bluuebunny/crossref_metadata_2025 huggingface dataset:
Stage I nonfunctioning neuroendocrine tumors of the pancreas: Surgery or surveillance?
Authors: Strosberg J. R. , Cheema A. , Kvols L. K.
Published: February 2017

349

Background: An increasing number of nonfunctioning, early-stage pancreatic neuroendocrine tumors are detected incidentally as patients undergo radiographic procedures for unrelated indications. Endoscopic sonography with fine-needle aspiration now enables nonoperative biopsy of tumors smaller than 1 cm in diameter. It is unclear whether the risks of partial pancreatectomy or enucleation exceed the risks of surveillance in patients with these neoplasms.

Methods: We performed a database search of patients with pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center in order to evaluate outcomes of patients with stage I tumors who did not undergo surgical resection.

Results: Four patients were identified who elected to undergo surveillance of their stage I tumors instead of surgical resection. All had been diagnosed via endoscopic ultrasound-guided fine-needle aspiration. The tumor sizes were 7 mm, 12 mm, 13 mm, and 15 mm at initial diagnosis. Three tumors were cystic and one was solid. Three were located in the body of the pancreas and one in the tail. In two patients, the Ki-67 index was measured and was <1%. With a median of follow-up of two years, none of the patients experienced tumor growth. All three patients with cystic tumors experienced shrinkage of their tumors following the diagnostic needle aspiration and did not experience subsequent increase in size (Table).

Conclusions: Surveillance may be an appropriate strategy for management of incidentally discovered, stage I pancreatic neuroendocrine tumors.

[Table: see text]

No significant financial relationships to disclose.
Adjuvant therapy for gallbladder cancer: An institutional perspective.
Authors: Wang M. L.
Published: February 2017

353

Background: Gallbladder carcinoma is a rare malignancy of the gastrointestinal tract. While radical surgery remains the only potentially curative treatment modality, relapse rates are high. Due to the paucity of data on the effectiveness of adjuvant therapy, only patients with high risk factors are referred for adjuvant therapy at our institution. We evaluate the effect of adjuvant chemoradiotherapy on the outcome of this group of patients.

Methods: Records of patients who underwent adjuvant radiotherapy at our institution from January 1, 2001, to December 31, 2009, were reviewed. All patients had stage II disease. Patients received adjuvant radiotherapy (dosage 4,500 to 5,040 cGy in 25 to 28 fractions) with concomitant capecitabine or 5-fluorouracil chemotherapy. The effect of adjuvant therapy on disease-free survival (DFS) and overall survival (OS) was evaluated.

Results: A total of 11 patients were included in the analysis, of which nine (82%) were females. Patients had stage IIA (27%) or IIB (73%) disease. Surgical margins were clear in 3 (27%), close (<1 mm) in 3 (27%) and positive in 5 patients (45%), including 1 with R2 resection. Ten patients underwent chemoradiotherapy with the exception of one, who received chemotherapy followed by consolidation radiotherapy. With a median follow-up of 46.2 months for surviving patients at the point of analysis, 4 patients were still alive. Eight patients had developed disease recurrence, with the first site being locoregional in 1 (12%), distant in 4 (50%) and both in 3 patients (38%). All relapse occurred within 20 months of surgery, with 88% within 12 months. The median time to relapse was 7.4 months. The estimated disease- free survival rate at 1 and 3 years was 36% and 27%, respectively. The estimated overall survival of the group at 1 and 3 years was 36% and 27%, respectively.

Conclusions: Data from numerous studies have shown varied results with regard to the use of adjuvant therapy in gallbladder carcinoma. There are studies where adjuvant therapy have produced 5-year OS rates of up to 70% in patients with negative surgical margins. From our results, patients with high-risk disease may benefit from aggressive adjuvant therapy. A combination of chemoradiotherapy followed by further chemotherapy may be useful.

No significant financial relationships to disclose.
Gemcitabine, oxaliplatin, and bevacizumab (GEMOX-B): A promising regimen for the treatment of advanced biliary tract cancers.
Authors: Mahipal A. , Rosato E. , Littman S. J. , Hargrove H. , Bapat A. R. , Doria C. , Mitchell E. P.
Published: February 2017

355

Background: Biliary-tract cancers (BTCs) arise from the epithelium of the gallbladder and bile ducts and are relatively rare, affecting 9-12,000 people in the United States annually. Peak incidence is in the seventh decade of life. Prognosis of advanced BTCs is poor with median overall survival of approximately 10 months. There has been no standard treatment regimen because of lack of randomized clinical trials data. Phase II trials have demonstrated the efficacy of the combination of gemcitabine and oxaliplatin with the response rate of ∼50%. In a recently published phase II trial, the addition of bevacizumab to this regimen (GEMOX-B) resulted in 63% progression-free survival (PFS) at 6 months. In this retrospective study, we evaluated the efficacy of GEMOX-B in patients with advanced biliary tract cancers treated at Thomas Jefferson University.

Methods: All patients received treatment on day 1 and 15 of 28-day cycle: bevacizumab 10 mg/kg, followed by gemcitabine 1000 mg/m2 and oxaliplatin 85 mg/m2. All patients were administered diphenhydramine, dexamethasone, and ondansetron prior to chemotherapy. Response was assessed using the RECIST criteria. PFS was measured from start of chemotherapy to disease progression or death.

Results: A total of 6 patients with BTCs were treated with GEMOX-B. One patient was male and 5 were female. The median age was 45 years (40-64 years). All patient had ECOG performance score 0-1. Three patients had progressed on prior therapy. A total of 65 cycles were administered with the median being 9 (range: 7-21) cycles. Two patients (33%) had partial response and 4 patients (66%) had stable disease. One patient progressed after 6.4 months of therapy. One patient died due to pneumonia but had stable disease at time of death. One patient developed encephalopathy, likely due to bevacizumab. Two patients are still receiving treatment. The median PFS has not been reached (range: 6-42 months).

Conclusions: This retrospective study further suggests that GEMOX-B is an active regimen in BTCs. Additional studies are needed to further evaluate the toxicity and efficacy of this regimen and understand molecular pathways governing sensitivity to chemotherapy.

No significant financial relationships to disclose.
The impact of time to adjuvant chemotherapy (AC) on survival in colorectal cancer (CRC): A systematic review and meta-analysis.
Authors: Biagi J. J. , Raphael M. , King W. D. , Kong W. , Mackillop W. J. , Booth C.
Published: February 2017

364

Background: The optimal timing from CRC surgery to initiation of AC is unknown. We report a systematic review and meta-analysis to determine the relationship between time to adjuvant chemotherapy (TTAC) and survival.

Methods: A systematic review of literature was done to identify studies that described the relationship between TTAC and survival. Studies were only included if the distribution of relevant prognostic factors was adequately described, and either comparative groups were balanced or results adjusted for the prognostic factors. Hazard ratio (HR) and TTAC for overall survival (OS) and disease free survival (DFS) from each study were converted to a regression coefficient (β) and standard error (SE) corresponding to a continuous representation per 4 weeks of TTAC. The adjusted β from individual studies were combined using a fixed-effect model. Inverse-variance (1/SE2) was used to weight individual studies. The possible effect of publication bias was investigated using the trim and fill approach.

Results: We identified 9 eligible studies involving 14,357 patients (4 published articles, 5 abstracts). Two studies were randomized trials and 7 were cohort studies. Six studies reported TTAC as a binary variable and 3 reported TTAC as ≥3 categories. An estimate of HR for OS was derived from all 9 studies and estimate for DFS was derived from 5 studies. Meta-analysis demonstrated that a 4-week increase in TTAC was associated with a significant decrease in both OS (HR = 1.12, 95% CI 1.09-1.15), and DFS (HR = 1.15, 95% CI 1.11-1.20). The analysis showed no significant heterogeneity among studies. These TTAC associations remained significant after analysis for potential publication bias, and when the analysis was repeated excluding the two studies of largest weight.

Conclusions: This study demonstrates a 12% increase in the risk of death for each 4 week of delay in the start of AC for CRC. These findings indicate the need for clinicians and health systems managers to take the steps necessary to keep TTAC as short as reasonably achievable. In addition, our results suggest there may be some benefit to AC after a 3-month TTAC delay.

No significant financial relationships to disclose.
A randomized, phase I/II trial of AMG 102 or AMG 479 in combination with panitumumab (pmab) compared with pmab alone in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC): Safety and efficacy results.
Authors: Van Cutsem E. , Eng C. , Tabernero J. , Nowara E. , Swieboda-Sadlej A. , Tebbutt N. C. , Mitchell E. P. , Davidenko I. , Chen L. , Smethurst D.
Published: February 2017

366

Background: Pmab is a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb) approved as monotherapy for pts with mCRC. AMG 102 and AMG 479 are investigational, fully human mAbs against hepatocyte growth factor (HGF) and insulin-like growth factor receptor 1 (IGF1R), respectively. This 3-part study evaluated the safety and efficacy of AMG 102 or AMG 479 in combination with pmab.

Methods: Part 1 was a phase 1b, open-label, dose-finding study to determine a tolerable dose of AMG 102 in combination with pmab. Part 2 was a phase II, randomized, blinded, placebo-controlled trial that explored pmab + the dose of AMG 102 selected in Part 1 vs pmab + AMG 479 vs pmab + placebo. Part 3 is a 2-arm randomized extension study for pts who developed disease progression (PD) or intolerability to pmab + placebo in part 2. Eligible pts were ≥ 18 years old with WT KRAS mCRC and ECOG PS 0/1. In part 1, all pts received 6 mg/kg pmab + 10 mg/kg AMG 102 Q2W IV until PD or intolerability. The primary endpoint of part 1 was the incidence of dose-limiting toxicities (DLTs). The primary endpoint for part 2 is objective response rate (ORR).

Results: In part 1, no DLTs were reported for the first 6 DLT-evaluable pts. A total of 11 pts were enrolled in part 1 prior to the decision to use the 10 mg/kg Q2W AMG 102 dose in part 2; 5 pts were men; mean (range) age was 56 (37-75) yrs; ECOG 0/1 was 55%/45%. Grade 3 treatment-related adverse events (AEs) were acneiform dermatitis or rash (55%), paronychia (18%), infection (9%), capillary leak syndrome (9%), erythema (9%), nail disorder (9%), and pruritus (9%). There were no grade 4 or 5 treatment-related AEs. Serious AEs included acneiform dermatitis (n = 1), intestinal obstruction (n = 1), cerebrovascular accident (n = 1), capillary leak syndrome (n = 1), and anemia/general health deterioration (n = 1). One pt died on study from PD. In part 2, 142 pts received at least one dose of study drug; enrollment is complete, and data analyses are ongoing.

Conclusions: In part 1, 6 mg/kg pmab + 10 mg/kg AMG 102 Q2W was well tolerated. Primary efficacy results from part 2, including ORR and progression-free survival, will be presented.

[Table: see text]
The impact of Asian race on colorectal cancer screening (CRCS).
Authors: Homayoon B. , Shahidi N. C. , Cheung W. Y.
Published: February 2017

381

Background: While research shows that African Americans and Hispanics frequently receive less CRCS than Whites, few studies have focused on CRCS among Asians. The aims of the current analysis were to 1) compare CRCS between Asians and Whites in a large U.S. population, 2) evaluate for other clinical predictors of CRCS, and 3) examine the impact of health insurance coverage, place of birth and English proficiency on potential racial disparities.

Methods: From the 2007 California Health Interview Survey, we identified all Asian (N=2,108) and White (N=23,237) average-risk respondents aged ≥50 years who were eligible for CRCS. Logistic regression was performed to evaluate for differences in CRCS between Asians and Whites. We used stratified and interaction analyses to examine whether associations between race and CRCS were modified by insurance status (insured vs uninsured), birthplace (U.S. vs non-U.S.) or language skills (good vs poor English), while controlling for other confounders.

Results: Baseline characteristics were similar between Asians and Whites: mean age was 64 years in both groups; 45% and 47% were male; and 47% and 50% were employed, respectively. Only 58% of Asians and 66% of Whites reported undergoing up-to-date CRCS (p<0.001). In multivariate analyses, female gender and those living in rural areas were less likely to receive CRCS (OR 0.84, 95%CI 0.76-0.93, p=0.001 and OR 0.88, 95%CI 0.81-0.98, p=0.015, respectively).When compared to Whites, Asians also had decreased odds of CRCS (OR 0.82, 95%CI 0.71-0.95, p=0.008), even after adjusting for confounders such as education and income. Stratified analyses revealed that this disparity existed mainly in the insured (OR 0.83, 95%CI 0.72-0.96, p=0.014), but not in the uninsured (OR 0.94, 95%CI 0.43-2.06, p=0.873). The relationship between race and CRCS was not modified by place of birth or English proficiency.

Conclusions: Despite its ability to reduce mortality, CRCS is suboptimal in our U.S. population-based cohort of Asians when compared to Whites. The racial disparity was more evident within the insured subset, suggesting that factors unrelated to healthcare access, such as patient preference, physician discretion or patient-physician rapport, may be more important drivers of CRCS among Asians.

No significant financial relationships to disclose.
Effect of probiotic treatment on the transition from chronic colonic inflammation to dysplasia and cancer.
Authors: Appleyard C. B. , Cruz M. L. , Passalacqua I. , Isidro A. A. , Isidro R. A.
Published: February 2017

385

Background: Effective prevention of colitis-associated cancer still needs to be achieved. There is evidence that the microflora plays an important role in the progression of chronic inflammation to neoplastic transformation, so the aim of this study was to evaluate the potential efficacy of the probiotic VSL#3 in preventing this transition.

Methods: Chronic colitis was induced in male Sprague Dawley rats by the administration of trinitrobenzene sulfonic acid (TNBS; 30 mg in 50% ethanol ic), followed six weeks later by reactivation with TNBS (5 mg/kg iv) for 3 days. To induce colitis-associated dysplasia and cancer the animals then received TNBS (iv) twice a week for ten weeks. One group of rats received the probiotic in drinking water (VSL#3; ∼5 billion cfu /100 gram body weight) from 1 week prior to initial colitis induction until the time of sacrifice (n = 22-23/group). After sacrifice the colons were removed and analyzed for total macroscopic damage, microscopic damage and presence of dysplasia or cancer. Tissue and serum samples were analyzed for cell proliferation and apoptosis, angiogenic factors and presence of alkaline sphingomyelinase.

Results: Those animals receiving the probiotic had significantly less macroscopic and microscopic damage than the vehicle treated-controls in all areas of the colon (p < 0.05). Pathological analysis revealed that 29% of the vehicle treated animals developed carcinoma, which was confined to the proximal region. None of the probiotic treated animals developed carcinoma. Treatment with the probiotic caused a significant shift to a less severe diagnosis with no high-grade dysplasia found in either the proximal or midcolon. Treatment with the probiotic reduced crypt cell proliferation by 22% as assessed by measurement of BrdU incorporation in comparison with the vehicle treated group. Levels of the antiangiogenic factor angiostatin were higher in the probiotic treated animals (5-fold), as were serum levels of alkaline sphingomyelinase (2-fold).

Conclusions: Treatment with the probiotic VSL#3 can delay the transition of chronic inflammation to dysplasia and cancer via effects on processes such as modulation of cell proliferation and angiogenesis.

No significant financial relationships to disclose.
Effect of Kampo medicine Juzen-taiho-to on adverse events induced by cetuximab.
Authors: Morimoto S. , Shimada M. , Kurita N. , Iwata T. , Nishioka M. , Yoshikawa K. , Miyatani T. , Mikami C. , Kashihara H.
Published: February 2017

396

Background: Cetuximab is now considered a standard treatment for advanced or unresectable colorectal cancer, unfortunately patients suffer a skin reaction as the main indication of the toxicity of cetuximab. It is recently reported that Kampo medicine (Goshajinkigan) is considered to be an effective agent for the neuropathy of oxaliplatin. Kampo medicine “Juzen-taiho-to” (TJ-48, Tsumura CO. Ltd.), which consists of 10 component herbs, is known as a tonic agent which improves the general systemic condition of cancer patients by reducing the adverse effects of chemotherapy, radiation therapy, and surgical treatment and to inhibit metastases. The aim of this study was to clarify the efficacy of TJ-48 for adverse events associated with cetuximab therapy.

Methods: From 2009, cetuximab was administered initially at a dose of 400 mg/m2 followed by weekly infusions at 250 mg/m2 to 20 patients with non-resectable or recurrent colorectal cancer. Eighteen patients received oral administration of 7.5 g/day of TJ-48 (TJ-48 group) every day in the first course and 7 patients did not receive TJ-48 (Control group). Adverse events were evaluated for every course according to CTCAE version 3.0.

Results: There was no statistically significant difference between the two groups based on any of patient characteristics. No patients complained of persistent Grade 3 infusion reaction. The percentage of Grade 2 or more skin reactions in each course tended to be lower in the TJ-48 group compared with the Control group (TJ-48 group 34% vs control group 57%). Incidence of Grade 2 anorexia in the TJ-48 group was significantly lower than in the Control group (TJ-48 group 34% vs control group 71%, p=0.03). There were no differences regarding tumor response between the two groups.

Conclusions: TJ-48 is useful to prevent anorexia in non-resectable or recurrent colorectal cancer patients treated with cetuximab regimen.

[Table: see text]
Association of PTEN loss and local recurrence in stage II-III colon cancer.
Authors: Jiang Z. , Mehta T. R. , You Y. N. , Chang G. J. , Eng C. , Overman M. J. , Maru D. , Hamilton S. R. , Kopetz S.
Published: February 2017

399

Background: Activation of the PI3K/Akt signaling pathway by PIK3CA mutations has been associated with increased risk for local recurrence (LR) in rectal cancer patients (pts). We hypothesized that loss of expression of PTEN, a tumor suppressor gene and negative regulator of the PI3K/Akt pathway, may also be associated with increased rates of LR in colon cancer.

Methods: We studied 156 pts with stage II-III colon cancer resected from 1/1990 to 12/2002, including pathology review, PTEN immunohistochemistry, microsatellite instability (MSI) status, 18q loss of heterozygosity (LOH) status and clinical follow-up. PTEN expression with a CLIA-compliant protocol (DAKO antibody) was determined in a tissue microarray with four cores from each tumor and with non-neoplastic mucosa. PTEN loss was defined as complete absence of expression in malignant epithelium with preserved expression of adjoining non-neoplastic tissue serving as a positive control. LR was defined as anastomotic or pericolic peritoneal disease.

Results: 83 M and 73 F pts with median age of 63 were included, with median follow-up of 7.6 yrs. PTEN loss was identified in 26 (16.7%) pts. There were no significant differences in age, sex, T stage, N stage, tumor differentiation, tumor site, lymphovascular invasion (LVI), mucinous component, MSI status or 18q LOH between the PTEN-lost and PTEN-intact groups. The overall survival, relapse-free survival, and distant metastases rate were similar. However, PTEN loss was associated with higher rates of LR (15.4% vs. 4.6%, p = 0.041), and the time to LR was shorter for pts with PTEN loss in their tumor than in PTEN-intact pts (HR 3.3, p = 0.049 by log-rank). LR was associated with LVI, R-sided tumor, 18qLOH, and PTEN loss in univariate analysis. In a multivariate analysis, PTEN loss was associated with a 10.6 fold increased risk of LR (95% CI: 1.7-64.8, p = 0.011).

Conclusions: PTEN loss is associated with a higher rate of and shorter time to LR after resection of colon cancer. This result is consistent with a prior report on the role of PI3K pathway in LR of rectal cancer and suggests that PTEN alteration is a prognostic indicator and that the PI3K/Akt pathway is a potential therapeutic target for these pts.

No significant financial relationships to disclose.
Specific activity of cyclin dependent kinase 1 as a novel predictor of recurrence risk in stage II colon cancer.
Authors: Maak M. , Zeestraten E. , Shibayama M. , Schuster T. , Friess H. , Van De Velde C. J. , Ishihara H. , Rosenberg R. , Kuppen P. J. , Janssen K.
Published: February 2017

402

Background: Altered cell cycle dynamics and check points are typical features of solid tumors, and cyclin dependent kinases (CDKs) play pivotal roles in these processes. Previously we have demonstrated that CDK-based analysis, composed of CDK1 and CDK2, is useful in the prediction of outcomes in early breast cancer patients (Ann Oncol. 19(1):68-72, 2008, Br J Cancer. 100(3):494-500, 2009). Clinically, there is a need for risk stratification in patients with stage II colon cancer who have a recurrence risk of 20 to 30%. Therefore we investigated the use of CDK-based analysis for recurrence prediction of stage II colon cancer patients.

Methods: Fresh frozen tissue samples of 254 patients with histologically confirmed adenocarcinoma of the colon, UICC stage II, who received primary tumor resection in Munich (217 cases), and Leiden (37 cases) were used. Protein expression and activity of CDK1 and CDK2 were determined by in vitro assays as previously described. Specific activity (SA) of CDKs was calculated as kinase activity in relation to its corresponding mass concentration.

Results: Development of distant metastasis was observed in 27 patients (10.6%) after a median follow up of 86 months. We found that predictive performance of CDK1SA, but not CDK2SA, for the metastasis was substantial and almost constant for long-term event prediction (average area under the curve (AUC) = 0.69). Tumor recurrence risk analysis in association with CDK1SA identified a low- (41% of population) and high- risk group (59%). Cox proportional hazard model analysis retained the CDK-based patient classification as an independent prognostic factor for distant metastases-free survival (low vs. high-risk group: Hazard ratio = 6.2, 95% CI: 1.45 to 26.9, p=0.0049). Clinical parameters such as grading, T-categories, age, and sex were excluded as confounding factors for CDK1SA-risk.

Conclusions: CDK1SA allows stratification of different risk subgroups of stage II colon cancer patients. CDK1SA-based analysis is useful for predicting patients with high risk of distant recurrence, who should be treated with chemotherapy.

No significant financial relationships to disclose.
Use of the XRCC1 single nucleotide polymorphism to predict pathologic complete response to neoadjuvant chemoradiation in stage II/III rectal cancer.
Authors: Duldulao M. P. , Li W. , Ho J. , Chen Z. , Lee W. , Kim J. , Garcia-Aguilar J.
Published: February 2017

409

Background: The X-ray repair cross-complementing protein 1 (XRCC1) gene plays an important role in DNA damage repair; and the R194W and R399Q single nucleotide polymorphisms (SNPs) are associated with attenuated DNA repair activity. Our objective was to determine whether XRCC1 SNPs were associated with response to neoadjuvant chemoradiation therapy (CRT) in rectal cancer patients.

Methods: We conducted a prospective multicenter phase II trial to investigate the effect of additional chemotherapy with a longer CRT-to-surgery interval on treatment response in patients with rectal cancer. Paired normal and rectal cancer tissues were prospectively collected from enrolled patients (n=110). DNA was extracted from normal rectal mucosa and analyzed for XRCC1 R194W and R399Q by polymerase chain reaction and sequencing. Each SNP was compared to response to CRT. Response to CRT was determined by a central pathologist.

Results: Of the 110 patients, 25% (n=27) achieved a pathologic complete response (pCR). We examined the XRCC1 R194W SNP and observed that the allelic frequency of patients with the R/R genotype was 84% (n=92), the R/W genotype was 14% (n=16), the W/W genotype was 1% (n=2). By Fisher's Exact test, patients harboring either the R/W or W/W genotype, had a significantly higher rate of pCR compared to patients with the R/R genotype (44% vs. 21%, respectively; p=0.04). We then examined the R399Q SNP and observed that the allelic frequency of patients with the R/R genotype was 34% (n=37), the R/Q genotype was 49% (n=54), and the Q/Q genotype was 17% (n=19). In contrast, the detection of XRCC1 R399Q SNPs was not associated with pCR.

Conclusions: We demonstrate that XRCC1 R194W SNP is associated with increased rate of pCR in our prospective multi-center trial. Although the detection of XRCC1 R399Q SNP is not associated with pCR, the detection of XRCC1 SNPs that predict treatment response may help identify patients who are unlikely to respond to CRT and therefore may potentially avoid treatment-associated morbidities.

No significant financial relationships to disclose.
Detecting deficient DNA mismatch repair in stage II and III colon cancers.
Authors: Sinicrope F. , Benatti P. , Foster N. R. , Marsoni S. , Monges G. , Labianca R. , Yothers G. A. , Gallinger S. , Sargent D. J.
Published: February 2017

419

Background: Deficient DNA mismatch repair (MMR) results in microsatellite instability (MSI) that is detected in ∼15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information. We developed a model to predict MMR deficiency using clinically available data, and thereby facilitate the selection of patient tumors for MMR testing.

Methods: Data were utilized from stage II and III colon carcinoma patients (n = 2016) who participated in 5-fluorouracil-based adjuvant studies (NCCTG, FFCD, NCIC, GIVIO, NSABP) and an Italian cohort. MMR status in tumors had been determined by MSI testing or by immunohistochemistry for hMLH1 and hMSH2 proteins. Logistic regression and a recursive partitioning and amalgamation analysis was used to identify factors (histologic grade, gender, tumor site, stage, age, lymph node status, T-stage) predictive of MMR status.

Results: Of the cancers, 357 (17.7%) showed deficient MMR. Tumor site was the most important predictor of MMR status followed by histologic grade, then stage (II vs. III) and then gender. Distal tumors had a low likelihood of deficient MMR (5% rate overall), whereas proximal tumors had a greater likelihood of deficient MMR (30%). For patients with proximal tumors, the addition of histologic grade and stage increased the prediction of deficient MMR (Table). Using tumor site, histologic grade, and stage, the logistic regression model showed excellent discrimination (c-statistic = 0.80).

Conclusions: Routine clinicopathological data can facilitate the identification of MMR deficient cases. Tumor site and histologic grade were the strongest predictors of MMR deficiency. Within proximal, poorly differentiated tumors, stage was highly predictive. These findings suggest that our model can assist in selecting sporadic colon cancers for MMR testing for use in clinical decision-making, especially for stage II patients.

[Table: see text]

[Table: see text]
Use of serum CXCL16 to predict liver metastasis and prognosis in colorectal cancer patients.
Authors: Matsushita K. , Toiyama Y. , Tanaka K. , Yasuda H. , Saigusa S. , Fujikawa H. , Inoue Y. , Miki C. , Kageyama S. , Kusunoki M.
Published: February 2017

424

Background: Colorectal cancer (CRC) is one of the major causes of cancer death worldwide. In CRC, serum levels of CEA have become well-established prognostic indicators. However, it is not generally accepted as optimal in its prognostic power. The aim of this study was to identify novel and reliable serum prognostic markers.

Methods: We performed cytokine array to identify novel prognostic serum marker, and CXCL16 was selected. To investigate the relationships between sCXCL16 and clinicopathological findings including survival, the serum levels of CXCL16 in 237 CRC patients and 20 normal volunteers were assessed by enzyme-linked immunosorbent assay. Furthermore, we investigated proliferation, invasion and wound healing assay to investigate the biological role of CXCL16 to colon cancer cell by recombinant CXCL16 exposing to HT-29.

Results: The mean sCXCL16 concentration in patients was significantly higher than that in normal volunteers (p<0.0001). In addition, sCXCL16 levels increased significantly in accordance with the progression of UICC stage classification (p < 0.05). In clinicopathologic findings, sCXCL16 was significantly associated with the presence of lymph node (p=0.019) and the presence of liver metastases (p=0.011). Elevated sCXCL16 level demonstrated a significant association with poor survival, and was an independent risk factor for poor survival. Furthermore, sCXCL16 was an independent marker for predicting liver metastasis (logistic analysis; p=0.0015). In vitro, recombinant CXCL16 promoted epithelial mesencymal transition (EMT) phenotype characterized by impaired E-cadherin and induction of Vimentin. In addition, CXCL16 promoted cell growth, migration and invasion.

Conclusions: Our data demonstrate that preoperative sCXCL16 level increased in colorectal cancer patients, and that sCXCL16 correlated with liver metastasis, and is an independent prognostic factor for overall survival. Elevated CXCL16 has been proposed as a useful predictive marker for liver metastasis and overall survival in CRC. In vitro, CXCL16/CXCR6 axis might play an importance role in mediating cell survival, migration and invasion by EMT in CRC cell.

No significant financial relationships to disclose.
A single-arm trial of panitumumab in cetuximab refractory KRAS wild-type colorectal cancer.
Authors: Wadlow R. C. , Hezel A. F. , Wolpin B. M. , Allen J. N. , Blaszkowsky L. S. , Kwak E. L. , Wang R. , Zhu A. X. , Ryan D. P. , Clark J. W.
Published: February 2017

428

Background: While FOLFOX or FOLFIRI with bevacizumab are the standard first-line regimens in the treatment of metastatic colorectal cancer, a role for epidermal growth factor receptor inhibitiion in KRAS wild-type colorectal cancer has been established in the second and third line setting. Cetuximab is a chimeric antibody that consists of approximately 30% murine protein, and panitumumab is a fully human monoclonal antibody. Correspondingly, the rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). Presently, cetuximab is typically used in combination with irinotecan in the second or third line setting, and panitumumab is occasionally substituted if hypersensitivity occurs. The value of panitumumab as a salvage agent in cetuximab-resistant colorectal cancer is unknown.

Methods: Panitumumab (6 mg/kg every 14 days) was administered to patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab. Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate (RR). Twenty patients were enrolled in the first stage and, if at least one responded, 12 additional patients were to be enrolled in a second stage. This two-stage design tested the null hypothesis that the RR is less than or equal to 1% versus greater than or equal to 10% with a type I error of 3.6% and 80% power. Blood samples were collected at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies using the Biacore immunoassay.

Results: 22 patients with ECOG PS 0-2 were treated for a median of two cycles. The best response was stable disease (45%) and the RR was 0%. There were a total of 266 toxicities reported, the majority of which were mild (n = 184, 69%) or moderate (n = 63, 24%) in severity. There were 19 grade 3 and 0 grade 4 toxicities. Median overall survival was 1.9 months. Immunologic data will be reported at the time of presentation.

Conclusions: Panitumumab is not active as salvage therapy for patients with cetuximab-resistant, KRAS wild-type metastatic colorectal cancer.

[Table: see text]
Preclinical development of small-molecule CRM1 inhibitors as novel therapy for the treatment of colorectal cancer (CRC).
Authors: Shacham S. , Kauffman M. , Sandanayaka V. , Draetta G. , Shechter S. , Williams J. , Nir R.
Published: February 2017

430

Background: CRM1 (XPO1) is a key nuclear export protein which controls the location of multiple tumor suppressor (TSP) and growth regulatory (GRP) proteins including p53, PI3K/AKT, Wnt/ß-catenin and NF-kB. Forced nuclear expression of TSP and GRP by CRM1 inhibition can lead to apoptosis in cancer cells while sparing normal cells.

Methods: Novel small-moleculeCRM1 inhibitors were synthesized and nuclear distribution studies were performed in cells transfected with HIV-rev GFP proteins. Cell proliferation studies were performed in 16 CRC cell lines: LS-123, SW-626, Colo-201, Colo-205, Colo-320DM, Colo-320HSR, Lovo, DLD-1, HCT-15, WiDi, LS-174T, LS-180, SW-620, C2BBe1, HCT-8, HCT-116, and in human peripheral leukocytes (PBMC). Cellular distribution and apoptosis assays were performed on HCT-116. Antitumor activity is assessed in human HCT-116 xenografts in scid-mice.

Results: The lead CRM1 inhibitor, KPT-0127, blocks CRM1 mediated nuclear export of HIV-Rev-GFP, FOXO, and p53 with an IC50 of ∼300 nM. KPT-0127 is cytotoxic to various CRC cell lines with EC50s of 0.07-1.1 μM; in 9 CRC lines EC50s were < 0.3 mM. In contrast, normal cell lines and PBMCs had EC50 > 5-20 μM. In HCT- 116 cells, KPT-0127 induces cell cycle arrest at both G1/S and G2/M checkpoints and dose dependently increases nuclear p53, followed by an increase in caspase 3. KTP-0127 10μM shows no significant effect on 37 proteins including several cysteine proteases. In mice, KPT-0127 given by SC injection of 30-100 mg/kg leads to serum levels exceeding the effective CRM1 inhibitory concentration for at least 4 hours and is well tolerated. KPT-0127 given SC to mice bearing HCT-116 colon xenografts results in dose-dependent antitumor activity.

Conclusions: The novel small- molecule CRM1 inhibitor KTP-0127 kills CRC lines with multiple TSP, GRP, and oncogenic abnormalities, including p53 mutations/deletions and PTEN deficiency/AKT activation, while sparing normal cells. This likely reflects the ability of CRM1 inhibition to affect multiple critical and non-redundant regulatory pathways. These results support the development of CRM1 inhibitors for the treatment of CRC. IND-enabling CMC and toxicology work are in preparation.

[Table: see text]
External validation of a tumor-derived 5-gene prognostic signature for recurrence (R) of stages I/II colon and stage I rectal cancer following potentially curative resection.
Authors: Lenehan P. F. , Boardman L. A. , Fry D. W. , Heyman E. R. , Ohrnberger J. , Worzel W. P.
Published: February 2017

437

Background: Optimizing post-operative clinical management for early-stage (I/II) colorectal cancer (CRC) patients (pts) is a significant unmet medical need. We hypothesized that a molecular prognostic test using primary CRC tissue would better predict the chances of tumor R within 36 months (mo) than current NCCN Clinical Practice Guidelines (NCCN).

Methods: Pts had tumor R by 36 mo (n=46) or confirmed non-recurrence (NR) for ≥36 mo (n=69) after surgery; none had received neoadjuvant or adjuvant therapy. Archival formalin-fixed paraffin-embedded primary adenocarcinoma tissues (median storage 7 years; range 4-15) obtained at initial surgical resection with curative intent were retrieved for 86 stage I/II (pT1-4 pN0 M0) colon cancer and 29 stage I (pT1-2, pN0 M0) rectal cancer pts from 2 US and 2 European sites that were different from those previously used to generate the molecular test. Tumor gene expression was assessed by qRT-PCR with custom 384- well TaqMan Low Density Arrays (Applied Biosystems) using RNA that had satisfied a set of rigorous quality control parameters.

Results: For stages I/II CRC (n=115), the dichotomous rule correctly classified 32/46 R and 38/69 NR pts: sensitivity (S) 0.70, specificity (SP) 0.55. High-risk pts had a significantly higher probability of R by 36 mo than low-risk pts: PPV 0.51, NPV 0.73; hazard ratio (HR) 2.06 (95% CI: 1.10 to 3.86; p=0.020). NCCN (V.1.2011) was not able to differentiate 36-mo R vs NR in this population: S 0.72, SP 0.42, PPV 0.45, NPV 0.69; HR 1.38 (95% CI: 0.73 to 2.63; p=0.315). The SP of the molecular test was significantly greater than that for NCCN (p=0.05). For stage I pts (n=29; 13R, 16NR), the prognostic accuracy of the test (0.79; 23/29) surpassed that for NCCN (0.55; 16/29).

Conclusions: External validation of a 5-gene prognostic rule confirmed its ability to differentiate early stage CRC pts at high risk vs low risk for R within 36 mo after surgery better than current NCCN Guidelines, especially for stage I. The improved specificity and high sensitivity of the molecular test confirm its potential utility for optimizing post-op clinical management of early stage CRC.

[Table: see text]
Feasibility of combining EGFR- and VEGF(R)-targeted agents in colorectal cancer.
Authors: Larsen A. K. , Poindessous V. , Ouaret D. , El Ouadrani K. , Megalophonos V. F. , Batistella A. , Petitprez A. , Escargueil A. E. , Tournigand C. , De Gramont A.
Published: February 2017

443

Background: The extensive cross-talk between EGFR and VEGF(R) argues for joint targeting of the two signaling pathways. Unexpectedly, large clinical trials with combinations of EGFR-targeted antibodies and bevacizumab, a VEGF-blocking antibody, showed no added benefit in colorectal cancer (CRC) patients compared to bevacizumab alone. One difference between the antibodies and the small molecule tyrosine kinase inhibitors (TKIs) is the potential of the TKIs to inhibit intracellular signaling pathways.

Methods: We here characterize the activity of two TKIs, the irreversible EGFR/HER2 inhibitor BIBW2992 (B2) and the VEGFR/PDGFR/FGFR inhibitor BIBF1120 (B1) toward human CRC models in vitro and in vivo.

Results: B1 and B2 together showed strong activity toward HT-29 CRC xenografts, compared to either drug alone, and was associated with increased tumor cell death. In comparison, cetuximab and bevacizumab together were no more active than either drug alone and showed exclusively cytostatic activity. Recent findings provide evidence for intracellular VEGF-signaling in epithelial tumors which synergizes with EGFR for proliferation and survival (Cell 140:268, 2010). In agreement, HT-29 tumors expressed abundant intracellular VEGFR1 as shown by immunohistochemistry. Furthermore, targeted knock-down of VEGFR1 in cellular models was accompanied by increased sensitivity to B1 and B2 combinations thereby confirming the relevance of intracellular VEGFR1 signaling for CRC survival.

Conclusions: Combinations of B1 and B2 show synergistic activity in CRC models. These findings favor clinical studies with combinations of the two agents and suggest that rationally selected EGFR- and VEGF-targeted agents can be combined for clinical benefit.

[Table: see text]
Establishment of primary human esophageal xenografts: Rationale for selection and cancer model.
Authors: Dodbiba L. , Teichman J. , Ramjaun A. , Li M. , Sun B. , Chen Z. , Renouf D. J. , Tsao M. S. , Ailles L. , Liu G.
Published: February 2017

45

Background: New animal models of esophageal cancer are required to accelerate research into novel treatment strategies. Mouse xenografts used in pre-clinical drug testing are typically derived from cell lines, but several esophageal cancer cell lines have been contaminated (PMID 20075370). Xenografts implanted from surgically resected human tumors are a potentially viable model, and may better recapitulate the characteristics of the original tumor. We describe the feasibility of such an approach.

Methods: 2-10 mm esophageal carcinoma fragments obtained from resected patient tumors were implanted directly into NOD/SCID mice. Tumors that grew beyond 1.5 cm in diameter were passaged serially. Pathologic properties were assessed from passage to passage. Potential clinicopathological predictors of engraftment were evaluated.

Results: Of the 63 patients with tumors used for implantation, 67% were male; median age 66 (range 31-89); 31% node negative disease; 69% node positive disease; 12% metastatic; 55% received neoadjuvant therapy; 12% had prior Barrett's esophagus; 46% had pre-existing heartburn; 88% were distal esophageal/GE junction cancers. Engraftment occurred in 14/43 (33%) adeno-, 1/14 (7%) squamous, and 1/1 adenosquamous carcinomas (p=0.05; 5 others were rare tumors e.g. granular or small cell). Engraftment occurred in 6/31 well/moderately vs 7/18 poorly differentiated tumors (p=0.08). Because we amended our implantation procedures, we compared engraftment rates pre- (7/39; 18%) and post-amendment (8/23; 35%; p=0.13). The primary architecture of the xenografted tissue remained similar pathologically for up to 5+ passages. None of the following variables predicted for engraftment (p>0.20 each comparison): cancer location, age, gender, history of heartburn, pre-operative therapy, presence of Barrett's esophagus, disease stage, or recurrence of primary cancer.

Conclusions: Creation of esophageal cancer xenografts from primary human resected specimens is feasible. Adenocarcinomas, higher tumor grade, and newer implantation strategies were associated with improved engraftment. We are treating these models with chemotherapy to discover new pharmacogenomic predictive biomarkers.

No significant financial relationships to disclose.
Retrospective study to elucidate a K-ras phenotype in patients with colorectal cancer.
Authors: Garrido-Laguna I. , Janku F. , Falchook G. S. , Naing A. , Fu S. , Wheler J. , Tsimberidou A. M. , Hong D. S. , Kurzrock R.
Published: February 2017

462

Background: Activating mutations of the K-ras oncogene in colorectal cancer (CRC) are associated with resistance to EGFR antibodies and poor prognosis. Clinical and pathological characteristics associated with K-ras mutations have not been systematically analyzed.

Methods: Patients with CRC referred to the phase I program for targeted therapy were analyzed for K-ras mutations using PCR-based DNA sequencing. Patients with mutant K-ras were matched with wild-type (wt) K-ras controls. Multiple clinical and pathological characteristics were analyzed to determine, whether there is a phenotype associated with K-ras mutations.

Results: A total of 107 patients with CRC were identified; 58 with K-ras mutations; and 49 with wt K-ras. Patients with K-ras mutations compared with wt K-Ras had more frequently lung metastases (80% vs. 57%, p = 0.013). There was a trend towards higher number of metastatic sites in K-ras mutant patients compared with wt K-ras (3.16 vs. 2.69; p = 0.07). There were no associations between K-ras mutations and gender, age at diagnosis, liver metastases, peritoneal metastases, and lymphatic involvement. The median time from diagnosis to development of metastatic disease was similar in K-ras mutant and K-ras wt patients (194 vs. 196 weeks, p = 0.43). The median survival from diagnosis was also similar in K-ras mutant and K-ras wt patients (254 vs. 223 weeks, p = 0.32). There was no difference in the median survival from diagnosis in patients with different types of K-ras mutations (codon 12, codon 13, and codon 61). Dukes staging was the only statistically significant prognostic factor on multivariate analysis (p < 0.05).

Conclusions: K-ras mutations in CRC in comparison with wt K-ras were associated with more frequent lung metastases. K-ras mutations did not impact survival.

No significant financial relationships to disclose.
Novel multiphoton microscopy probe and feasibility study for colon cancer: Probe on trace elements–related antioxidant.
Authors: Kim E. , Jeen Y. , Cho H. , Keum B. , Kim Y. , Lee H. , Chun H. , Kim C. , Ryu H.
Published: February 2017

463

Background: Multiphoton microscopy (MPM) has gained increasing popularity during the past few years because of the distinct advantages over single-photon microscopy, which includes increased penetration depth and low out-of-focus photodamage. However, there had been no report on multiphoton probes for malignancy. Previous studies reported that Zn and Cu ions which are co-factor of antioxidants such as superoxide dismutase (SOD), altered in malignancy tissue. The aim of this study was to evaluate application of the multiphoton (MP) probe of Zn and Cu for colon cancer tissues.

Methods: We monitored the Zn/Cu ions in the colon cancer cell lines with multiphoton probe Microscopy. The multiphoton probe AZn2+ (C38H38N6O3) and ACu+ (C34H47N3O3S4), we developed and obtained the patent on it, were stained in live cancer cell lines. The tissues of colon cancer, adenoma and normal mucosa were obtained by biopsy during colonoscopy. Then the tissues were stained with 20μM of the MP probes for Zn/Cu ions. The distribution and concentration of zinc and copper ions were monitored by MPM by following the change in MPEF along the depth of tissue.

Results: The majority of Zn2+ and Cu+ ions distributed in cytosole. The average multi-photon excited fluorescence (MPEF) intensities due to Cu, Zn, and Cu/Zn ratio were remarkably different between the normal mucosa and adenoma/adenocarcinoma tissues. The Zn2+ content was significantly lower and the Cu2+ content was significantly higher to result in a much lower the Zn/Cu ratio in adenoma/adenocarcinoma than in normal mucosa tissues.

Conclusions: We have obtained multiphoton microscopy images of normal and cancer cell lines as well as mucosa and adenoma/adenocarcinoma tissues labeled with newly developed MP probes AZn1 and ACu1.

No significant financial relationships to disclose.