bluuebunny/crossref_metadata_2025 huggingface dataset:
Biopsy for custom-made treatment: mRNA expression level of cancer-critical genes from gastric/colorectal cancer tissues obtained by endoscopic biopsy.
Authors: Tamura Kazuhiko , Watanabe Takafumi , Enomoto Masanobu , Sudou Hideo , Ogata Jiro , Satou Shigeki , Kataba Yoshiaki , Osaka Yoshiaki , Takagi Yuu , Tsuchida Akihiko , Aoki Tatsuya
Published: February 2017

33

Background: In this study, we measured the mRNA expression level of cancer-critical genes from the gastric/colorectal cancer tissues obtained through endoscopic biopsy before treatments and compared its consistency with the sample tissues surgically resected from identical cases.

Methods: The study was made on 13 gastric and 19 colorectal cancer cases with patients’ consent. We picked identical cases and measured mRNA expression levels from the tissues endoscopically taken before treatment and the surgically resected ones. For the measurement, DNP (DanenbergTumorProfile) method was used. Examination items are as follows: TS, DPD, TP, FPGS, GGH, DHFR, ERCC1, Topo-I, EGFR, and VEGF.

Results: Upon comparing the consistency between endoscopically sampled biopsy tissues and surgically taken tissues from identical cases, it was found that eight out of ten items showed strong correlations in colorectal cancer cases. The results are as follows: FPGS(r=0.91, p<0.001); GGH(r=0.87, p<0.001); EGFR(r=0.86, p<0.001); Topo I (r=0.81, p<0.001); TS(r=0.79, p<0.001); DHFR(r=0.70, p<0.01); VEGF(r=0.67, p<0.01); and TP(r=0.62, p<0.05). In case of gastric cancers, strong correlations were found in three out of ten items with the following results: EGFR (r=0.98, p<0.001); TS (r=0.91, p<0.001; and DPD (r=0.74, p<0.05).

Conclusions: Today’s progresses of preoperative chemotherapy and radiotherapy and developments of endoscopic and surgical treatments allow diverse options for treatments. In such circumstances, the significance of knowing the expression of cancer-critical genes between individuals before treatment in conducting custom-made treatment is profound. There are two issues in applying the expression of cancer-critical genes found through endoscopic biopsy: one is whether enough cancer cells can be obtained through biopsy, and the other is whether the sampled cancer cells reflect the characteristics of primary focus. While there remain issues to be addressed, certain results were achieved in this study. Currently, we are working on accumulating cases to compare them and find out whether the results can be applied to custom-made treatments.
Quality of life and acute radiation toxicity following hypofractionated stereotactic body radiation therapy with concurrent full-dose gemcitabine for unresectable pancreatic adenocarcinoma.
Authors: Gurka Marie Kate , Tse Gary , Unger Keith Robert , Haddad Nadim G , Marshall John , Johnson Colin , Ley Lisa , Slack Rebecca , Pishvaian Michael J. , Collins Sean Patrick
Published: February 2017

336

Background: Quality of life (QoL) is of paramount importance when cure is not obtainable. The aim of this study is to report QoL outcomes and acute radiation toxicity in patients with pancreatic cancer treated with stereotactic body radiation therapy (SBRT) and concurrent gemcitabine.

Methods: This prospective study reviewed the charts of 10 patients with locally advanced, unresectable pancreatic cancer treated with SBRT and 6 cycles of gemcitabine. The primary tumor and adjacent para-aortic nodes received a total dose of 2500 cGy in 500 cGy fractions on consecutive days between cycles 1 and 2 of gemcitabine. QoL was assessed on the 1st day of each cycle using the EORTC QLQ-C30 and EORTC QLQ-PAN26 questionnaires. Wilcoxon rank sum test was used to determine statistical significance between QoL scores. Toxicity was graded by NCI Common Terminology Criteria for Adverse Events, Version 3.0.

Results: The median age was 62.5 years. All patients completed the prescribed SBRT. Median overall survival was 13 months (range 5- 17). QoL scores at baseline compared to immediately after SBRT showed an increase in the following symptoms: fatigue, nausea/vomiting (N/V) and anorexia, which were statistically significant (P < 0.05). These were not statistically different from baseline by cycle 3 except N/V. No symptoms were significantly improved after radiation therapy; however, there was a trend towards improvement in back pain, night pain and abdominal discomfort. Functional scales declined after treatment, but not significantly. Global QoL did not significantly change from baseline. There were no grade 3 or 4 acute toxicities related to SBRT.

Conclusions: Hypofractionated SBRT with concurrent gemcitabine is feasible for locally advanced, unresectable pancreatic cancer. There is a temporary increase in selected symptoms due to radiation which resolve within one month. This may be an improvement compared to conventional fractionated radiation due to shorter duration of symptoms related to radiation treatment.
Alteration of the epigenome during carcinogenesis of intestinal-type gastric cancer.
Authors: Kim Yong Sung , KIM Hee-Jin , Haam Keeok , Kang Tae-Wook , Kim Seon-Young , Kim Mirang , Noh Seung-Moo , Song Kyu-Sang , Maley Carlo
Published: February 2017

34

Background:
Next-generation sequencing (NGS) is opening a new era for understanding how the human genome is altered in the process of cancer development. We sought to establish an epigenome map based on the DNA methylome during gastric carcinogenesis, paving the way to a better understanding of the origins of gastric cancer using NGS-based epigenome analysis.

Methods:
We purified DNA in laser-capture microdissected (LCM) cells of normal mucosa, intestinal metaplasia (IM), and gastric cancer from frozen samples of one patient with intestinal type gastric tumor. Two NGS-based epigenome analyses were performed on each DNA: ‘MBD-seq’ (methylated DNA binding domain sequencing) and ‘RRBS’ (reduced representation bisulfite sequencing).

Results:
MBD-seq and RRBS generated ~25.7 million and ~15.1 million reads respectively, per lane on average. The sequence data matched with 79% (21,514/27,191) and 55% (14,991/27,191) of promoter sequences from UCSC genome browser, respectively. We then identified about one thousand differentially methylated promoters (DMPs), which were altered in IM and in gastric cancer or in gastric cancer compared to that of gastric mucosa. In particular, hypomethylation was detected in 30 promoters by MBD-seq and 173 by RRBS, indicating that RRBS is highly informative for identifying hypomethylated DMPs associated with gene activation during carcinogenesis.

Conclusions:
We identified several novel hyper- or hypomethylated biomarkers for IM or gastric cancer using NGS-based epigenome analysis. Our reference epigenome map may provide a foundation for future studies exploring the prognostic or preventive biomarker for early stage of gastric cancer.
90Y radioembolization for neuroendocrine cancers liver metastases provides sustained therapeutic effect with minimal toxicity.
Authors: Kennedy Andrew S. , Elkordy Maha , Campbell Elizabeth Estill , Albertson Brent , Sailer Scott Lee , Deutsch Margaret Ann
Published: February 2017

343

Background: Radioembolization (RE) is the delivery of radioactive microspheres (90Y) via the hepatic artery, which permanently implant preferentially in metastatic lesions, sparing adjacent normal liver. Metastatic neuroendocrine tumors in the liver are a common clinical problem which can be treated with RE. It is an outpatient procedure performed with increasing frequency worldwide for a variety of solid tumor types.

Methods: A single institution retrospective review of all neuroendocrine patients treated with radioactive resin microspheres to control hepatic metastases. Details reviewed included: specifics of treatment and delivery, RECIST response at 3 and 6 months, acute and delayed radiation toxicities by CTC3ae, and analyses of tumor and radiation factors related to response and liver control.

Results: A total of 56 patients; 26 male, 30 female, received a total of 85 separate treatments with resin 90Y microspheres. Treatment volume was all hepatic tumors with each treatment, usually selective whole liver in one fraction. Whole liver in 1 treatment comprised 86%, right lobe only in 10% and left lobe in 4%. Thirty-six patients (64.3%) received 1 treatment, 12 patients 2 fractions, 7 patients 3 fractions, and 1 patient 4 fractions. The median activity of 90Y delivered was 1.49 GBq (0.35 – 2.9 GBq). BSA approach was used for pretreatment activity calculations for all patients, with median of 100% planned activity delivered (26% - 147%). No grade 4 toxicities occurred, and only two grade 3 events were found (gastric ulcers). The median follow up is 24.2 mo. (1 – 93.4 mo.). RECIST at 3 and 6 months: CR 6.5%, SD 49.1%, PR 42.6% and PD 1.6%. Delivered activity (GBq) was associated with PR at 3 months (p=0.07, two-tailed t-test).

Conclusions: Our experience is consistent with other published reports confirming the efficacy and low toxicity of this liver-directed ablative approach for unresectable neuroendocrine carcinomas. Multiple treatments to the whole liver were well tolerated. The BSA method of pretreatment radioactivity estimation is useful and safe in this tumor type.
Predicting survival in resected pancreatic cancer: A Canadian provincial experience.
Authors: Gresham Gillian , Ng Sylvia , Chang Anderson , Valdez Shannon , Gill Sharlene
Published: February 2017

361

Background: Surgical resection offers the only hope for long-term disease control in patients (pts) with pancreatic adenocarcinoma. Randomized trials (ESPAC 1, ESPAC3) further support a role for adjuvant chemotherapy (AC) in the management of pancreatic cancer (PC). Trial outcomes may not reflect clinical reality due to pt selection bias, and it is often difficult to predict which pts are most likely to benefit from adjuvant intervention.

Methods: Consecutive pts between 2003 and 2008 referred to the BC Cancer Agency (BCCA) with operative intent at diagnosis (dx) were retrospectively reviewed.

Results: 145 pts were identified; median age 65 years (y) (range 38-84), male/female (45.5%, 54.5%). EUS/PET staging was performed in 21% of pts. Median CA19-9 value at dx was 210 ku/L. Pancreaticoduodenectomy was performed in 65% of pts. Complete resection (RO) of tumours occurred in 87 pts (60%) overall. 66% of pts were node positive. 43% of pts were subsequently treated with adjuvant therapy (AT) where 5% of these pts received chemoradiotherapy and 95% received AC (65% gemcitabine). There was no statistically significant difference in either OS (p=0.39) or DFS (p=0.28) amongst resected pts who were treated by sx alone versus pts who received AC. In subgroup analysis, AC was associated with significantly improved OS in pts (n=58) with positive margins (R1) (median 17.3 mos vs 8.9 mos, p=0.0045) but benefit was not seen in R0 pts (n=87) (22.9 mos vs 22.4 mos, p=0.20). In multivariate analysis, poor performance status (ECOG 3-4), weight loss of more than 10% of initial body weight, baseline CA19-9 value greater than 210 ku/L, positive nodes, R1 status and histological grade 3-4 were significant adverse prognostic factors.

Conclusions: PC continues to have poor outcomes with a 5yOS of 5% in pts treated with sx alone. Among pts with resectable PC treated at the BCCA, AC tended towards increased DFS and OS. Although R1 status was associated with inferior OS, the benefit of AT was greater in this subgroup.

[Table: see text]
Comparison of the efficacy between the gemcitabine/cisplatin (GP) and capecitabine/cisplatin (XP) for the advanced biliary tract cancer: Retrospective analysis in a single institution.
Authors: Lee Ji Eun , Lee Myung Ah , Hong Tae Ho , Lee In Seok , You Young Kyoung
Published: February 2017

365

Background: Bile duct cancers (BTC) are known to be the chemotherapy resistant cancer, and more common in old-age group. Gemcitabine and cisplatin (GP) has been widely used as first line treatment for unresectable BTC. Capecitabine and cisplatin (XP) combination chemotherapy has been also used as another option treatment. We retrospectively compared the efficacy of GP and XP for advanced BTC.

Methods: Between Jan, 2009 and Jun, 2011, Fifty five patients who were diagnosed with unresectable BTC at Seoul St. Mary’s hospital were enrolled for analysis of the efficacy in the present study. All the patients had recurrent disease or metastatic cancer, confirmed by histologically adenocarcima. In GP group, gemcitabine was given with 1,000mg/m2, I.V for 30min on d1 and d8, and cisplatin was injected with 75mg/m2, d1, repeated every 21 days. In XP group, capecitabine was administered by orally 2,000mg/m2, divided dose d1-14, and cisplatin was administerd with 75mg/m2, d1, repeated every 21 days. Response evaluation with CT scan was taken after 2 cycles.

Results: Of the 55 patients enrolled, 28 patients were treated with GP and 27 patients were treated with XP. Median age was 69 years old in GP, 65 years old in XP. Median number of cycle was 2.5 in both groups. There was no difference in patients’ characteristics between two groups in terms of sex, age, number of cycle and disease status. In analysis of the response rate, Partial response rate was 38.5% in XP, and 7.1% in GP, and stable disease was achieved in 23.1% in XP, 42.9% in GP (p=0.004). Median time to progression was 2.0 mon in GP, and 4 mon in XP (P=0.147). However, median survival time was 6 months vs. 4. 3months in GP and XP, respectively (p=0.510). There was no difference in toxicity between two groups.

Conclusions: GP and XP showed similar clinical outcome, such as TTP or OS, although XP had significantly better response rate. These two regimens had modest activity, but not effective in terms of TTP or OS. Median number of cycles was only 2.5 in both groups because most patients were over 65 years old, and had poor performance status. Development of new effective regimens in advanced BTC should be warranted.
Patient-reported symptoms from patients with advanced pancreatic cancer undergoing gemcitabine-based chemotherapy.
Authors: Wang Xin Shelley , Fogelman David R. , Shi Qiuling , Eng Cathy , Bokhari Raza H , Huang Furong , Mobley Gary M. , Gilmore Katherine R. , Cleeland Charles S.
Published: February 2017

370

Background: The symptoms reported by patients being treated for advanced pancreatic cancer (PC) could be driven by disease and treatment. Few clinical studies have addressed the interaction between disease, treatment, and symptom burden. We conducted a longitudinal study tracking multiple symptoms to provide an evidence-based symptom profile for patients with advanced PC receiving gemcitabine-based chemotherapy.

Methods: From start of the first chemotherapy cycle (baseline), patients rated symptoms weekly during chemotherapy via the M. D. Anderson Symptom Inventory (MDASI), then continued symptom assessment every two weeks for up to 40 weeks. Longitudinal symptom responses were analyzed by mixed-effect modeling.

Results: Among 100 PC patients enrolled, 87% were treatment-naïve. The median age was 65 yrs old (range 35-85). Half of the sample was female; 32% received opioids for severe pain. The three most severe MDASI symptoms at baseline were fatigue, lack of appetite, and pain. Poor performance status and opioid use were significantly related to severity of these baseline symptoms (all P<.05%). The marginal means of severity for these three symptoms were significantly higher over time in patients who discontinued therapy < 9 weeks, compared with those who remained on study for 26-40 weeks (fatigue, P=.028; lack of appetite, P=.012; pain, P<.0001). Over time, lack of appetite improved significantly (P=.039), while pain and fatigue tended to worsen (P=NS). Compared with patients who remained on study, patients discontinued treatment earlier had significantly worse baseline pain (P=.005) and a non-significant trend towards greater fatigue and lack of appetite.

Conclusions: Our results suggest that standard gemcitabine-based chemotherapy plus active palliative care for advanced PC was associated with significant improvement in appetite. However, worsening fatigue suggests a need to provide active intervention to minimize this symptom for PC patients. Patients suffering from greater symptom burden at baseline and overtime, seems consistent with greater disease burden, may be expected to discontinue treatment earlier.
Treatment and characteristics of patients treated for hepatocellular carcinoma (HCC) by physician types in the United States.
Authors: Seal Brian S. , Foltz Boklage Susan H , Asche Carl V
Published: February 2017

375

Background: This study provides a description of the characteristics of patients treated for HCC and how they differ in terms of those treated by 1 type of physician vs. those treated by ≥ 2 physicians.

Methods: This was a longitudinal, retrospective analysis of claims from the Thomson Reuters MarketScan database for patients treated for incident HCC. The patients were selected based upon those being treated for malignant neoplasm’s of the liver as their primary diagnosis (ICD-9 code 155.00) and they were required to have continuous eligibility around their initial liver cancer incidence data for 6 months prior and ≥ 12 months subsequent to treatment. Excluded were those having evidence of HCC and any other type of tumor in the prior 6 months. The study period was from 01/01/2006 until 06/30/2010. Descriptive analysis was used to draw comparisons between patients seen by 1 vs. ≥ 2 specialists.

Results: 967 patients were analyzed, of whom 631were seen by 1 and 336 were seen by ≥2 physicians. The groups were similar except for age (75.8% of 1 physician were aged 45 to 64 years vs. 89.9% ≥ 2 physicians), gender (55.8% males for the 1 vs. 75.3% ≥2 physicians), not having Hepatitis C (75.4% in the 1 vs. 57.4% ≥2 physicians), not having Cirrhosis (70.4% in the 1 vs. 56.3% ≥2 physicians), not having other diseases of the liver (56.6% in the 1 vs. 47.6% ≥2 physicians), not having chemotherapy (92.6% in the 1 vs. 71.4% ≥2 physicians), not having TAE (86.2% in the 1 vs. 60.7% ≥2 physicians), not having ablation (95.3% in the 1 vs. 84.2% ≥2 physicians), and not having resection (93.3% in the 1 vs. 84.2% ≥2 physicians). The top physicians consulted were: Internal Medicine (16.3%); Medical Doctor (16.03%); Gastroenterology (14.37%); Multispecialty Physician Group (13.65%); Oncology/Hematology (13.35%); Family Practice (9.41%); and Surgeon (7.86%).

Conclusions: It was found that the HCC patients treated by 1 vs. ≥ 2 physicians were younger, predominantly female [Odds Ratio (OR) of 1.977], less likely to have Hepatitis C (OR of 0.649], and less likely to have ≥ 1 selected treatment (OR of 0.224). The patients were seen by Internal Medicine, General Medical, Multispecialty Groups, and Family Practice more often than Oncologists.
Capecitabine plus oxaliplatin (XELOX) versus bolus 5-fluorouracil/leucovorin (5-FU/LV) as adjuvant therapy for stage III colon cancer: Survival follow-up of study NO16968 (XELOXA).
Authors: Schmoll Hans-Joachim , Tabernero Josep , Maroun Jean Alfred , De Braud Filippo G. , Price Timothy Jay , Van Cutsem Eric , Hill Mark , Hoersch Silke , Rittweger Karen , Haller Daniel G.
Published: February 2017

388

Background: The MOSAIC trial demonstrated that adding oxaliplatin to 5-FU/LV (FOLFOX4) improved 3-year disease-free survival (DFS) compared to infusional and bolus 5-FU/LV as adjuvant therapy in patients (pts) with stage II/III colon cancer [André et al. NEJM 2004]. A significant survival advantage for FOLFOX4 versus 5-FU/LV was not evident until after median duration of follow-up had exceeded 6 years [André et al. JCO 2009]. Study NO16968 demonstrated that XELOX was superior to bolus 5-FU/LV as adjuvant therapy in pts with stage III colon cancer in terms of DFS at 57 months median follow-up (HR 0.80; 95% CI 0.69–0.93; p=0.0045) [Haller et al. JCO 2011]. The difference between treatment groups in overall survival (OS) was not significant at 59 months median follow-up (HR=0.87; p=0.1486). Data from the planned final analysis of NO16968 are presented.

Methods: Pts with resected stage III colon cancer were randomized to receive XELOX (8 cycles, 24w) or bolus 5-FU/LV (Mayo Clinic, 6 cycles; 24w or Roswell Park, 4 cycles; 32w). The primary study endpoint was DFS. Secondary endpoints included OS.

Results: The ITT population included 1886 pts (XELOX, n=944; 5-FU/LV, n=942). After a median follow-up of 74 months, the HR (XELOX vs 5-FU/LV) for DFS was 0.80 (95% CI 0.69–0.93; p=0.0038). Seven-year DFS rates were 63% for XELOX and 56% for 5-FU/LV. After a median follow-up of 83 months, the HR for OS was 0.83 (95% CI 0.70–0.99; p=0.0367). Absolute 7-year OS rates were 73% with XELOX and 67% with 5-FU/LV. After adjusting for stratification and prognostic variables, HRs remained essentially unchanged for both DFS (0.79; 95% CI 0.68–0.91; p=0.0016) and OS (0.84; 95% CI 0.71–1.00; p=0.0477). Locoregional / systemic treatments after recurrence were given in 230 (24%) XELOX pts and 308 (33%) 5-FU/LV pts.

Conclusions: The combination of oxaliplatin and capecitabine improves OS significantly compared with 5-FU/LV in the adjuvant treatment of stage III colon cancer after a median follow-up of 83 months; these data are comparable to those achieved with FOLFOX4 in the MOSAIC trial. XELOX is an effective adjuvant therapy option for pts with resected stage III colon cancer.
Update of AMC 0101 study: A phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf) as adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer (NCT00296322).
Authors: Kang Yoon-Koo , Ryoo Baek-Yeol , Chang Heung-Moon , Zang Dae Young , Kim Tae Won , Yang Dae Hyun , Jang Se Jin , Yook Jeong Hwan , Oh Sung Tae , Kim Byung Sik
Published: February 2017

4

Background: To improve the adjuvant chemotherapy in serosa-involving AGC, we adopted intraperitoneal and early start of chemotherapy, as well as prolongation of fluoropyrimidine and addition of cisplatin (P) to Mf regimen. The primary efficacy results of AMC0101 study on 3y relapse free survival rate (RFSR) were presented in 2008 ASCO. Now, we update the results with longer follow up.

Methods: Pts with serosa-positive AGC who underwent curative resection were randomized to receive either Mf or iceMFP. Pts with postoperative stage I or IV (M1) were excluded. For Mf, 20 mg/m2 of mitomycin-C (M) was injected 3-6 wks after surgery and 4 wks later, 460-600 mg/m2/day of doxifluridine was administered orally for 3 months. For iceMFP, 100 mg of P was administered intraperitoneally for 2 h during surgery and 15 mg/m2 of M was injected 1 day after surgery. Doxifluridine was started 4 wks after surgery and extended for a total of 12 months and 6 shots of monthly 60 mg/m2 of P were added.

Results: Between Oct 2001 and Apr 2007, 640 pts were randomized (318 in Mf, 322 in iceMFP). One hundred and nineteen pts (60 in Mf, 59 in iceMFP) were excluded (postoperative stage I in 90, M1 in 13, positive resection margin in 10, and others in 6). Therefore, a total of 521 pts (258 in Mf, 263 in iceMFP) were eligible for intent-to-treat analysis. Postoperative stages were II in 33.4%, IIIA in 31.9%, IIIB in 17.5%, and IV in 17.3% of pts. As of April 2011, with a median follow-up of 6.6 years, iceMFP group had a significantly longer RFS (HR, 0.73; 95% C.I. 0.57 - 0.93; p=0.0092) and overall survival (HR, 0.77; 95% C.I. 0.60 - 0.98; p=0.0365) than Mf group.

Conclusions: We could confirm with longer follow up that benefit in 3y RFSR from iceMFP could be translated into benefit in 5y OSR. Considering no benefit of adding cisplatin and prolongation of doxifluridine to Mf chemotherapy in curatively resected AGC pts (AMC 0201), intraperitoneal cisplatin and/or early start of chemotherapy seemed to be responsible for the improved efficacy of iceMFP chemotherapy in this study.
Elevated CEA level in the asymptomatic patient with normal conventional imaging: How useful is PET-CT for the detection of colorectal cancer recurrence?
Authors: Aitken Katharine , Barbachano Yolanda , Sharma Bhupinder , Cunningham David , Cook Gary , Rao Sheela
Published: February 2017

400

Background: Serum carcinoembryonic antigen (CEA) level can be used as a sensitive marker of recurrence in the follow up of patients with colorectal carcinoma, enabling the early detection of recurrent disease at a stage where further curative therapy may be possible. However a subset of patients with asymptomatic elevated CEA levels will have no evidence of disease recurrence on conventional imaging (CI). Aim: The purpose of this study was to evaluate the utility of 18F-FDG PET CT in detecting occult disease recurrence where CI has failed to demonstrate a cause for a rise in CEA.

Methods: 88 consecutive patients on surveillance following treatment for colorectal cancer with an elevation in CEA level (>3ng/ml non-smokers, >5ng/ml smokers) with normal (67) or equivocal (21) findings on conventional imaging (defined as CT+/-MRI, ultrasound or colonoscopy) who had undergone PET-CT between 01.01.2004 and 31.08.2010 were retrospectively identified. Histopathological confirmation or a minimum of 12 months of follow up were used to ascertain disease relapse. Eligibility for further curative treatment was established from clinical notes.

Results: Recurrent disease was detected in 56/88 patients (prevalence 64%). The sensitivity of PET-CT to detect recurrence was 49/56 (88%, 95% CI 76-94) and specificity 28/32 (88%, 95% CI 72-95). The positive predictive value (PPV) and negative predictive value (NPV) for recurrence was 93% and 80% respectively. Sensitivity in subgroups with CEA levels 3-6, 6-10 and > 10ng/ml were 91%, 82% and 89% respectively. 27 out of 49 patients (55%) with relapsed disease were eligible for further curative therapy and 26 received treatment with curative intent. The commonest site for PET detected disease relapse was the liver (16/49, 33%).

Conclusions: PET-CT is a highly sensitive and specific tool for the detection of occult colorectal cancer recurrence in patients with raised CEA and normal CI thus should be considered mandatory in this setting. In over 50% of patients the recurrent disease detected before CI is positive, is still amenable for curative therapy.
Helicobacter pylori infection and the risk of colorectal cancer: A meta-analysis of epidemiologic evidence.
Authors: Njei Basile M. , Ditah Ivo C. , Appiah Juliet , Jinjuvadia Raxitkumar , Birk John W.
Published: February 2017

408

Background: The association between Helicobacter pylori infection (HPI) and gastric cancer is well known, but it is unclear whether HPI is also a risk factor for colorectal cancer. Several epidemiological studies on the latter association have yielded conflicting results. The aim of this study is to summarize available evidence on the association between HPI and CRC, evaluating its magnitude and direction in a meta-analysis.

Methods: Two reviewers independently conducted a systemic search on Medline, OvidSP and PubMed databases from January 1980 to July 2011 for studies on the association between HPI and CRC. The reference lists of eligible studies were next reviewed for additional studies on the subject. Firstly, a combined analysis including all studies was done. Next, subgroup analysis by study design and country of study (USA Vs Europe Vs Asia) were also performed. All analyses were done using the random effects model. Publication bias was assessed using the Begg’s and Egger’s tests and visual inspection of funnel plot. All analyses were performed using STATA 11.

Results: Sixteen studies (14 retrospective and 2 prospective) including 12,892 participants were included in the analysis. Overall, HP was associated with a 49% significantly higher risk of CRC (OR 1.49, 95% CI: 1.22-1.82; P < 0.001). By study design, the association persisted only among the retrospective studies with a pooled OR of 1.43 (95% CI: 1.31-1.56, P = 0.004). The subgroup analysis by study region showed significant associations in Europe (OR 1.35, 95% CI 1.09-1.66) and Asia (RR 1.43, 95% CI 1.29-1.58). Though there was a 17% higher risk noted among studies done in the USA, this was not statistically significant. There was no evidence of publication bias in all the analyses.

Conclusions: Current evidence on the association between H. pylori infection and CRC remains inconclusive. The absence of any association among the prospective studies (with less risk of bias) suggests that the association seen among the retrospective studies could be due to residual confounding. Better quality data is required before a conclusive statement on the association between HPI and CRC can be made.
Detection of hereditary nonpolyposis colorectal cancer (HNPCC) in non-Caucasian patients.
Authors: Russell Maria C. , Rodriguez-Bigas Miguel A. , Chang George J. , Skibber John Michael , Feig Barry W. , You Y. Nancy
Published: February 2017

417

Background: HNPCC is the most common hereditary colorectal cancer (CRC) syndrome. Its characterization has been limited to Caucasians in Europe or North America, and non-Caucasians in their countries of descent. Little is known about HNPCC in ethnically diverse patients in the U.S.

Methods: Patients whose self-reported ethnicity was not Caucasian and who were the probands in their families to undergo germline testing (GT) for DNA mismatch repair (MMR) genes between 1998 and 2011 were identified. Tumor microsatellite (MSI) testing was informative if immunohistochemistry (IHC) showed MMR protein loss of expression, and/or if PCR-based MSI testing showed >30% markers shifted. Tumor studies guided further GT.

Results: Fifty-eight unrelated probands (female, 53.4%) included 19 (32.8%) who were Hispanic, 18 (31.0%) African-American, 18 (31.0%) Asian, and 3 (5.2%) Arabic/Other. Amsterdam I, II and revised Bethesda criteria were satisfied in 9 (15.5%), 14 (24.1%) and 43 (74.1%) respectively. They were affected by 106 malignancies, most commonly: CRC (73.9%), endometrial (10.9%), small bowel (5.4%) and skin (sebaceous neoplasm, 3.3%). The CRCs arose from proximal colon (51.5%), distal colon (25%), rectum (16.2%) or multifocal/other (7.4%), at a median age of 46 (IQR: 38-55). PCR-MSI results were concordant with abnormal IHC, although less for MSH6 and PMS2. In GT, pathogenic mutations were detected in only a minority of patients ( Table ).

Conclusions: Ethnically diverse patients with informative tumor MSI results exhibited low rates of detectable pathogenic mutations. Caution should be exercised when GT is utilized to detect HNPCC in the absence of tumor studies as patients to be managed as HNPCC may be missed.

[Table: see text]
The effect of insurance status on the stage of colorectal cancer at diagnosis.
Authors: Greenbaum Arieh , Singhal Vinay , Cosgrove John Morgan , Farkas Daniel T
Published: February 2017

420

Background: There is currently a lot of focus on the number of uninsured patients in the country. Part of the recent healthcare debate revolved around the lack of preventative medicine and screening in such patients. The assumption is that patients without insurance present to hospitals with later stages of disease. The purpose of this study was to evaluate patients with colorectal cancer, and to see if their insurance status was related to the stage of their cancer at diagnosis.

Methods: All patients in our tumor registry with a diagnosis of colorectal cancer between 2000 and 2010 were initially included. Those who did not have their complete care in our hospital, or those for whom insurance information was not available, were excluded. Patients were categorized into insured and uninsured patients. Cancer staging at the time of diagnosis was done according to the American Joint Committee on Cancer guidelines, and patients with stage 3 or 4 disease were classified as having advanced cancer.

Results: There were 489 patients in the tumor registry for these ten years, of which 435 had their care in our hospital and were fully staged. Insurance information was available for 383 patients (88%). There were 360 patients (94.0%) in the insured group and 23 patients (6.0%) in the uninsured. In the insured group there were 128 patients (33.4%) with advanced cancer, while in the uninsured group there were 15 patients (65.2%). This difference was highly significant (Chi-square, p=0.007).

Conclusions: Patients without insurance present with more advanced stages of colorectal cancer. In our series, uninsured patients were almost twice as likely to present with stage 3 or 4 disease. Efforts at helping more patients gain access to healthcare insurance could perhaps lead to fewer people presenting with advanced stages of cancer.
Validation of a plasma-based miRNA PCR test for early detection of colorectal cancer.
Authors: Nielsen Søren Jensby , Willenbrock Hanni , Fog Jacob , Stenvang Jan , Blondal Thorarinn , Orntoft Torben , Brünner Nils , Andersen Claus Lindbjerg , Nielsen Hans J. , Baker Adam
Published: February 2017

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Background: Colorectal cancer (CRC) is a major cause of mortality in the western world. Early detection of CRC improves survival and screening for CRC has been clinically proven to lower CRC-related mortality in the screening population. However, although population screening programs have been implemented in a number of countries, screening rates among the 50-75 year olds are unsatisfactory. There is therefore a clear unmet need for a quick, sensitive, specific, and minimally invasive screening assay to select at risk individuals for definitive diagnosis by colonoscopy.

Methods: In order to detect microRNA (miRNA) biomarkers for CRC in blood plasma, we developed an LNA-enhanced miRNA RT-qPCR platform with high sensitivity and linearity for optimal quantitation of miRNAs from limited plasma samples. A clinical reference- lab compatible workflow that allows for the entire procedure from sample preparation through data acquisition and QC to test result to be completed within one working day was established. A reference melting curve database has been implemented to ensure the integrity of each data point, and appropriate controls monitor plate-to-plate and day-to-day variation. State-of-the-art normalization protocols have been evaluated to ensure optimal normalization of datasets prior to data analysis.

Results: We previously determined a miRNA signature in a multi hospital discovery cohort that is differentially expressed between healthy individuals and stage II CRC patients. Here we report on the validation of this miRNA signature in an independent set of plasma samples from CRC patients and healthy volunteers. We have counter-screened the miRNA signature in a set of patients with other prevalent diseases, including hypertension, diabetes, diverticulitis, and others.

Conclusions: A plasma miRNA signature for early detection of CRC from patient plasma was developed and validated in an independent clinical sample set. The signature was specific with respect to other diseases prevalent in the screening population. A second large-scale validation project is on-going. We conclude that plasma miRNA biomarkers can constitute an effective minimally invasive approach to population-wide CRC screening.
Determina KRAS: A consolidated project.
Authors: Garcia-Foncillas Jesus
Published: February 2017

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Background: The identification of KRAS mutation status as a predictive biomarker for the activity of anti-EGFR in mCRC patients, was the start of the personalize medicine. ASCO recognized it as a major advance in 2008 and it also gave a clinical opinion so every candidate for anti-EGFR therapy should be tested for KRAS mutations. NCCN guidelines recommends to do it at the first diagnose of metastatic disease. KRAS status testing was no widely available in Spain by 2008. The project Determina KRAS was developed in order to provide access to this test throughout the country to any mCRC patient.

Methods: Five well known Spanish centres were trained and provided with equipment so they could analyze KRAS status in a five working day period. First centre was initiated in July 2008, being the last one in October 2008. A validated KRAS mutation kit (DxS Ltd, Manchester, UK) which identifies 7 different somatic mutations located in codons 12 and 13 using allele-specific real-time polymerase chain reaction was used.

Results: 15.330 samples from mCRC patients have been analyzed since July 2008. 53,7% samples showed wild type KRAS status. G12D mutation was the most frequent mutation observed in general (35,1% of all mutation). G13D mutation was the most frequent of the codon 13 mutation, with a 20,2% of the global mutations.

Conclusions: KRAS status testing allows to patients with mCRC receive a personalized medicine. KRAS status testing is essencial for treatment decision-making in mCRC and access to it must be guaranteed for any patient. The determination of biomarkers to choose the most effective treatment for each patient will be the future of oncology. These futures assessments must be available for all patients through national Networks, as the Determina KRAS project has made with KRAS testing.
Randomized clinical trial of preoperative chemoradiotherapy by S-1 versus UFT to rectal cancer for personalized therapy.
Authors: Miyatani Tomohiko , Utsunomiya Toru , Kurita Nobuhiro , Iwata Takashi , Sato Hirohiko , Nishioka Masanori , Morimoto Shinya , Yoshikawa Kozo , Higashijima Jun , Kashihara Hideya , Mikami Chie , Shimada Mitsuo
Published: February 2017

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Background: Preoperative chemoradiotherapy (CRT) in rectal cancer reduces the local recurrence rate after operation and preserves the anus, but it is difficult to predict the effects of CRT. Our purpose of this study was to determine the effects and adverse events of CRT (S-1 or UFT) and to predict the response to CRT in rectal cancer by using both miRNA and DNA expression patterns.

Methods: Rectal cancer patients (n=60) who underwent preoperative CRT were randomly divided into two groups (40Gy radiotherapy combined with S-1: 31 patients or UFT: 29 patients). The effects and adverse events of CRT were compared between S-1 group and UFT group. Additionally, RNA and DNA isolated from biopsy specimens of rectal cancer before preoperative CRT were hybridized to miRNA and DNA microarrays. Response to CRT was determined by histopathologic examination of surgically resected specimens.

Results: Response to CRT determined by histopathologic examination of surgically resected specimens and RECIST were as follows: responders (grade 2 or 3) were 60%(S-1) and 52%(UFT) (p=0.52). Adverse events of CRT did not differ significantly between the 2 groups, and there was no adverse event of grade 3 or 4. As candidate predictive genes, 184 genes (S-1 group) and 193 genes (UFT group) were identified by DNA microarray, while 6 miRNA (S-1 group) and 16 miRNA (UFT group) were isolated by miRNA microarray as candidate predictive miRNA.

Conclusions: Preoperative CRT using S-1 or UFT to rectal cancer is effective and the adverse events were acceptable. Expression profiling of both gene and miRNA may predict the effects of preoperative CRT, implicating the possible personalized therapy for patients with rectal cancer.
CT imaging interval after complete cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (HIPEC) for well-differentiated adenocarcinoma of the appendix (WDAA).
Authors: Beaty Karen A. , Hill Joshua S. , Rafeeq Safia , Overman Michael J. , Sagebiel Tara L. , Matamoros Aurelio , Royal Richard E. , Mansfield Paul F. , Fournier Keith F.
Published: February 2017

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Background: WDAA with peritoneal dissemination (PD) is a rare disease with a prognosis related to the ability to perform adequate cytoreductive surgery (CRS) with cytoreductive scores of 0 or 1 (CC0 or CC1) followed by HIPEC. Diagnostic imaging is an important aspect of post-operative surveillance. Often, surveillance imaging follows metastatic colon cancer guidelines with frequent CT scans performed during the first 5 years after resection (every 3 months for 2 years, then every 6 months). Minimal evidence-based data exists to direct recommendations regarding optimal imaging intervals in patients with WDAA.

Methods: All patients with a pathologic diagnosis of WDAA with PD who were evaluated at a single institution between August 1993 and January 2010 were retrospectively reviewed to identify patients who underwent a CC0 CRS and HIPEC. Parameters evaluated included demographics, time to recurrence and time to intervention after recurrence. Disease free survival was calculated using the Kaplan-Meier method.

Results: 688 patients were evaluated during the study period. 67 patients (9.7%) had WDAA and underwent CC0 CRS/HIPEC. The mean age at diagnosis was 54.8 years. Twenty-two (32%) were male. Mean follow-up was 50.4 months. Disease free survival of the entire cohort at 10 yrs was 72 %. Eleven patients (16 %) experienced a recurrence. Median time to recurrence was 18.2 months. After recurrence, mean time to intervention was 6 months. In those patients that recurred, only 3 patients underwent intervention within 24 months of the index CRS/HIPEC (4% of overall cohort). Recurrence after 36 months occurred in only one patient (1.5% of cohort).

Conclusions: Patients with WDAA/PD who undergo CC0 CRS/HIPEC have an overall very favorable prognosis and low risk of recurrence. Surveillance imaging, as often done for colorectal cancer, every 3-4 months is inappropriate. For this group of patients, follow-up CT scans every 6 months for 2 years, and then annually is recommended.
Neutrophil to lymphocyte ratios and pathologic response to neoadjuvant therapy in esophageal cancer.
Authors: Bronson Nathan W. , Luna Renato , Bloker Lisa M. , Douthit Miriam A. , Diggs Brian S. , Dolan James P. , Hunter John G.
Published: February 2017

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Background: Esophageal cancer (EC) is increasing in incidence dramatically, and is associated with suboptimal outcomes despite the widespread adoption of neoadjuvant multimodality therapy (NAT) as a de-facto standard-of-care for clinically resectable disease. Between one-quarter and one-third of patients (pts) are found to have no evidence of tumor (pCR) at the time of surgical resection, a prognostic indicator of superior survival benefit. However, we currently lack a method to prospectively identify pts who will respond to (NAT). Identifying complete responders could reduce the number of patients requiring esophagectomy. The specific aim of this study was to determine if the pre-operative neutrophil to lymphocyte ratio (NLR), which has been reported as a prognosticator of mortality, is prognostic of pCR to NAT.

Methods: A prospectively collected database was queried for all pts that have undergone esophagectomy for EC, including both squamous cell carcinoma and adenocarcinoma. Records were evaluated for preoperative complete blood count (CBC) with differential from which a NLR was calculated as the absolute neutrophil count divided by the absolute lymphocyte count. A NLR greater than 5 was considered elevated. Pts were classified as pCR if they had no residual tumor on final pathology, partial responders (PR) if they demonstrated down staging after neoadjuvant therapy, or non-responders (NR) if they did not show any improvement in their stage on final pathology.

Results: Of 114 pts who underwent both NAT and esophagectomy for EC, 41 had a pre-operative CBC with differential from which a NLR could be calculated. There were 19 NR, 14 PR and 8 CR. These groups were demographically similar. The average NLR was 5.92 for NR, 6.56 for PR, and 4.89 among CR, with no statistically significant difference between groups. Overall survival at 5 years was 33%. By multivariate analysis NLR>5 did not correlate with pathologic response (p=0.78), and NLR >5 did not correlate with survival (p=0.33).

Conclusions: Elevated neutrophil to lymphocyte ratios are not predictive of pathologic response to NAT in esophageal cancer.
Evaluation of the prognostic value of guanylyl cyclase C (GCC) lymph node (LN) classification in patients with stage II colon cancer: A pooled analysis.
Authors: Sargent Daniel J. , Shi Qian , Resnick Murray B. , Lyle Stephen , Meyers Michael O. , Goldar-Najafi Atoussa , Clancy Thomas E. , Gill Sharlene , Haince Jean-Francois , Fradet Yves
Published: February 2017

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Background: Identification of a sensitive and specific prognostic marker would aid in the management of patients (pts) with standard histopathology node negative colon cancer (CC). We conducted a pooled individual pt data analysis to confirm the prognostic value of GCC for disease recurrence in untreated stage II CC.

Methods: GCC mRNA was quantified by RT-qPCR using formalin-fixed LN from 310 stage II pts diagnosed from 1991-2006 enrolled in two studies (Sargent 2011 [study1] and Haince 2009 [study2]). Patients were classified by GCC LN ratio (LNR) (high risk: LNR ≥ 0.1; low risk: LNR < 0.1), with LNR defined as number of GCC positive LN divided by number of informative LNs. Clinical outcomes included time to recurrence (TTR), overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS). Stratified log-rank tests and multivariate Cox models assessed the association between clinical outcomes and GCC LN status.

Results: The 5-year recurrence rate in study 1 (n=241) was 15.8%, 24.9% in study 2 (n=69). GCC LNR high risk pts had significantly higher risk of TTR, OS, DSS and DFS, which remained after adjusting for age, T stage, grade, number of LNs examined, and presence of lymphovascular invasion ( Table ). In a secondary analysis of low risk stage II pts (T3, ≥12 LNs examined, and negative surgical margins, n=241), a strong relationship between GCC LNR and each endpoint remained (TTR HR=4.34, 95% CI=2.07 – 9.13, p<0.001).

Conclusions: Pts with GCC LNR high risk status have significantly poorer outcomes compared to pts with low risk status, particularly among those traditionally considered to be low risk.

[Table: see text]
Predictive and prognostic markers of recurrence after resection of primary or metastatic colorectal cancer.
Authors: VanDeusen Jeffrey Bryan , Uronis Joshua , Morse Michael , Gatza Michael L. , Datto Michael B. , Mantyh Christopher , Lyerly H. Kim , Nevins Joseph R. , Clary Bryan M. , Hsu Shiaowen David
Published: February 2017

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Background: Current biomarkers for colorectal cancer sub-classify tumors based on single mutations, such as KRAS; however, studies of single mutations belie the molecular complexity of colorectal cancer in which an average of 14 key genes per tumor is dysregulated. We hypothesize that colorectal cancer may be molecularly sub-classified based on an oncogenic pathway prediction model in which tumors are grouped based on patterns of oncogenic pathway dysregulation/expression.

Methods: Affymetrix microarray data from 850 patients with primary colorectal cancer from publically available datasets were combined using Bayesian factor regression modeling normalization. The activity of 19 separate oncogenic pathways was predicted among tumors to generate patterns of pathway activity for each sample. Mixture modeling was applied to these samples to identify subgroups of tumors with unique patterns of pathway dysregulation. Validation of subclasses was performed on a dataset of 133 primary and metastatic colorectal cancer samples of patients undergoing curative surgical resection at our institution. Tumors were subgrouped according to our previous model and recurrence free survival was calculated. In vivo validation was performed by treating NOD/SCID mice bearing patient derived tumors with everolimus with changes in tumor size calculated between day 0 and day 21.

Results: Mixture modeling resulted in 6 individual subgroups of colorectal cancer based on pathway dysregulation. Kaplan Meier curves revealed that patients in subclass 4 had the poorest prognosis while patients in subclass 6 had the best prognosis (p=0.05). Further, tumors in subclass 4 were generally enriched for high mTOR pathway activation and patient derived explants from subclass 4 with high predicted mTOR activity were found to be sensitive to the MTOR pathway inhibitor everolimus.

Conclusions: Prediction of oncogenic signaling pathway activity is a powerful tool that may be used to molecularly sub-classify colorectal cancer into biologically relevant subgroups. These subgroups have prognostic and predictive implications for recurrence following surgical resection and responsiveness to targeted therapy.