bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of diabetes mellitus with increased mortality in patients receiving curative surgery for colon cancer.
Authors: Chen Kuo-Hsing , Shao Yu Yun , Yeh Yi-Chun , Shau Wen-Yi , Kuo Raymond Nienchen , Lin Zhong-Zhe , Chen Ho-Min , Yeh Kun-Huei , Cheng Ann-Lii , Lai Mei-Shu
Published: February 2017

399

Background: Diabetes mellitus (DM) is associated with increased risk of colon cancer and has potential impact on its prognosis. This study aimed to investigate the association between DM and the prognosis of patients with early colon cancer who underwent curative surgery. Methods: We established the patient cohort of the study by searching the database of the population-based Taiwan National Cancer Registry. All patients who had newly diagnosed stage I or II colon cancer from 2004 to 2007 and underwent surgical resection with uninvolved surgical margins were enrolled. Information of DM, anti-DM medication, and other comorbidities was retrieved from the database of National Health Insurance, Taiwan. Colon cancer-specific survival (CSS) and overall survival (OS) were compared between patients with and without DM. The Cox proportional hazard model was used to estimate the adjusted hazard ratio (HR) of clinicopathologic variables in multivariate analysis. Results: A total of 5,525 patients were identified; 1,009 of them (18.9%) had DM and 4,325 of them (81.1%) had no DM. Patients with DM had an older median age at diagnosis (69.9 y vs. 66.8 y, p < 0.001), similar initial stage and grade, fewer adjuvant chemotherapy (26.5% vs. 31.2%, p = 0.003). Patients with DM had significantly poorer CSS and OS than patients without DM (Table). In multivariate analysis adjusting for age, gender, stage, adjuvant chemotherapy and comorbidities, DM remained an independent prognostic factor for poorer OS (adjusted HR: 1.45, p < 0.001). Among patients with DM, patients who used insulin had significantly poorer CSS and OS than patients who did not (5-year CSS: 79.5% vs. 85.5%, p = 0.047; 5-year OS: 50.9% vs. 70.4%, p < 0.001). Conclusions: In patients receiving curative surgery for early colon cancer, patients with DM had poorer OS than patients without DM. [Table: see text]
The relationship between tumour necrosis, circulating IL-6 concentrations, and inflammatory responses in patients undergoing curative resection for colorectal cancer.
Authors: Guthrie Graeme JK , Roxburgh Campbell SD , Richards Colin H , Horgan Paul G. , Mcmillan Donald C.
Published: February 2017

404

Background: Cancer-associated inflammation, in the form of systemic and local inflammation, and tumour necrosis are known to have prognostic value in colorectal cancer (CRC). In addition, recent work has reported a direct relationship between the systemic inflammatory response and loss of skeletal muscle in patients with CRC. However, the inter-relationships between these inflammatory responses, tumour necrosis, metabolic upset and circulating biochemical mediators are unclear in CRC. Interleukin-6 and its downstream signalling cascades have been implicated in both cancer-associated inflammation and cancer-associated muscle wasting. The aim of the present study was to examine whether circulating IL-6 concentrations may link tumour necrosis, local and systemic inflammatory responses, and metabolic upset in patients undergoing curative resection for colorectal cancer. Methods: The study included 118 patients undergoing surgery for CRC between 2004 and 2009. Data were collected from pre-operative blood tests. Routine pathology specimens were scored for Klintrup criteria and tumour necrosis. Results: Tumour necrosis was associated with increased T-stage (p<0.01), reduced inflammatory cell infiltrate (p<0.05), increased IL-6 (p<0.001), IL-10 (p<0.01), and VEGF (p<0.001) and with markers of the systemic inflammatory response: mGPS (p<0.001), anaemia (p<0.05); increased white cell (p<0.001), neutrophil (p<0.05) and platelet (p<0.001) counts. Circulating IL-6 was associated with increased IL-10 (p<0.01), VEGF (p<0.001), increased mGPS (p<0.001), increased white cell (p<0.01) and platelet (p<0.01) counts and low skeletal muscle index (p<0.01). On Spearman rank correlation there were significant associations between circulating concentrations of IL-6 and IL-10 (rs= 0.39, p<0.001) and CRP (r= 0.42, p<0.001). Conclusions: Interleukin-6 appears to be associated with systemic inflammation, tumour necrosis, and sarcopenia in colorectal cancer. However, the lack of an association between IL-6 and the local inflammatory response suggests a more complex relationship with the tumour inflammatory cell infiltrate.
The in situ local immune response, tumour senescence, and proliferation in colorectal cancer.
Authors: Roxburgh Campbell SD , Richards Colin H , Powell Arfon , Mcmillan Donald C. , Edwards Joanne E. , Horgan Paul G. , Shiels Paul G.
Published: February 2017

412

Background: Immune cell infiltrates play a key role in determining colorectal cancer outcome. It is unclear whether they are tumour or host specific. Increased immunogenicity may relate to senescence or proliferation. Senescence, a state of cell-cycle arrest, slows tumour progression. In animal models, senescence associated regression is mediated by upregulated antitumour immune responses. High proliferation may provoke immune responses. Relationships between senescence, proliferation and immune cell infiltrates have not previously been studied. We explore whether p16ink4a associated senescence relates to T cell infiltrates in colorectal tumours and whether p16ink4a expression, proliferation and T cell infiltrates confer similar survival relationships. Methods: Immunostaining of nuclear p16inka and Ki67 was performed using a tissue microarray. Nuclear p16inkaand Ki67 were scored as high or low expression. (T cell markers CD3/CD45RO/CD8/FOXP3) were scored high/low grade on corresponding full sections (margin/stroma/ cancer cell nest). Results: 230 Stage I-III cancers were studied. High nuclear p16ink4a was expressed in 63% and high proliferation (Ki67 >15% ) in 61%. P16ink4a expression related to reduced margin, stroma and cancer cell nest (CCN) CD45RO cells (P=0.054, P=0.062, P=0.025) and reduced margin CD8 cells (P=0.016). High Ki67 labeling related to increased margin, and CCN CD3 cells (P=0.017, P<0.001), increased margin and CCN CD45RO cells (P=0.023, P<0.001), increased margin, stroma and CCN FOXP3 cells (P<0.001, P=0.001, P<0.001) and increased margin and CCN CD8 cells (P=0.026, P=0.001). On multivariate analysis, TNM stage (P<0.001), low margin CD3 (P=0.014), low margin CD8 (P=0.037), low proliferation (Ki67) (P=0.013) and low senescence (P16ink4a) (P=0.002) conferred poorer cancer survival. Conclusions: p16ink4a expression, proliferation and immune cell infiltrates are independent prognostic factors in colorectal cancer. Proliferation relates to increasing T cell infiltrates but independently influences survival. P16ink4a associated senescence does not appear to mediate improved outcome by upregulating T cell responses. Relationships observed here suggest the opposite.
Association of telomere length (TL) with clinical outcomes in patients with colorectal carcinoma (CRC).
Authors: Baig Mahadi Ali , Merla Amartej , Augustine Titto A , Atzmon Gil , Budagov Temuri , Goel Sanjay , Maitra Radhashree
Published: February 2017

418

Background: Telomeres (T) consist of thousands of copies of TTAGGG tandem repeats capping the ends of the chromosome. T along with enzyme telomerase provides protection against any threats to the genome that might arise as a consequence of “end replication problem.” During aberrant cell proliferations the normal check points of cell cycle is compromised leading to unrestricted cell division with extremely short T and subsequent genomic instability. Studies have linked short TL with premalignant and malignant stages of CRC carcinogenesis. However, the relation of TL to the clinical outcomes has not been conclusively determined. In this study we evaluated the association of TL with clinical outcomes in a cohort of 75 CRC patients. Methods: Tumor DNA was isolated from formalin fixed paraffin embedded specimens. TL was measured by using a qRT-PCR method that provided the relative T copy number, compared to reference copy number of the housekeeping gene, β-Globin, which resulted in a T/S ratio. One T/S ratio unit is equivalent to a mean TL of 4,270 base pairs (BP). Results: From 75 patients, 122 tissue samples were identified (66 primary, 52 metastases, 29 matched pairs). Age at diagnosis (>/< median) had a statistically significant difference in TL (mean BP 4700 vs. 4374; p=0.05) with shorter TL in the advanced age. Females had longer TL compared to men (mean BP 4722 vs. 3669 respectively; p=0.04). Shorter TL was associated with shorter progression free survival (PFS) for patients treated with cetuximab/panitumumab (3963 vs. 5295 p=0.04). There was a trend towards increased overall survival (>/< median) with longer TL (4934 vs. 4117; p=0.08). We failed to find a difference in the TL between primary and metastatic sites in the 29 patients with paired samples. Conclusions: TL is a potential biomarker predictive of clinical outcome (PFS) for patients treated with cetuximab/panitumumab. Tumor TL reduces with advancing age and appears to be sex dependent. Further studies to validate TL’s predictive role in patient outcomes are underway.
Global profiling of fecal and tissue mirnas in Asian Chinese colorectal cancer patients.
Authors: Phua Lee Cheng , Koh Poh Koon , Cheah Peh Yean , Chan Eric Chun Yong , Ho Han Kiat
Published: February 2017

439

Background: Fecal miRNAs are increasingly explored as non-invasive diagnostic markers of colorectal cancer (CRC). However, a holistic understanding of the global fecal miRNA profile in CRC patients is lacking, particularly in Asian patients. Also, it remains to be determined if the fecal miRNA profile mirrors the tumor profile. Here, we assayed the global human fecal miRNAs in Asian Chinese CRC patients to elucidate relevant diagnostic fecal markers. The disease-related profiles between feces and resected tumor of matched patients were also compared. Methods: MiRNAs were extracted from the feces of sporadic CRC patients (stage B – C, n=8) and healthy subjects (n=8) recruited into the study from September 2011 – July 2012. MiRNA expression profile was analyzed on Agilent miRNA array (miRBase Release 16.0). Biopsied tumor tissue (n=8) and matched normal mucosae (n=8) from the same CRC patients were also analyzed. Results: Univariate tests uncovered novel fecal markers (p<0.05) characterizing CRC (e.g. elevated miR-3619-5p and miR-4269; decreased miR-3164 and miR-3917), even though global fecal miRNA profiles did not differentiate CRC patients from healthy subjects. Fecal miR-223 was appreciably higher in CRC patients, corroborating with Caucasian studies. Tumor miRNA signature was clearly distinct from matched normal mucosa (PLS-DA Q2=0.883). Discriminating tumor miRNAs (p<0.05) included previously unreported (e.g. miR-874 and miR-4290) and known oncogenic miRNAs (e.g. miR-17-92 cluster and miR-135b) in the context of CRC. Notably, the global fecal miRNA profile was markedly different from that of tissue, suggesting that miRNA aberrations within CRC tumor did not significantly influence the fecal miRNA profile. Conclusions: A global profiling approach identified novel sets of differentially expressed miRNAs at the fecal and tissue level that may complement existing diagnostic markers and provide new insights into CRC pathogenesis. Interestingly, dysregulated miRNAs in the feces were different from the tumor, suggesting the presence of other contributors to the fecal miRNA profile. There is a need to reconsider using tissue biomarkers indiscriminately in different biological matrices.
Circulating tumor cells as predictive marker in panitumumab after progression of cetuximab in Japanese patients with KRAS wild-type metastatic colorectal cancer.
Authors: Ohhara Yoshihito , Matsusaka Satoshi , Shinozaki Eiji , Suenaga Mitsukuni , Mizunuma Nobuyuki , Hatake Kiyohiko , Yamaguchi Toshiharu
Published: February 2017

440

Background: Panitumumab has a high affinity for epidermal growth factor receptor. Its utility as a salvage therapy is unknown in cetuximab-resistant colorectal cancer. We assessed the prognostic and predictive role of circulating tumor cells (CTC) in KRAS wild-type metastatic colorectal cancer (mCRC) patients treated with panitumumab after progression of cetuximab. Methods: Panitumumab (6 mg/kg, every 2 weeks) was administered as a salvage therapy to cetuximab-resistant mCRC. CTCs of whole blood at baseline were isolated and enumerated using immunomagnetics. Results: Nineteen patients were enrolled in this prospective study between July 2010 and March 2011. Five patients had stable disease (SD) with a response rate of 0%. Four patients reached long SD, which was defined as continuous SD of more than 120 days. All of the four patients had <2 CTC. <2 CTC showed an independent predictive role for progression-free survival (PFS) at multivariate analysis (HR; 7.275, p=0.013). Patients with >2 CTC had shorter median PFS than those with <2 CTC (1.8 and 3.6 months, p=0.008). There was no statistical significance in median OS between patients with <2 CTC and those with >2 CTC (3.2 and 6.7 months, p=0.164). Conclusions: Panitumumab may be effective for patients with <2 CTC, KRAS-wild-type mCRC after progression of cetuximab.
Validation of TPX2 as a novel prognostic marker for malignant progression and metastasis of colon cancer.
Authors: Wei Ping , Li Dawei , Xu Ye , Cai Sanjun
Published: February 2017

442

Background: We previously identified aberrant overexpression of TPX2 in colon cancer by using a genome-wide gene expression profiling analysis. Here, we aimed to investigate its expression pattern, clinical significance, and biological function in colon cancer. Methods: The expression of TPX2 was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis and metastasis was examined in vitro and in vivo. Results: Overexpression of TPX2 was found in metastatic lesion of colon cancer, significantly higher than primary cancererous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with the clinical staging, vessel invasion and metastasis. In survival analyses, patients with TPX2 expression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistently, Silencing TPX2 inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT mediated MMP9 activity. Conclusions: These findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer and may represent a novel prognostic biomarker and therapeutic target for the disease.
Bevacizumab (Bev) with or without erlotinib as maintenance therapy, in patients (pts) with metastatic colorectal cancer (mCRC): Exploratory analysis according to KRAS status in the gercor DREAM phase III trial.
Authors: Samson Benoit , Tournigand Christophe , Scheithauer Werner , Lledo Gérard , Viret Frédéric , André Thierry , Ramée Jean François , Tubiana-Mathieu Nicole , Dauba Jérôme , Dupuis Olivier , Rinaldi Yves , Mabro May , Aucoin Nathalie , Khalil Ahmed , Latreille Jean , Louvet Christophe , Brusquant David , Bonnetain Franck , Chibaudel Benoist , De Gramont Aimery
Published: February 2017

448

Background: In the GERCOR-DREAM trial, maintenance therapy (MT) with bev + EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC significantly improved PFS compared with bev alone. Here we explore the influence of KRAS status on erlotinib efficacy. Methods: Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (Bev 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). KRAS determination was established by local assessment in each center. Results: Among the 452 randomized patients, KRAS status was available in 403 pts (89%): 234 pts (58%) KRAS wt and 169 pts (42%) KRAS mut. Clinical characteristics were similar between both populations. For the whole population of randomized patients (n=452), median PFS from inclusion were 9.33m and 10.55m in arm A and B, respectively (HR=0.76 [0.61-0.94], p=0.011). For KRAS wt population, median PFS from inclusion was 9.66 m and 10.94 m in arm A and B, respectively (HR=0.80 [0.59-1.08], p=0.141). For KRAS mut population, median PFS from inclusion was 9.79 m and 9.79 m in arm A and B, respectively (HR=0.86 [0.61-1.22], p=0.393). In KRAS wt pts treated with erlotinib, cutaneous toxicity was predictive of PFS: mPFS was 9.66m in pts with grade 0 (n=101) and 10.91m in pts with grade ≥1 (n=114) (HR=0.69 [0.51-0.95], p=0.0186). Conclusions: The addition of erlotinib to bevacizumab as maintenance treatment in first-line metastatic colorectal cancer significantly improves progression-free survival from inclusion. However, in both wt and mut KRAS pts, difference was not statistically significant. Unlike anti-EGFR monoclonal antibodies, the addition of erlotinib to bevacizumab does not appear to be antagonist in KRAS mutant patients. Clinical trial information: NCT00265824.
Analysis of overall survival and safety during the course of the phase III VELOUR trial comparing FOLFIRI and aflibercept or placebo in patients with mCRC that progressed on prior oxaliplatin treatment.
Authors: Ruff Paul , Lakomy Radek , Prausová Jana , Van Hazel Guy , Moiseyenko Vladimir Mikhailovich , Bhargava Pankaj , Tabernero Josep , Van Cutsem Eric
Published: February 2017

451

Background: VELOUR is a large international, randomized placebo-controlled study that compared the efficacy and safety of FOLFIRI with aflibercept (ziv-aflibercept in the US) or with placebo in 1,226 mCRC patients who received prior oxaliplatin treatment. Aflibercept demonstrated statistically significant and clinically meaningful improvements in median OS (13.5 vs 12.06 months; HR=0.817, p=0.0032) as well as PFS and response rate. (Van Cutsem et al., J Clin Oncol. 2012). This analysis estimates the treatment effect and safety over the time course of the study. Methods: Hazard ratios (HR) by 6-month time periods were estimated using a piecewise Cox proportional hazard model. NCI-CTCAE version 3.0 was used to grade the severity of AEs. Results: There was improvement in the HR over time (Table) consistent with the survival curves that continue to separate past the median time point, indicating that the magnitude of the aflibercept treatment effect continues to increase over time. Incidence of grade 3 AEs (45.1% vs. 62.0%) was higher in the aflibercept + FOLFIRI arm; grade 4 AEs were placebo 17.4% vs. 21.4% aflibercept. More common AEs only occurred in a small proportion of aflibercept + FOLFIRI cycles (e.g., grade >3 hypertension and diarrhea occurred in 3.6% and 2.8% of treatment cycles, respectively). The majority of grade 3-4 AEs occurred in early treatment cycles (first 3-4 cycles). Most patients experienced only a single episode of grade ≥3 AEs with aflibercept + FOLFIRI. Importantly, AEs in VELOUR did not impact patients’ ability to receive chemotherapy. Conclusions: Treatment with aflibercept plus FOLFIRI showed a continuous and consistent improvement in OS over time. Although combined grade 3-4 AEs were higher with aflibercept, AEs occurred early in treatment, in a small proportion of total cycles administered, and the majority were single episode in nature. Clinical trial information: NCT00561470. [Table: see text]
Progression-free survival in metastatic, BRAF-mutated colorectal cancer.
Authors: Morris Van Karlyle , Overman Michael J. , Maru Dipen M , Kopetz Scott
Published: February 2017

458

Background: BRAF mutations occur in 5-8% of metastatic colorectal cancers and are associated with a significantly worse overall prognosis relative to patients with BRAF wild-type tumors. However, the outcomes with standard chemotherapy of a large cohort of patients with BRAF mutant tumors have not been described. Methods: We searched the MD Anderson Cancer Center databases for colorectal cancer patients with identified BRAF mutations between December 2003 and May 2012. Patients were analyzed for clinical characteristics, progression-free survival, and chemotherapeutic agents used. Survival was estimated according to the Kaplan-Meier method. Results: Among the 1567 patients tested for BRAF mutations at our institution, 127 (8.1%) had tumors with BRAF mutations. The average age was 59.6 years at the time of diagnosis, and 65/127 patients (51.2%) were male. The 71 patients who presented with metastatic disease received a median of 2 lines of chemotherapy. For the first three lines of chemotherapy, median progression-free survival was 5.6 months (n=69 patients), 3.9 months (n=58), and 3.4 months (n=31), respectively. Median PFS was not affected by the backbone chemotherapeutic agent in the first-line setting, whether oxaliplatin-based or irinotecan-based (6.1 months vs. 5.1 months, respectively, p-value = 0.78). Conclusions: Progression-free survival is expectedly poor for patients with BRAF-mutated metastatic colorectal cancer. Despite the ascertainment bias present in this cohort (with testing preferentially performed in patients suitable for clinical trials in refractory disease), fewer than half of patients with metastatic disease received more than 2 lines of therapy. This data not only provides historic controls suitable for future study design in this population but also supports the idea that novel therapeutic options are essential for this group of patients.
Validation of the survival benefit from metformin use in patients with type 2 diabetes and colorectal cancer.
Authors: Sahin Ibrahim Halil , Hassabo Hesham Mohamed , Shen Yehua , Kee Bryan K. , Hassan Manal , Garrett Chris R.
Published: February 2017

462

Background: We previously reported improved overall survival (OS) associated with metformin usage in a retrospective study of type 2 diabetes mellitus (DM) patients with colorectal (CRC) (Br J Cancer 2012;106:1374-8). We sought to determine whether this effect could be validated in an independent data set. Methods: Under an IRB-approved protocol, 6,128 patients with CRC based on ICD-9 billing codes diagnosed between 1995-2005 were reviewed; of these 683 were determined to have type 2 DM. Results: Of the 683 diabetic CRC patients, 407 (59.5%) were male. The patient’s stage at diagnosis was: stage I (67, 9.8%), II (162, 23.7%), III (247, 36.1%), IV (166, 24.3%) and unknown stage (41, 6%). The number of patients using metformin at the time of first evaluation was 146 (21.3%). A significantly better median OS was observed in CRC patients with metformin use in both all-stage and stage III groups (p = 0.017, p = 0.029 respectively); median OS results demonstrated in table below. Conclusions: This independent retrospective data set validated the OS benefit associated with metformin use previously reported in patients with type 2 DM and CRC. Future prospective studies will be required to confirm the benefit of metformin in this clinical setting. [Table: see text]
North American (NA) subgroup results from VELOUR: Ziv-aflibercept versus placebo (pbo) plus FOLFIRI in mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen.
Authors: Mitchell Edith P. , Guarino Michael J. , Allegra Carmen Joseph , Boelle Emmanuelle , Andria Michael L. , Bhargava Pankaj , Kirshner Jeffrey J.
Published: February 2017

465

Background: Ziv-aflibercept (trade name ZALTRAP; known outside the US as aflibercept) is a new multiple angiogenic inhibitor that prevents VEGF-A, VEGF-B and PLGF from binding their receptors. Ziv-aflibercept was recently approved by the FDA in combination with FOLFIRI for patients with mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen. Approval was based on the multinational phase III VELOUR trial (N=1226) which showed statistically significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with aflibercept + FOLFIRI. Detailed analyses of the NA subgroup are presented here. Methods: Patients were randomized 1:1 to ziv-aflibercept (4 mg/kg) + FOLFIRI or pbo + FOLFIRI every 2 wk. Patients had ECOG performance status (PS) ≤2, 1 prior oxaliplatin-based regimen, and prior bevacizumab (bev) was allowed. Primary endpoint was OS. The NA analysis was pre-specified, but not powered, to compare within or between subgroups. Results: NA patients (N=138) were randomized to ziv-aflibercept + FOLFIRI (n=63) or pbo + FOLFIRI (n=75). Baseline characteristics were similar in both arms (ziv-aflibercept: median 61 yrs; 60% male; 96% PS 0-1; 56% >1 metastatic organ; 74% prior bev). Ziv-aflibercept vs pbo improved median OS (17.94 vs 12.88 mos; HR=0.691, 95% CI: 0.442-1.079), median PFS (6.01 vs 4.17 mos; HR=0.536, 99.9% CI: 0.222-1.296) and ORR (12% vs 9%). Patients on average received more cycles (median 8.5 vs 7.0) and had longer duration of exposure (median 20 vs 14 wk), but had more treatment modifications with ziv-aflibercept vs pbo. Most of the severe AEs (grade ≥3) with ziv-aflibercept were grade 3 including hypertension, venous thromboembolic events, proteinuria, diarrhea, fatigue/asthenia, infection, stomatitis/ulceration and neutropenia. There were few grade 4 AEs. Conclusions: Ziv-aflibercept + FOLFIRI in NA mCRC patients previously treated with an oxaliplatin-based regimen (with or without prior bev) resulted in improved OS, PFS, and ORR, with an acceptable safety profile. The NA results are consistent with the VELOUR worldwide population. Clinical trial information: NCT00561470.
HPV in upper aerodigestive tract tumors in southern Brazil.
Authors: Antunes Luis Carlos Moreira , Muller Leandro Bizarro , Lopes Antonio de Barros , Fagundes Renato Borges
Published: February 2017

47

Background: The highest rates of esophageal cancer in Brazil occur in Rio Grande do Sul (18/100,000/year for men), where squamous cell carcinoma is the most common. Furthermore, the incidence of head and neck squamous cell carcinoma (HNSCC) is significant in this region (11/100,000/year for cancer of the oral cavity and 10/100,000/year for laryngeal cancer in men). Tobacco smoking and alcohol consumption are the major risk factors for esophageal squamous cell carcinoma (ESCC) and HNSCC. The role of HPV in the development of ESCC remains controversial. Otherwise, there are some evidence that HPV-related HNSCC is a distinct entity compared with HNSCC associated with smoking and alcohol consumption. Methods: Polymerase chain reaction (PCR) was used to evaluate the presence of Human Papillomavirus from 218 samples from three groups of patients. Group 1 comprised 51 patients with ESCC who underwent esophagectomy, in which two samples from each patient were analyzed: one sample of the tumor and another of normal esophageal mucosa distant from the tumor. Group 2 comprised 37 patients with HNSCC who underwent Lugol chromoendoscopy. In this group, samples were analyzed from the primary tumor, the stained areas of mucosa from the middle esophagus, and, when present, discolored and tumoral areas of the esophageal mucosa. Thirty-seven dyspeptic patients, not exposed to smoking or alcohol consumption, comprised Group 3, in which one sample per patient of mucosa with normal appearance from the middle esophagus was evaluated. Nested-PCR with MY09/11 and GP5/6 L1 primers was used to detect HPV L1 in samples fixed in formalin and stored in paraffin blocks. Results: Of a total of 224 samples fixed in formalin and stored in paraffin, only 6 samples had insufficient material for PCR analysis: one sample from normal distal epithelium in Group 1, one sample from a stained area and 2 samples from unstained areas in Group 2 and two samples from normal esophageal mucosa in Group 3. PCR was positive for one of conserved genes GAPDH, G3PDH or B-globin and negative for HPV DNA in all the 118 samples tested. Conclusions: There is no evidence that HPV is involved in carcinogenesis of the upper aerodigestive tract in southern Brazil.
Prognostic markers of time to local recurrence and overall survival in early-stage rectal cancer.
Authors: Patel Sagar A , Chen Yu-Hui , Hornick Jason L. , Catalano Paul J. , Nowak Jonathan , Zukerberg Lawrence R. , Hong Theodore S. , Mamon Harvey J.
Published: February 2017

473

Background: Surgical resection without adjuvant therapy results in a low recurrence rate for patients with early stage (i.e. T1-2 N0) rectal cancer, in the range of 4-15% at 5 years. There are limited data regarding clinical or pathologic markers that are prognostic for recurrence in this population. This study assesses factors associated with time to local recurrence (TTLR) and overall survival (OS) in these patients. Methods: From 2000 to 2008, 177 patients with stage I rectal cancer treated with surgery alone were identified. Data were retrospectively reviewed to identify markers associated with TTLR and OS, including staging method, preoperative CEA, type of surgery, tumor size, lymph node resection, histological grade, circumferential resection margin, and presence of lymphovascular invasion (LVI), lymphocytic infiltration, or ulceration on pathology. Data were analyzed using a Cox proportional hazards regression model. Results: Of the eligible cohort, 137 patients had complete follow up data for analysis of TTLR, and 23 (16.8%) locally recurred. Among these 23 patients, the median TTLR was 1.1 years (0.1-7.8). On univariate analysis, male gender, current alcohol use, LVI and tumor ulceration were associated with heightened risk for LR, and male gender (HR 3.3, p=0.02), current alcohol use (HR 3.4, p=0.01) and tumor ulceration (HR 4.2, p=0.001) remained statistically significant on multivariate analysis. Of the original cohort, 173 patients had complete follow up for OS analysis. Among these patients, the median OS was 12 years. On univariate analysis, age at diagnosis > 65 years, T2 pathologic stage, and tumor size > 4.5 cm were associated with decreased OS, and age at diagnosis > 65 years (HR 2.1, p=0.04) and T2 pathologic stage (HR 2.5, p=0.008) were predictors of reduced OS on multivariate analysis. Conclusions: For patients with stage I rectal cancer treated with surgery alone, male gender, current alcohol use, and tumor ulceration are poor prognostic markers for TTLR. Within this population, age at diagnosis > 65 years and T2 pathologic stage are predictive for reduced OS. These results provide important prognostic information for patients and may help identify those who could benefit from additional therapy.
Randomized phase II study of mixing steroid to reduce venous pain in patients with colorectal cancer receiving oxaliplatin through peripheral vein (APOLLO study).
Authors: Hata Taishi , Toyokawa Akihiro , Kobayashi Michiya , Miyake Masakazu , Tsuda Masahiro , Tobimatsu Kazutoshi , Okamoto Ken , Tokunaga Yukihiko , Takase Kozo , Morita Satoshi , Sakamoto Junichi , Mishima Hideyuki
Published: February 2017

474

Background: Although theCapeOX (capecitabine+oxaliplatin) regimen obviates the need for a central venous port, administration of oxaliplatin through peripheral vein can cause venous pain. One of the reasons is pH. The pH level of oxaliplatin solution is about 4.8 and that of buffered by steroid is approximately 7.0. To test the hypothesis that adjusting the pH of oxaliplatin solution by mixing steroid can reduce venous pain, we have conducted the randomized control study to compare pH-adjusted oxaliplatin solution with unadjusted oxaliplatin solution. Methods: This was a single-blinded multicenter randomized phase II study. Colorectal cancer patients receiving oxaliplatin through peripheral vein were enrolled and randomly assigned to arm A (oxaliplatin 130 mg/m2 with dexamethasone (DEX) 2 mg) or arm B (the same, without DEX) (UMIN000004286. Venous pain was evaluated according to CTCAE criteria (ver. 4.0) and the verbal rating scale (VRS). Assessments were conducted every 3 weeks until cycle 4. Results: A total of 53 patients (38 men and 15 women; median age, 67 y.o.) were enrolled at 9 institutions in Japan. Of these, 47 evaluable patients were randomized to either arm A (n = 24) or arm B (n = 23). The incidence of venous pain (grade ≥ 2) was 33.3% in arm A and 60.9% in arm B (relative risk 0.55; p = 0.082). The venous pain (VRS score ≥ 3) was 12.5% in arm A and 26.1% in arm B (relative risk 0.48; p = 0.286). No difference was observed in response rate and safety. Conclusions: Adjusting the pH of oxaliplatin solution by addition of a low dose of DEX reduced severe venous pain without influence on response rate and safety. Clinical trial information: UMIN000004286. [Table: see text]
Ultra-staging of node negative (pN0i-) colon cancer: Preliminary results of an international prospective clinical trial.
Authors: Bilchik Anton J. , Nissan Aviram , Protic Mladjan , Wainberg Zev A. , Wasserberg Nir , Avital Itzhak , Stojadinovic Alexander
Published: February 2017

484

Background: We recently reported in a prospective randomized trial that ultra-staging of patients with colon cancer is associated with significantly improved disease-free survival (DFS) compared with conventional staging (Ann Surg, Sept 2012). This trial was not controlled for lymph node (LN) number, nor use of adjuvant chemotherapy. Methods: The purpose of the present trial, “Ultra-staging in Early Colon Cancer” (UECC) NCI Clinical Trial #00949312 is to evaluate prospectively whether the 12-LN quality measure with ultra-staging impacts DFS without adjuvant chemotherapy. Eligibility criteria included: a) biopsy-proven colon adenocarcinoma; b) no evidence of metastatic disease; c) ≥ 12 LNs staged pathologically; d) pan-cytokeratin immunohistochemistry(IHC) of H&E-negative LNs; d) no adjuvant chemotherapy. The accrual goal is 300 patients with minimum three-year follow-up. Results: To date 126 patients have been accrued with mean and median follow-up of 40 months; 30 didn’t meet the ≥12-LN threshold. Of 52 males and 74 females, 23, 24, and 66 had T1, T2, T3 tumors, respectively. Ninety-six patients had ≥12 H&E and IHC negative LNs (pN0i-). Thirty patients were <12 LNs/pN0i-. Three-year DFS for all patients was 95%. Three-year DFS for patients with ≥12 LNs and pN0i- was 98% compared with 84% for <12 LNs / pN0i- (p=0.002). Three-year DFS differed significantly according to nodal yield in pN0i- patients: 96% vs. 80%, ≥12 vs. <12 LNs, respectively, p=0.03. Conclusions: This is the first prospective trial to demonstrate that adjuvant chemotherapy does not offer any disease-free survival benefit if patients have ≥12LNs ultra-staged by both H&E and IHC (pN0i-). Both surgical and pathological quality measures are essential in the planning of adjuvant chemotherapy trials in node-negative colon cancer. Clinical trial information: NCT00949312.
A phase II trial of salvage treatment with gemcitabine and S-1 combination in heavily pretreated patients with metastatic colorectal cancer.
Authors: Sym Sun Jin , Hong Junshik , Ahn Hee Kyung , Park Jinny , Cho Eun Kyung , Lee Jae Hoon , Lee Won-Suk , Baek Jeong-Heum , Park Yeon Ho , Shin Dong Bok
Published: February 2017

488

Background: We conducted a phase II trial of gemcitabine with S-1 to evaluate the activity and toxicity of such a combination in heavily pre-treated patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after treatment with 5-fluorouracil (5-FU), oxaliplatin and irinotecan. Methods: 34 pts were enrolled, with the following characteristics: 17 (50%) females, median age 57 years (28-72), 28 (82%) ECOG PS 0-1. S-1 was given orally (30 mg/m2) b.i.d for 14 consecutive days and gemcitabine (1000 mg/m2) was given on days 1 and 8, every 21 days, until disease progression and for a maximum of 9 cycles. The primary endpoint was objective response rate (ORR). Results: The median number of cycles was four (range 1-9). ORR was 14.7% (95% confidence interval [CI] 2.8-26.6) and disease control rate was 58.8% (95% CI 42.2-75.3) with five partial responses and fifteen stable diseases. Median duration of disease control was 5.1 months (95% CI 3.3-7.0). Median progression-free survival was 3.2 months (95% CI 2.3-4.1) and median overall survival was 11.8 months (95% CI 7.0-16.5). Grade 3-4 toxicities were neutropenia (12%), anemia (12%), thrombocytopenia (3%) and diarrhea (3%). Conclusions: Combination chemotherapy with gemcitabine and S-1 was well tolerated and efficacious for heavily pre-treated mCRC pts, and could be an alternative for pts with good PS but no further treatment options.
Clinicopathologic significance of expression of nuclear factor kappa Β and vascular endothelial growth factor in gastric cancer patients.
Authors: Park Keon-Woo , Kwon Hyuk-Chan , KIm Su-Jin , Lee Hyung-Sik
Published: February 2017

50

Background: Nuclear factor-κB (NF-κB) and vascular endothelial growth factor (VEGF) are involved in cell proliferation, invasion, angiogenesis and metastases. The principal objective of this study was to assess the prognostic significance of NF-κB and VEGF expression in gastric cancer Methods: The tumor tissues of 154 patients with gastric cancer, all of whom underwent potentially curative resection, were immunohistochemically evaluated using monoclonal antibodies against NF-κB and VEGF. Results: Positivity rates of NF-κB and VEGF were 44.2% and 39.6%, respectively. NF-κB expression in tumor tissues was correlated significantly with VEGF expression (p < 0.001). VEGF expression was related to Lauren’s classification (p = 0.002), differentiation (p = 0.043), depth of invasion (p = 0.005), carcinoembryonic antigen (p = 0.032), and stage (p = 0.026). However, NF-κB expression was not related to any of these parameters. Univariate analysis demonstrated that NF-κB expression was significantly related with both 5-year disease free survival (65.2% vs. 46.4%, p = 0.007), and 5-year overall survival (60.0% vs. 42.5%, p = 0.014). Multivariate analysis verified that NF-κB was independently associated with disease free survival (hazard ratio: 2.082, p = 0.005), and overall survival (hazard ratio: 1.841, p = 0.008). However, VEGF did not appear to be related to adverse clinical outcome. Conclusions: NF-κB expression in tumor tissue is associated with poor survival in gastric cancer patients.
Outcomes in patients (pts) with colorectal cancer (CRC) treated with oxaliplatin-based chemotherapy (OC) following prior oxaliplatin exposure.
Authors: Bhadkamkar Nishin Anil , Sahin Ibrahim Halil , Shen Yehua , Hassabo Hesham Mohamed , Kee Bryan K. , Hassan Manal , Garrett Chris R.
Published: February 2017

500

Background: Pts frequently treated with OC in the adjuvant, perioperative, or first-line setting for CRC may be retreated with oxaliplatin at the time of relapse or progression; the efficacy of retreatment is not known. Methods: Under an IRB-approved protocol, the pharmacy records identified 1,166 pts who received OC for CRC at our institution from 1/1/2004-12/30/2009. Pts were categorized as having previously received OC initially for the indication of adjuvant (group A, n=29), unresectable metastatic disease (group B, n=75), or perioperative therapy for metastasectomy (group C, n =22). Results: Four RECIST responses (14%) were seen in group A (2 of these pts received cetuximab in combination), four responses in group B (5%), and no responses in group C. Retreatment with OC following initial oxaliplatin exposure was associated with a low radiographic and biochemical response rate and a short time to progression or withdrawal of OC (Table). Retreatment duration was limited by cumulative neurotoxicity and allergic reactions (data not presented). Significant activity was observed more frequently when a novel biologic agent was added to the pt's treatment. Conclusions: Retreatment with OC demonstrated minimal clinical efficacy and is limited by cumulative neurotoxicity and hypersensitivity reactions. [Table: see text]
Effect of primary tumor resection on survival in patients with metastatic colorectal cancer in the post-2000 era: A California Cancer Registry analysis.
Authors: Rodriguez Fahrni Ana Milena , Gong I-Yeh , Chen Yingjia , Cress Rosemary , Semrad Thomas John , Khatri Vijay P.
Published: February 2017

504

Background: Resection of primary tumors in the setting of metastatic colorectal cancer (MCRC) is controversial. Fewer primary tumor resections are being performed due to the improved tumor response and disease control rates associated with modern systemic therapy. Recent studies suggest a survival benefit for patients with MCRC who had primary tumors resection prior to systemic therapy. This analysis evaluates the independent prognostic impact of primary tumor resection on overall survival (OS) for patients with MCRC using the California Cancer Registry (CCR). Methods: We queried the CCR for all patients with MCRC diagnosed between 2003 and 2010. Patients were categorized by whether or not they had primary tumor resection at time of diagnosis. Covariates included gender, age, race/ethnicity, socioeconomic status (SES), and rural-urban commuting area (RUCA) score of patients. Univariate comparisons were made using the Kaplan Meier method. Multivariate comparisons were performed using the Cox proportional hazards regression method. Results: 19,836 patients met the criteria for analysis of whom 11,566 (58%) had primary tumor resection. Primary tumor resection rates declined over this time period (63% in 2003 v. 52.8% in 2010, p<0.0001), varied by SES (55% v. 62%: lowest versus highest, p<0.001) and residence (63% in rural versus 58% for urban, P=0.0160). On multivariate analysis, overall survival was significantly better for patients that had primary tumor resection (HR: 0.467 [95% CI: 0.467-0.482]; p<0.0001). Survival was statistically longer in younger patients (HR: 1.385 for age 65-75, HR: 2.217 if greater than age 75), highest SES (HR: 0.869, p<0.0001), Hispanics (HR: 0.884, p<0001), and Asian/Pacific Islanders (HR:0.892, p<0.0001). Overall survival was worse for African Americans (HR:1.105, P=0.0001). Conclusions: Our study demonstrates the independent prognostic value on survival of primary tumor resection in patients with MCRC. There is significant variability of resection rates by SES and rural-urban residence. As analysis of CCR data cannot eliminate the influence of patient and provider biases, a prospective randomized trial is warranted.
Impact of relative dose intensity on the outcome of metastatic colorectal cancer.
Authors: Nakayama Goro , Asada Takahiro , Hayashi Naomi , Tanaka Chie , Yamada Suguru , Fujii Tsutomu , Koike Masahiko , Fujiwara Michitaka , Kodera Yasuhiro
Published: February 2017

508

Background: Relative dose intensity (RDI) is the ratio of delivered dose intensity of chemotherapy to standard dose intensity. There is established evidence supporting the significance of RDI in patients with various cancer, however data in patients with metastatic colorectal cancer (mCRC) are limited. In this study, we evaluate the significance of RDI of irinotecan and oxaliplatin-based chemotherapy on the outcome of mCRC. Methods: A retrospective analysis of mCRC patients entered into two prospective clinical trials, testing FOLFIRI (CCOG-0502) and mFOLFOX6 (CCOG-0704), was performed. RDI was calculated as the delivered dose intensity divided by standard dose intensity calculated for each regimen and compared to objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Results: The median RDI of irinotecan in FOLFIRI and oxaliplatin in mFOLFOX6 were 80% and 79%. ORRs In higher RDI (>median) group and lower RDI (<median) group were 64.7% and 5.9% of irinotecan (p=0.001), and 46.7% and 33.3% of oxaliplatin (p=0.456). DCRs in higher and lower group were 100% and 41.2% in FOLFIRI (p=0.003), and 100 and 73.3% in mFOLFOX6 (p=0.032). PFS in higher and lower group were 9.9 and 5.6 months in FOLFIRI (p=0.002), and 8.5 and 6.2 months in mFOLFOX6 (p=0.064). Conclusions: RDI of key cytotoxic agents is a significant predictor of disease control in patients with mCRC, especially in irinotecan-based regimen. Dose reductions and treatment delays could be minimized to achieve an RDI of at least 80%.
Time from surgery to first adjuvant chemotherapy: Experiences at an inner-city Canadian hospital.
Authors: Marchand Christina , Hassan Maha , Ebrahim Jalal , Bookwala Ammar , Sevick Laura , Ansari Ata , Wong Audrey , Hogeveen Sophie , Nisenbaum Rosane , Topic Delilah Lisa , Brezden-Masley Christine
Published: February 2017

527

Background: Cancer Care Ontario (CCO) guidelines advise that colorectal cancer (CRC) patients receive their first adjuvant chemotherapy (AC) no later than 8 weeks after surgical resection, with new data suggesting optimal treatment to commence between 4 and 6 weeks. This retrospective study was performed to determine treatment timelines and identify barriers at St. Michael’s Hospital (SMH). Methods: Of the 507 patients diagnosed with CRC between Jan 1, 2005 and May 1, 2012 at SMH, 304 patients had stage II or III CRC. Our sample population of 159 patients received both surgical resection and AC at SMH. Data collected included: time between surgery and first AC, patient demographics, systemic/clinical barriers and recurrence-free survival. Data was analyzed using SAS statistical software assuming p-values <0.05 as significant. Results: Of our 159 patients, mean age was 61.3 years (range 28 – 91); 54% male and 70% had stage III disease; colon cancer (64%) and mean follow-up was 2.2 years (range 0.1 – 5.7). Mean time from surgery to first AC was 50.4 days (sd = 15.8) or 7.2 weeks ranging from 3 to almost 17 weeks. Medical complications affected 21.4% of patients. The presence of a complication was associated with delay in AC (9.5 days, p=0.001). Moreover, 11.1% of patients were excluded from sample, since complications exceeded treatment past 12 weeks, equating to no AC. Referral from surgeon averaged 21 days (sd=12.0), 10 days awaiting pathology. Medical Oncology consult to first AC averaged 19 days (sd=12.7), 12 days awaiting port-a-cath insertion. Each part of referral process was correlated with delay to AC. Only 18.9% of patients recurred. While trends were identified, association between delay and recurrence was weak (p=0.1457). Medical complication correlated strongly with recurrence (p=0.0472). Patients with complications had a higher rate of recurrence (32.4% vs 15.2%). Conclusions: Compliance to current CCO guidelines can be optimized in CRC patients at SMH. Barriers to timely treatment include patient age, timely referral and presence of a medical complication. Quality improvement rapid cycling of confounding barriers will be used prospectively to lower variance and achieve greater consistency in treatment.