS mutation in codon 12 and 13 as well as of BRAF mutation, and to validate prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC.

Methods: The population consisted of 230 unselected patients who had undergone first-line chemotherapy for advanced and recurrent CRC between November 2002 and June 2010. Cycleave PCR was performed to detect a point mutation at codon 12, 13 or 61 in KRAS, and the V600E mutation in BRAF. Prognostic factors associated with survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses.

Results: KRAS mutations were present in 34.8% (n= 80) of patients, including 23.5% (n = 54) in codon 12, 11.3% (n = 26) in codon 13, and 0% in codon 61. 6.5% (n = 15) of patients had BRAF mutation. None of the CRC patients carried both KRAS and BRAF mutations. The primary tumor lesions were located on the right side of the colon in 60% of the BRAF mutant patients (p=0.0371). Furthermore, BRAF mutant was significantly associated with the pathological subtypes of poorly differentiated adenocarcinoma/mucinous carcinoma (p<0.0001) and peritoneal metastasis (p=0.0059). The median overall survival for BRAF mutant and KRAS 13 mutant patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for KRAS wild-type (wt)/BRAF wt (40.6 months) (BRAF; HR=3.89, 95% CI 1.83-8.24, p<0.001, KRAS13; HR=2.03, 95% CI 1.10-3.74, p=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor overall survival (HR, 3.70, 95% CI, 1.48-9.28; p=0.005), together with performance status 2.

Conclusions: This retrospective analysis shows that clinicopathological features of CRC patients with BRAF mutations seem to be distinct from those with wild type BRAF. BRAF mutation is one of the most powerful prognostic factors in advanced and recurrent CRC.

No significant financial relationships to disclose.
In vitro and in vivo activities of KRN330, a fully human monoclonal antibody against colon cancer.
Authors: Sawada N. , Taguchi E. , Takahashi M.
Published: February 2017

432

Background: KRN330 is a novel recombinant human IgG1 monoclonal antibody (mAb) targeting A33 surface differentiation antigen that is uniformly expressed on the surface of 95% of colorectal cancer (CRC) cells. In this study, we characterized the activity of KRN330 for its in vitro properties, as well as for its in vivo antitumor activity.

Methods: A kinetic analysis of the interaction between KRN330 and recombinant human A33 was conducted using a Biacore 3000. Western blot analysis was conducted using A33 expressing COLO205 lysates under reducing and non-reducing conditions. Binding of KRN330 to human colorectal cancer tissues were investigated using FITC-labeled KRN330. We also developed more conventional staining methods of A33 and investigated A33 expression using human colon cancer tissue microarray (TMA). ADCC and CDC activities of KRN330 were assessed using a standard 51Cr release assay. A33 expression levels of 14 CRC cell lines were analyzed using flow cytometer. In vivo antitumor activities of KRN330 alone or in combination with chemotherapeutic agents against subcutaneous or intraperiotoneal human CRC (COLO205 and LS174T) models were investigated using mice and rats xenograft model.

Results: A kinetic analysis revealed that KRN330 showed a high binding affinity to A33. Western blot analysis also showed that antibody recognized not any protein under reducing condition, but non-reducing condition. A33 staining of TMA with 204 different samples revealed the majority of tumor expressed A33. KRN330 exhibited ADCC activity against A33 expressing human colorectal cancer cell lines which include both K-ras wild and mutated types. KRN330 showed dose-dependent antitumor activities in vivo. KRN330 also significantly prolonged survival of human colon tumor bearing mice. In addition, combination treatment of KRN330 with irinotecan showed increased antitumor activitiy and prolongation of survival, compared to either irinotecan or KRN330 alone.

Conclusions: These results suggest that KRN330 is a promising candidate of novel therapy for CRC. The phase I/II study of KRN330 plus irinotecan in patients with second line metastatic CRC is ongoing.

[Table: see text]
Evaluation of the association of matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-2 (MMP-2) expression with KRAS and BRAF mutational status or survival outcomes in colorectal cancer (CRC) patients.
Authors: Ho J. , Woods R. , Kennecke H. F. , Tai I. , Lim H. J.
Published: February 2017

452

Background: MMP-1 and MMP-2 proteins are felt to be involved in tumor growth, invasion and metastasis and may be regulated by the KRAS pathway.

Methods: A tissue microarray was constructed from archival formalin-fixed paraffin-embedded primary tumor tissue samples of 96 patients with metastatic CRC. MMP-1 and MMP-2 expression was measured semiquantitatively by immunohistochemistry and graded 0 to 2. Mutation analysis was done for KRAS in codons 12 and 13, and patients without KRAS mutations were tested for BRAF V600E mutation. Chi-squared test, Fisher's exact test and Cox-proportionate hazard ratios were used for statistical analysis.

Results: 96 patients had samples available for analysis (median age at diagnosis 60, 57% male, 46% stage IV at diagnosis, 33/93 (35%) KRAS mutated, 7/51 (14%) BRAF mutated, 22% received anti-EGFR therapy). No significant association was identified between MMP-1 and KRAS (p=0.88) or BRAF (p=0.54), or between MMP-2 and KRAS (p=0.08) or BRAF (p=0.41). Neither overall survival nor survival from diagnosis of metastatic disease were affected by MMP-1 or MMP-2 expression.

Conclusions: MMP-1 and MMP-2 expression is not associated with KRAS or BRAF mutational status and is not a prognostic factor in our cohort of CRC patients.

No significant financial relationships to disclose.
Cisplatin (C) based chemoradiation (CXRT) for locally advanced squamous cell carcinoma (SCCA) of the anal canal (AC): A 20-year perspective.
Authors: Eng C. , Xing Y. , You Y. N. , Chang G. J. , Das P. , Phillips J. , Wolff R. A. , Rodriguez-Bigas M. A. , Ohinata A. , Crane C. H.
Published: February 2017

482

Background: The standard of care for locally advanced SCCA of the AC is 5-fluorouracil (5-FU)/mitomycin C (MMC) with concurrent XRT. C was evaluated with 5-FU in 2 large phase III studies (RTOG 98-11 and ACT II) to establish superiority over 5-FU/MMC. Neither study showed significant differences for disease-free survival (DFS) or overall survival (OS). RTOG 98-11 reported reduced colostomy-free survival (CFS) in the C-induction arm; no differences were noted in the ACT II study. We present our 20-year experience with C for locally advanced SCCA of the AC which has been adopted as the standard unless contraindicated.

Methods: A retrospective, single institution analysis for locally advanced SCCA of the AC was completed in patients (pts) that received concurrent 5-FU/C/XRT from 1989-2009. Medical records were reviewed for history of STDs, chronic immunosuppression, stage, dose of XRT, toxicity, clinical response (CR), recurrence, and OS. Multidisciplinary management included surgical, radiation, and medical oncologists. OS, DFS, and CFS were calculated using the K-M method. The log-rank test was used to compare OS among these subgroups.

Results: 185 pts were identified (51 M:134 F). The median age was 56 (35-83 y.o.). AJCC stage was I (n = 25); II (n = 76); IIIA (n = 36); and IIIB (n = 48). The median XRT dose was 55 Gy in 30 fractions. 181 pts were evaluable for response; 4 were lost to follow up. Complete CR (cCR) was noted in 169 pts (93%); partial response (n = 12); 6 pts received an APR. After a median follow up of 8.6 years, 14 pts (8%) developed local recurrence; 11 received salvage surgery. 16 pts (9%) developed distant metastases (DM). The 5-yr DFS = 81%, 5-yr OS = 85% and 5-yr CFS was 88%. By univariate analysis, N-stage was a poor prognostic indicator for 5-yr DFS (p = 0.02) and DM (p = 0.046) but not OS or CFS. Increased T-stage correlated with salvage surgery (p = 0.005).

Conclusions: Cisplatin-based chemoradiation for locally advanced SCCA of the anal canal resulted in favorable DFS, OS, and CFS compared to historical data and phase III studies. Platinum-based therapy for anal cancer appears to be an acceptable alternative to MMC and should be considered as a standard option for locally advanced disease.

No significant financial relationships to disclose.
Geriatric subgroup of AGITG MAX trial: International randomized phase III trial of capecitabine (C), bevacizumab (B), and mitomycin C (M) in first-line metastatic colorectal cancer (CRC).
Authors: Price T. J. , Zannino D. , Wilson K. , Simes J. , Van Hazel G. A. , Robinson B. A. , Broad A. , Ganju V. , Ackland S. P. , Tebbutt N. C.
Published: February 2017

510

Background: In an aging population a greater proportion of geriatric patients will be considered for systemic chemotherapy. CRC is a common cancer and will be a major health issue in geriatrics.

Methods: MAX, a three arm study of C v CB v CBM, found an improvement in PFS with addition of B (± MMC) to C (Tebbutt NC et al. JCO 2010; 28(19): 3191–3198). This analysis assesses effect of adding B (± MMC) to C on PFS, OS, RR and toxicity in geriatric patients (age >75y).

Results: 99 patients (21%) were >75y. Number/Median age: C 37/78.5y (75.2–86), CB 32/78.7y (75.2–84.9), CBM 30/80.2y (75.2–83.4). Baseline characteristics were well balanced. 88% commenced C dose of 2000mg/m2/day, d1–14, q21 (61% for <75y). ECOG 0–1 for 88%. Comorbidities were: (%) Ex/smoker 13/2, diabetes 15, HT 56, IHD 15, CVA/TIA 10. These are similar to reported rates ( http://www.aihw.gov.au/cdarf/data_pages/incidence_prevalence/index.cfm ) in this population. Proportion receiving all three chemotherapy drugs at some time (5FU/oxaliplatin/irinotecan) was 10% >75y v 20% <75y. RR, median PFS & OS reported in Table. Interaction test for OS, RR and PFS revealed no impact of age. Gd 3-4 tox for >75y C/CB/CBM respectively was (%); vomiting 5/13/3, diarrhea 19/22/20, stomatitis 3/0/3, HT 0/3/3, thrombosis/thrombus/embolism 5/6/13, cardiac 0/6 (3 Gd5)/3. There was one perforation (Gd5) in C. Grade 2/3 HFS (%) was 38/59/53. One Gd 3-4 neutropenia episode in CB, no Gd 3-4 thrombocytopenia. Overall, toxicity rate similar to <75 y.

Conclusions: Significant improvement in PFS with addition of B to C was seen in this geriatric population, similar to results of ITT group and those <75yrs. Treatment was well tolerated with no signal of increased toxicity when compared to those <75yrs, including VTE/ATE.

[Table: see text]

[Table: see text]
Patterns of care and survival trends in elderly metastatic colorectal cancer patients: A SEER-Medicare analysis.
Authors: Shankaran V. , Beck S. J. , Blough D. K. , Yim Y. , Yu E. , Ramsey S. D.
Published: February 2017

520

Background: Over the last decade, the treatment of metastatic colorectal cancer (mCRC) has changed dramatically as new drugs and hepatic resection have been incorporated into practice. The goal of this study is to examine treatment patterns and survival trends for older patients (pts) with mCRC.

Methods: Pts ≥ age 65 with mCRC diagnosed (dx) 2001-2005 were identified from the SEER-Medicare database. Pts were excluded for lack of Medicare parts A and B in the year prior to dx, second malignancy, or non- adenocarcinoma histology. First-line (1L) chemotherapy (CTx) use was identified by claims within 3 months of dx. Metastatectomy was identified by various claims for liver resection. Comorbidity was assessed by Klabunde index. A Cox proportional hazards regression model was used to assess the effect of demographic and treatment factors on survival.

Results: A total of 5,725 pts (median age 77) met inclusion criteria. 274 pts (5%) underwent hepatic resection and 2,647 (46%) received CTx. From 2001-2003, 43% of pts received 1L CTx (34% and 1% with regimens containing irinotecan (Iri) and oxaliplatin (Ox) and 49% with 5-FU/cap alone). From 2004-2005, 51% of pts received 1L CTx (25%, 14%, and 37% with regimens containing bevacizumab (Bv), Iri, and Ox and 40% with 5-FU/cap alone). In the multivariate analysis using the Cox proportional hazards model, survival was significantly improved in pts receiving CTx or hepatic resection and in pts dx 2004-2005 (Table).

Conclusions: In an older mCRC population, hepatic resection, CTx use, and mCRC dx in 2004-2005 are associated with improved survival. Improved survival of pts dx in 2004-2005 coincides with the 2004 approval dates and uptake of Bv and Ox, and may be associated with the use of these therapies. Further analysis will examine the associations between specific Ctx regimens, Bv, and survival and will include pts dx through 2007.

[Table: see text]

[Table: see text]
Role of L1 cell adhesion molecule in gastric carcinoma.
Authors: Ito T. , Kodera Y. , Tanaka C. , Ohashi N. , Nakayama G. , Koike M. , Fujiwara M. , Nakanishi H. , Nakao A.
Published: February 2017

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Background: L1 cell adhesion molecule (L1) is a 200-220 kDa transmembrane glycoprotein of the immunoglobulin super family initially identified in neural cells. L1 was detected in ovarian cancer in a stage-dependent manner, was found exclusively in the invasion front of colorectal cancer, and has been considered a stem cell marker in glioma. The authors have shown that mRNA expression of L1 was a significant prognostic factor in gastric cancer (Kodera et al. Gastrointestinal Cancer Symposium 2009, abst 37). Its role in gastric cancer was further investigated.

Methods: Expression of L1 was observed by immunostaining in 72 surgically resected pT4A-stage gastric cancer specimens. The association of L1 with peritoneal seeding and prognosis was elucidated. mRNA expression of L1-expressing gastric cancer cell line, KATO3, was suppressed using siRNA (KATO3 L1-). Microarray was used to indentify molecules that differ in expression between KATO3 L1- and the parental cell line.

Results: L1 was scarcely stained in non-cancerous epithelial cells and intestinal metaplastic cells. L1 was detected mainly in the cell surface membrane of cancer cells in 15 of 72 specimens, more often in the intestinal type cancer. No correlation was found between L1 expression and detection of cancer cells in the peritoneal washes or development of peritoneal carcinomatosis. Nevertheless, the prognosis of L1-positive cancer was significantly inferior (p = 0.024). Prognosis was particularly poor among 6 cases where L1 was expressed in cancer cells at the invasive front (median survival time 149 days). Of 40,000 genes evaluated in the microarray, mRNA expression of 50 genes were amplified by > 4-fold whereas the expression of 20 genes were attenuated to less than 1/4. Of these, expression of DYRK1A that induces apoptosis in conjunction with p53 was markedly suppressed to less than 1/8. Suppression of DYRK1A in the KATO3 L1- in comparison with the parental cell line was confirmed by RT-PCR.

Conclusions: L1 affects prognosis of gastric cancer, particularly when it is expressed in cancer cells at the invasion front. Its role in the biology of gastric cancer has began to be elucidated.

No significant financial relationships to disclose.
Sites of gastric cancer recurrence after adjuvant chemoradiotherapy.
Authors: Conrad T. , MacLellan S. , Kassam Z. , Mackay H. , Khalili I. , Jacks L. M. , Okrainec A. , Ringash J.
Published: February 2017

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Background: Since the Intergroup 0116 study in 2000, adjuvant post-operative chemoradiotherapy (CRT) has been offered routinely to similar patients with resected gastric cancer at Princess Margaret Hospital (PMH) using CT-planned and 3D conformal/intensity modulated radiotherapy (RT). The objective of this study was to analyze patterns of recurrence with respect to RT treatment volumes.

Methods: Date and site (local, locoregional or distant) of first recurrence data was obtained from chart review for all patients treated at PMH with adjuvant CRT for resected gastric adenocarcinoma (Jan. 1, 2000-Nov. 30, 2009). Patients whose recurrences were limited to local (gastric remnant, duodenal margin, gastric bed recurrence) and/or regional sites (regional lymph node recurrence) were selected for analysis. When available, diagnostic imaging of recurrence site was registered to the original planning RT dataset. The center of mass for each recurrence was identified as a point and its location categorized according to the isodose encompassing it; in-field (≥ 90%), marginal (50%-89%), and out-of-field (< 50%).

Results: Three-year OS, and RFS were 66% (95% CI: 58-73) and 58% (50-60), respectively. Of 203 patients treated, 75 recurrences were identified (Table). Of the 13 local/locoregional recurrences, 4 were in-field, 1 marginal, 1 could not be registered due to change in body habitus, and 7 did not have an available original dataset.

Conclusions: Rates of isolated local and/or regional recurrence in this study were low. This represents a change in the pattern seen with surgery alone suggesting the addition of CRT results in decreased isolated local and/or regional recurrence. Of the small number of local and/or regional recurrences available for analysis, all were in-field or marginal. Further studies involving a larger cohort of patients might allow for more meaningful analysis of trends in recurrence site with evolving RT techniques.

[Table: see text]

No significant financial relationships to disclose.
Feasibility study of neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF) for clinical stage II/III esophageal squamous cell carcinoma.
Authors: Kato K. , Hara H. , Daiko H. , Igaki H. , Hamamoto Y. , Nagase M. , Kadowaki S. , Tahara M.
Published: February 2017

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Background: In JCOG 9907, neoadjuvant chemotherapy with cisplatin and 5-fluorouracil (CF) improved overall survival without additional serious adverse events in treating stage II/III esophageal squamous cell carcinoma (ESCC). However, ESCC patient survival remains unsatisfactory. We conducted a feasibility study of neoadjuvant chemotherapy with docetaxel plus CF (DCF) for clinical stage II/III ESCC.

Methods: Eligibility criteria included clinical stage II/III (non-T4) ESCC, PS 0–1, and age 20–70 years. Chemotherapy consisted of a 1-h infusion of docetaxel at 70 mg/m2 and 2-h infusion of cisplatin at 70 mg/m2 (day 1), and continuous infusion of 5-FU 750 mg/m2 (days 1 to 5). Antibiotic prophylaxis on days 5 to 15 was mandatory. This regimen was repeated every 3 weeks (maximum 3 cycles) until unacceptable toxicity, patient refusal, or disease progression was observed. After chemotherapy completion, transthoracic esophagectomy with extended (> D2) lymphadenectomy was performed. The primary endpoint was the completion rate of protocol treatment.

Results: From July 2009 to Feb 2010, 34 patients were enrolled, including 2 ineligibles. The 32 eligibles had a median age of 61 (range 36–70; male/female: 30/2), with PS0/1 of 20/12 and cStage IIA/IIB/III of 6/8/18. During chemotherapy, the most common grade-3 or -4 toxicities were neutropenia (88%), febrile neutropenia (3%), anorexia (9%), and stomatitis (6%). Thirty-one (97%) patients underwent surgery. The protocol completion rate was 87.5% (28/32). No treatment-related death was observed, and the operative morbidity incidence was comparable to those in previous studies. According to RECIST, the overall response rate was 61.5% after DCF completion. Primary-lesion pathological complete response was achieved in 26% of patients (8/31) who underwent esophagectomy.

Conclusions: Neoadjuvant DCF was well tolerated. Although these data are preliminary, the protocol is highly promising and warrants further investigation.

No significant financial relationships to disclose.
Multiplex panel of metabolomic markers for early detection of prostate cancer.
Authors: Vareed S. K. , Siddiqui J. , Putluri V. , Putluri N. , Rajendiran T. M. , Wei J. T. , Terris M. K. , Chinnaiyan A. , Michailidis G. , Sreekumar A.
Published: February 2017

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Background: Prostate cancer (PCa) is the second leading cause of cancer deaths among men in US. Prostate specific antigen (PSA) the clinical standard for early detection of PCa is not specific for the disease necessitating development of additional markers. Metabolites are stable, measurable in biological fluids and function as physiological indicators of the individual. Earlier we described the metabolomic alteration in PCa and nominated sarcosine as a tissue marker for PCa progression. Further, elevated sarcosine levels were seen in cancer urine. The current study describes a multiplex panel of metabolomic markers in urine that include sarcosine, for early detection of PCa.

Methods: A sensitive liquid chromatography- mass spectrometry based assay was used to quantify relative levels of tissue specific metabolites in urine of PCa patients. The urine specimens examined in this study were collected at University of Michigan from post DRE and pre-biopsy from clinically challenging patients with PSA between 4-10 ng/mL where biopsy was either positive or negative for tumor. The urine supernatants were recovered post-centrifugation, adjusted to have an osmolarity between 350-400 mOsm/kg, spiked with defined amount of internal standards and evaluated by multiple reaction monitoring (MRM) using a triple quadrupole mass spectrometer. The MRM data was examined using random-forest (RF)-to generate a panel of discriminatory compounds that were validated in an independent test set.

Results: A panel of 11 metabolites (glutamic acid, sarcosine, spermidine, histidine, methionine, adenosine, inosine, thymine, hydroxyphenyl lactic acid, acetyl valine and lauric acid) when employed in a RF-based 2-stage training model (n=63) delineated PCa and benign with a cross-validated (out-of-bag validation based on 20000 decision trees) accuracy of 76 %. When applied to an independent set of test samples (n=98) from the same cohort the accuracy, sensitivity, specificity, positive predictive value and negative predictive values were 72 %, 77.5 %, 62.5 %, 67.8 % and 73.2 % respectively.

Conclusions: The study describes a first-generation multiplex panel of metabolic markers for early detection of PCa in urine supernatants.

No significant financial relationships to disclose.
Phase II trial of bevacizumab (A), lenalidomide (R), docetaxel (D), and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Huang X. , Ning Y. M. , Gulley J. L. , Kluetz P. G. , Adelberg D. , Mulquin M. , Madan R. A. , Bassim C. , Figg W. D. , Dahut W. L.
Published: February 2017

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Background: Angiogenesis appears to play critical role in the progression of mCRPC. Previously we have shown anti-tumor activity in mCRPC with the combination of D, thalidomide (T), A and P (Ning JCO 2010). We hypothesized that combining R, an analogue of T, with A, D and P would have a more favorable toxicity profile and similar anti-tumor activity.

Methods: All pts had chemotherapy-naïve progressive mCRPC. 6 pts were treated with R at 15 and 20 mg prior to doses at 25 mg. Treatment is 75 mg/m2 D, 15 mg/kg A every 21 days as one cycle (C), plus 25 mg R for 14 days with daily 10 mg P and enoxaparin. After grade 3 neutropenia was seen in > 80% of pts in all cohorts, the protocol was amended to include prophylactic pegfilgrastim. PSA is tested each C with imaging after C2 and then every 3C. Dental exams with mandible CT's are at baseline, after C5, and then every 6C or earlier if needed.

Results: 28 of a planned 51 pts have been enrolled. Pt characteristics include: median age 65.5 [51-78], Gleason score 8 [67.9% 8-10, 32.1% 6-7], on-study PSA 94.3 ng/mL [9.2-3520], and pre-study PSA doubling time 1.43 months [0.52-4.07]. Median C number was 8 [1-21]. 2/28 pts were off study due to clinical or radiographic progression. 26 pts remain on study. 22/24 (91.7%) and 20/24 (83.3%) pts who have completed ≥ 4C had PSA- decline of ≥ 50% and ≥ 75%, respectively. 14 pts with measurable disease were evaluable with 2 CRs (1 unconfirmed), 9 PRs (2 unconfirmed), and 3 SDs (a 78.6% overall RR). Grade ≥ 3 toxicities include neutropenia (16/28), anemia (6/28), thrombocytopenia (3/28), hypertension (1/28), and infection (2/28). 1/28 pts had febrile neutropenia. 8/28 pts (28.6%) developed grade 2 osteonecrosis of the jaw (ONJ), defined as bone death on dental exam, higher than 18.3% as reported by Ning. 5/8 had concomitant and 2/8 pts had history of bisphosphonate use.

Conclusions: Combined therapy with anti-angiogenic agents R and A, plus D and P is associated with high response rates, 91.7% in PSA and 78.6% in measurable disease in mCRPC pts, with manageable toxicities. Further study is underway to characterize the activity and to explore the high incidence of ONJ, including the possibility of ascertainment bias.

No significant financial relationships to disclose.