bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of dose-modified FOLFIRINOX on toxicity and effectiveness in Japanese patients with unresectable pancreatic cancer (PC).
Authors: Uesugi Kazuhiro , Asagi Akinori , Hino Kaori , Nadano Seijin , Iguchi Haruo
Published: February 2017

480

Background: FOLFIRINOX has been shown superior to GEM in terms of OS, PFS and/or RR for treatment of metastatic PC in Accord 11, and this regimen has become the standard of care for the first-line chemotherapy. However, the major disadvantage of FOLFIRINOX is significantly higher toxicity, and, in particular, quite higher incidence of neutropenia(78%) and febrile neutropenia(22%) was observed in the PII clinical trial of FOLFIRINOX performed in Japan (LOHP-PII-05, JSCO 2013). Thus, in clinical practice for the Japanese patients, it should be needed to make modification on this regimen in terms of dose reduction without compromising in its effectiveness. We evaluated the safety and efficacy of modified(m) FOLFIRINOX in Japanese patients with unresectable locally advanced PC(LAPC) and/or metastatic PC(MPC). Methods: The modifications to FOLFIRINOX include discontinuation of the bolus 5-FU and dose-reduction(25%) of irinotecan. 20 patients with unresectable LAPC and/or MPC (PS 0-1) were treated with m FOLFIRINOX given every 2 weeks, and toxicity and efficacy were evaluated in these patients who received more than 3 courses. All patients did not receive prophylactic filgrastim. Results: Patient characteristics were as follows: LAPC/MPC 4/9; median age 65 yrs(range 39~75); male/female 15/5. Median number of cycles was 5.5 (range 1~17). Grade 3/4 toxicities included neutropenia(25%), nausea(30%), anorexia(35%) and diarrhea(20%). Grade 1/2 toxicities were sensory neuropathy(45%) and vomiting(40%). Febrile neutropenia was noted in 2 patients(10%). Toxic death was not observed, and 12 patients(60%) required dose reduction due to toxicity. Hematologic toxicities were decreased, however, those concerned with gastrointestinal toxicities were observed in a bit higher incidence compared to those in LOHP-PII-05. Response by CA19-9 was evaluable in 11 patients. 9 of 11 patients (82%) showed a decline in CA19-9 levels from baseline, and a greater than 50% decline was noted in 5 of 11 patients(45%). Conclusions: m FOLFIRINOX seems to have an improved safety profile even without prophylactic filgrastim and to maintain its efficacy.
Optimal timing of surgical resection after radiation therapy in locally advanced rectal adenocarcinoma: An analysis of the National Cancer Database (NCDB).
Authors: Huntington Ciara R , Boselli Danielle , Hill Joshua S. , Salo Jonathan C.
Published: February 2017

510

Background: In treatment of rectal adenocarcinoma, an increased time delay (TD) of 6-12 weeks from the end of radiation therapy to surgery may increase the rate of complete pathologic response (pCR), but the optimal TD with respect to survival has not been established. This study evaluates the impact of TD on overall mortality. Methods: The NCDB was queried for patients with adenocarcinoma of the rectum and no evidence of metastasis at diagnosis, who underwent preoperative chemoradiation followed by radical surgical resection. Standard statistical methods were employed for descriptive statistics and Cox model development. Results: The study included 6805 patients, predominantly Caucasian (87.2%) and males (63.9%) who generally were treated with low anterior resection (57.3%), colonanal reanastomosis (8.4%), or abdominoperineal resection (28.4%), and had median survival of 66.6 months. The effects of age, surgical margins (-/+), comorbidity index, time to discharge after surgery, TMN pathologic staging, surgical volume, and patient income significantly impacted mortality after radiation and surgery (p<0.05 for all values). There was a significant relationship between TD and pCR (p=.0002). At TD less than 30 days, 4.0% of patients achieved pCR, while 9.3% of patients have achieved pCR by 75 days. In TD of greater than 75 days, the rate of pCR decreased. Overall, 6.8% of patients (n=461) achieved pCR. Using a refined cox model, a TD of more than 60 days was associated with 20% greater risk of mortality (95% CI 1.068 – 1.367). This effect became more pronounced with increasing TD; a TD of greater than 75 days was associated with 28% (95% CI 1.06-1.55) increased risk of mortality, while patients with TD less than 60 days saw a survival benefit. Conclusions: Though an interval up to 75 days between radiation and surgery may achieve higher rates of complete pathologic response, delay of more than 60 days from radiation to surgical resection and subsequent systemic chemotherapy decreases overall survival in patients with rectal cancer.
Colon cancer in immigrants from Ethiopia.
Authors: Yarom Nirit , Gorbatsevich Elena , Geva Nir , Evron Ella , Kovel Svetlana , Cyjon Arnold , Sella Avishay
Published: February 2017

521

Background: During the period 1980-1990, 26,000 African Jews immigrated from Ethiopia to Israel. Reports of the prevalence of cancer in Ethiopia are scarce and difficult to verify. Kaposi sarcoma, liver, prostate, cervical and breast cancer as reported to be the most common cancers. Colon cancer entails less than 7% of all cancers. The aim of this study was to describe and characterize cancer in immigrants from Ethiopia in Israel, in order to tailor screening and treatment approaches to this unique population. Methods: In this retrospective single center study, patients were identified based on the country of birth as registered in the medical records. Clinical data including age at diagnosis, pathology, tumor stage, interval from onset of symptoms to diagnosis and to treatment, response to treatment and survival, were obtained from the clinical charts. Local REB approved the study. Results: Between the years 2003 and 2011, 53 immigrants were treated for cancer in our center. Median survival was 30 months. Patients diagnosed more than 22 years after immigrating to Israel had a better survival (median 79 m) than patients who were diagnosed earlier (median 16 m). The interval from onset of symptoms to diagnosis was found to correlate negatively with stage at diagnosis (R2=0.717). Out of 53 patients 10 had colon cancer (19%). Three patients were diagnosed at stage I or II and 7 at stages III or IV. Median age at diagnosis of patients with colon cancer was 56 (31-81). Median interval from immigration to diagnosis was 22 years (16-31). Median survival (all stages) was 12.5 m and the mean was 33.2 m. Seven patients had well to moderately differentiated adenocarcinoma, two had mixed adeno-neuroendocrine carcinoma and one patient had neuroendocrine tumor. Three out of four patients who were diagnosed with locally advanced, stage IIb-III, refused adjuvant chemotherapy. All those with recurrence consented to palliative treatment. None of the patients offered genetic consultation opted for consultation. Conclusions: Jewish immigrants from Ethiopia to Israel have a high prevalence of colon cancer at younger age and complicated pathology. Further molecular testing and epidemiologic studies should be pursued in order to understand the unique properties of cancers arising in this population.
Prediagnostic plasma adiponectin and survival among patients with colorectal cancer.
Authors: Chong Dawn Q. , Mehta Raaj , Song Mingyang , Kedrin Dmitriy , Meyerhardt Jeffrey A. , Ng Kimmie , Wu Kana , Ogino Shuji , Fuchs Charles S. , Giovannucci Edward L. , Chan Andrew T.
Published: February 2017

526

Background: Adiponectin is a hormone secreted by adipose tissue and has been demonstrated to possess anticarcinogenic, anti-inflammatory and insulin-sensitizing effects. Circulating adiponectin has been shown to be inversely associated with the risk of colorectal cancer (CRC) in prospective studies. However, the association of prediagnostic adiponectin with survival among patients with established colorectal cancer is unclear. Methods: We conducted a prospective study of 621 incident colorectal cancer cases from the Nurses’ Health Study and Health Professionals Follow-up Study to evaluate the association between prediagnostic plasma adiponectin and mortality. Plasma adiponectin levels were determined by enzyme-linked immunosorbent assay from ALPCO Diagnostics. The interbatch coefficient of variation from quality control samples randomly interspersed among the case samples was 8.6%. We examined the associations between quartiles of plasma adiponectin and mortality using a Cox proportional hazards model adjusted for established and putative risk factors. All statistical tests were two sided. Results: After a median follow-up of 9 years, there were 267 (43%) total deaths and 130 (21%) CRC deaths in the total study cohort. Compared with patients in the lowest quartile of adiponectin, patients in the highest quartile had a multivariate hazard ratio (HR) for CRC-specific mortality of 2.70 [95% confidence interval (CI), 1.54-4.75; Ptrend = 0.001]. The corresponding multivariate HR for overall mortality was 1.64 (95% CI, 1.14-2.36; Ptrend = 0.007). These associations were reasonably consistent in analyses according to subgroups defined by age, gender, body mass index, stage, grade and site of primary cancer. Similar results were yielded after excluding patients diagnosed within 4 years of blood collection (Ptrend = 0.027). Conclusions: Prediagnostic adiponectin is associated with an increased risk of colorectal cancer- specific and overall mortality. Further studies are needed to elucidate the mechanistic basis for these findings and determine the potential role of adiponectin as a prognostic marker in colorectal cancer.
Japanese D3 lymph node dissection in low rectal cancer with inferior mesenteric lymph node and/or lateral lymph node metastases.
Authors: Ubukata Mamiko , Itabashi Michio , Ogawa Shimpei , Hirosawa Tomoichiro , Bamba Yoshiko , Nakao Sayumi , Kameoka Shingo
Published: February 2017

530

Background: The current Japanese Classification of Colorectal Carcinoma defines inferior mesenteric lymph nodes (IMLN) and lateral lymph nodes (LLN) as regional lymph nodes in rectal cancer. It states that these lymph nodes should be dissected when performing D3 dissection for rectal cancer. However, there is currently no consensus on the significance of Japanese D3 lymph node dissection in low rectal cancer. A retrospective study involving a large number of patients was conducted. Methods: The subjects were 2,743 patients registered in the multi-institutional registry of the Japanese Society for Cancer of the Colon and Rectum. The data were analyzed for outcomes in R0 cases with IMLN and/or LLN metastasis (IMLN(+)LLN(-) or IMLN(-)LLN(+) or IMLN(+)LLN(+)). Results: In the control group, 67 patients (2.7%) were considered positive for IMLN metastasis, 181 patients (7.4%) for LLN metastasis, and 34 patients (1.4%) for IMLN + LLN metastasis. The outcomes in the R0 cases with IMLN and/or LLN metastasis were 52.8% for 5-year RFS and 63.1% for 5-year OS, which were each better than for R1+R2 cases (5-year RFS 26.2%, p<0.0001; 5-year OS 30.5%, p<0.0001). Including only those with a total of seven or more metastatic lymph nodes, the outcomes in the R0 cases with IMLN and/or LLN metastasis were 53.6% for 5-year RFS and 64.9% for 5-year OS, which did not differ significantly from those for IMLN(-)LLN(-) cases (5-year RFS 54.4%, 5-year OS 55.2%) (RFS: p=0.9718, OS: p=0.4049). Conclusions: We confirmed that cases of IMLN and/or LLN metastasis in low rectal cancer tend to have a large total number of metastatic lymph nodes, but a good outcome can be expected if curative resection can be performed. These results demonstrate the value of radical Japanese D3 lymph node dissection in low rectal cancer with IMLN and/or LLN metastasis.
Controlling the quality of RAS mutation testing by a dichotomous approach: Ring trials and benchmarking mutation frequencies by a RAS monitor.
Authors: Jung Andreas , Dietel Manfred , Gabbert Helmut E , Kloor Matthias , Penzel Roland , Schafer Karl-Ludwig , Schirmacher Peter , Sers Christine , Kirchner Thomas
Published: February 2017

536

Background: The PRIME study (Douillard et al. New Engl. J. Med. 2014) demonstrated that testing all coding exons of both KRAS and NRAS proto-oncogenes (all-RAS) predicted response for anti-EGFR targeting antibody panitumumab better than testing only KRAS exon 2 (PFS: 8.9 vs 9.6 mo, OS: 20.2 vs. 26 mo). Thus, the EMA changed the label of this drug for Europe. Now all RAS testing has to be done on a high quality level. Therefore, an improved quality assurance (QA) system was developed. Methods: The German RAS Advisory Board as part of QuIP (Quality initiative Pathology) launched ring-trials to assure quality of RAS mutation detection. 12 test cases of metastatic colorectal cancers (mCRC) containing WT or mutated sequences in one of the three coding exons 2 – 4 of either the KRAS or the NRAS oncogenes. Additionally many QA passed participants supplied the results of all-RAS testing of mCRC for one year resulting in a RAS monitor. Results: In less than half a year an area-wide coverage of quality certified all-RAS testing laboratories was reached. In three ring-trials 89 of 93 (96%) institutions for pathology passed the QA using Sanger-Sequencing (60%), pyrosequencing (25%) or the COBAS system (15%). None of the methods was superior to another as comparable amounts of methods passed or failed the ring trials. As only 12 cases were tested the result is reliable with a lower limit of confidence of only 0.7. Thus, a RAS monitor was introduced as an additional instrument of QA. Here, the results of almost 4000 cases of mCRC tested for all-RAS were collected indicating RAS mutations in 45.7% of investigated cases (KRAS: 41.5%, NRAS: 4.2%). Conclusions: Ring-trials are a versatile tool to establish a network of quality tested diagnostic laboratories in a short time. In parallel data sets for benchmarking the frequencies of RAS mutations were generated region specifically. Thereby quality was brought to a higher level than without the RAS monitor.
Burden of high-risk oral HPV infection in men in the United States and implications for oropharyngeal cancer screening: NHANES (1999-2012).
Authors: Dunn Erin , Moore Kevin J. , Koru-Sengul Tulay
Published: February 2017

55

Background: In men high-risk human papilloma viruses (HPVs) have been implicated in causing cancer of the penis, anus, and oropharynx. HPV infection, specifically HPV 16, is currently one of the most common causes of oropharyngeal cancer. National population-based surveys provide estimates of population-specific prevalence, trend, and determinants to identify the burden of high-risk HPV in the oropharynx of men. Methods: We calculated HPV infection prevalence by oral testing in the US from 1999-2012 National Health and Nutrition Examination Survey (NHANES) to obtain a representative sample of non-institutionalized civilian population. We provided epidemiology of HPV infection for both females and males with prevalence estimates, unadjusted odds ratio (OR) with 95% confidence interval (95%CI). Analysis was performed by SAS v9.3 with complex sampling design. Results: Among HPV-positive persons, high-risk HPV infection (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82) was more prevalent for men (79.4%) than for women (20.6%). Men also had the highest prevalence for each high-risk type tested. Notably, men held 84.9% of the HPV 16 burden, which has the highest risk for orophargyngeal cancer. Mexican-American men had lower odds of high-risk HPV infection than White men (OR=0.47; 95%CI=0.261, 0.86). Further, divorced/separated/widowed men had lower (0.48; 0.26, 0.88) and never married men had greater (1.76; 1.01, 3.07) odds of high-risk HPV compared to men who are married/living with partner. Conclusions: Using a large population-based survey, our results show increased prevalence of high-risk HPV infection in men. Stratification by ethnicity and marital status will increase understanding and awareness of the burden and demographic disparities of potentially oncogenic HPV infections in men and may provide a base for culturally and gender competent oropharyngeal cancer screening programs. Recognizing demographic disparities and behaviors could guide further research into risk factors and conditions that guide the prevalence of HPV infection and oropharyngeal cancer in specific male populations.
Analysis of correlation between oncogene mutation and response to chemotherapy in all RAS wild type metastatic colorectal cancer, using next-generation sequencing technology.
Authors: Higuchi Akio , Kasajima Rika , Shiozawa Manabu , Asari Masahiro , Murakawa Masaaki , Katayama Yusuke , Yamaoku Koichiro , Aoyama Toru , Kanazawa Amane , Morinaga Soichiro , Rino Yasushi , Akaike Makoto , Masuda Munetaka , Miyagi Yohei
Published: February 2017

553

Background: Targeted therapies of monoclonal antibodies have changed the treatment of metastatic colorectal cancer (mCRC). A target therapy with chemotherapy regimen for mCRC was decided by KRAS mutation status (KRAS exon2 [codon12, codon13]). Currently, there are many reports suggesting that in addition to analysis of KRAS mutation status, the evaluation of EGFR gene copy number, levels of EGFR ligands, BRAF, NRAS, PIK3CA mutations could be helpful to have a more accurate selection of patients who may have a benefit from anti-EGFR targeted drugs. Methods: Mutation status of 50 oncogenes were analysed in 35 mCRC patients with all RAS wild type, using next-generation sequencing technology. The response for chemotherapy was classified response group (R group) and non-response group (N group) by RECIST. The relation between mutation status of 50 oncogenes and the response for chemotherapy was assessed. Results: There were 25 oncogene mutations in the 50 genes. Driver mutation associated with oncogenic mutation deeply were 5 oncogenes, which were PIK3CA, AKT1, BRAF, PDGFRA and TP53. Only BRAF mutation was significantly associated with poor chemo response in the 5 oncogenes. A case which had two driver mutations was only in the N group. One of the two driver mutations was tumor suppressor gene, TP53. Conclusions: BRAF mutation and the number of driver mutations are key predictors of chemosensitivity in the mCRC cases with all RAS wild type.
An observational study of a team management approach for first-line XELOX therapy in patients with advanced/recurrent colorectal cancer: The SMILE study (the study of metastatic colorectal cancer to investigate impact of learning effect).
Authors: Nakamura Michio , Matsuoka HIroshi , Shibata Yoshihisa , Munemoto Yoshinori , Okuda Hiroyuki , Uchida Hiroshi , Ogata Yutaka , Nishimura Genichi , Shiroiwa Takeru , Kishimoto Junji , Maeda Kotaro
Published: February 2017

554

Background: Although oral chemotherapies such as XELOX are widely favored for convenience and flexibility, these have several disadvantages such as drug non-compliance and delayed discovery of adverse events. So we designed a multicenter, prospective, observational study to evaluate the efficacy of supportive interventions in first-line XELOX for colorectal cancer (CRC) patients (pts). Methods: CRC pts undergoing first-line XELOX (+Bevacizumab) therapy practicing one or more of supportive interventions as follows: 1) a telephone follow-up (TF), 2) instruction on dosage and administration by a pharmacist, 3) skin care instruction by a nurse, and 4) pts education by a doctor were eligible. The objective was to evaluate the incident rate of grade 2 or worse hand-foot syndrome (HFS), QoL, safety, and efficacy. QoL was assessed at baseline, 2, 4, 5 and 8 cycles after the treatment started, using the Hospital Anxiety and Depression Scale (HADS) and the Mental adjustment to cancer scale (MAC). Results: From April 2011 to September 2012, 80 pts were enrolled from 14 institutes. The characteristics were as follows: male/female: 46/34, age median: 63 (36-75), and supportive intervention 1)/2)/3)/4): 36/68/73/78. The incidence of grade 2 or worse HFS during 6 months were 11.1% (n=4) for those received TF (n=36), and 20.5% (n=9) for those received other intervention except TF (n=44). Relative dose intensity (RDI) was 75.7% (TF+/-: 77.7/74.3%) in oxaliplatin and 77.5% (TF+/-: 80.2/75.3%) in capecitabine, respectively. Although a tendency of the QoL score improvement about anxiety, fighting spirit and helplessness in a TF group was observed during the periods from start of therapy to 4 courses, there were no significant differences compared to other interventions except TF. Conclusions: We confirmed that HFS incidence was mitigated in a TF group. In regard to QoL, although we could not show the statistical differences due to some limitations of this study such as small sample size and non-randomized, it was indicated that TS had the potential to improve several QoL about anxiety, fighting spirit, and helplessness. Clinical trial information: UMIN000007185.
Muscle volume loss after the induction of first-line chemotherapy as a novel prognostic factor in metastatic colorectal cancer patients.
Authors: Yoshikawa Yusuke , Okabayashi Koji , Hasegawa Hirotoshi , Tsuruta Masashi , Seishima Ryo , Takahashi Hidena , Yamada Toru , Matsui Shimpei , Kondo Takayuki , Shimada Takehiro , Matsuda Mutsuhito , Yahagi Masashi , Asada Yusuke , Sugiura Kiyoaki , Suzuki Yoshiyuki , Tajima Yuki , Nakadai Junpei , Kitagawa Yuko
Published: February 2017

558

Background: Muscle volume loss (MVL) is observed in end-stage cancer patients as cachexia. However, the impact of MVL on tumor response and survival still remains unclear during chemotherapy in metastatic colorectal cancer (mCRC) patients. The aim of this study is to evaluate correlation between MVL and oncologic outcomes in mCRC patients. Methods: A total of 91 mCRC patients who received first-line chemotherapy were identified in our prospective registry between February 2007 and April 2013. Skeletal muscle index at the level of L3 vertebra (SMI) was calculated by muscle volume normalized by stature at the time of the induction of first-line chemotherapy (bSMI) and first evaluation of tumor response (fSMI). Patients whose SMI decreased more than 10% were classified as MVL group. The impact of these variables on oncologic outcomes (overall survival [OS], progression free survival [PFS], and tumor response rate [RR]) were analyzed. Results: Mean bSMI and fSMI were 35.0 (SD: 7.11) cm2/m2, and 34.2 (SD: 6.85) cm2/ m2, respectively. Eighteen patients were classified into the MVL group. The patients in MVL group significantly responded to the chemotherapy (RR of MVL: 11.1% vs. RR of non-MVL: 49.3%, p < 0.01). There was no significant difference in terms of high grade adverse effect between MVL and non-MVL group. Patients in MVL group had a significant shorter median PFS (MVL: 5.5 [2.5 - 10.1] months vs. non-MVL: 12.8 (3.8-80.5) months, p < 0.01) and median OS (MVL: 13.9 [6.2-61.2] months vs. non-MVL: 29.3 (8.2-94.0) months, p < 0.01). Multivariate analysis demonstrated that patients with MVL had significantly worse prognostic factor (OS: HR 3.51 [1.99-6.21], p < 0.01 and PFS: HR 8.27 [2.91-23.5], p < 0.01. Conclusions: The findings of this study suggested that MVL after the induction of the first line chemotherapy could be a novel predictive factor for chemotherapy response and prognosis. Further investigation should be required to clarify the mechanistic background.
Relation between carcinoembryonic antigen (CEA) production in colorectal cancer (CRC) tissue and serum CEA levels: Comparison between the time of recurrence and initial diagnosis.
Authors: Saito Gota , Sadahiro Sotaro , Okada Kazutake , Tanaka Akira , Suzuki Toshiyuki , Kamijo Akemi
Published: February 2017

561

Background: Because serum CEA often becomes positive before the diagnosis of recurrence, CEA is widely used for postoperative surveillance. Serum CEA is negative at initial diagnosis as well as at recurrence in some patients. We examined the relation between serum CEA levels and tissue CEA staining status both at initial surgery and at recurrence. Methods: Between 1998 to 2012, 1,306 patients (pts) with colon cancer (CC) underwent curative resection. Serum CEA levels were measured at initial surgery and at recurrence and immunohistochemical staining for CEA in primary and metastatic lesions was performed in 46 pts. Serum CEA levels of 10ng/mL or more were regarded as positive. Results: Serum CEA were positive in 17 pts (37%) at initial surgery and in 20 (43%) at recurrence. CEA staining was positive in primary lesions in 24 pts (52%) and metastatic lesions in 33 (72%). The positive rate was higher in metastatic lesions (p=0.053). Among pts in whom serum CEA was positive at initial surgery, CEA staining in primary lesion was positive in 12 pts (71%) and negative in 5 (29%). Among pts in whom serum CEA was negative, CEA staining in primary lesion was positive in 12 pts (41%) and negative in 17 (59%). Serum CEA at initial surgery was not related to CEA staining in primary lesion(p=0.0722). Among pts positive for serum CEA at recurrence, CEA staining in metastatic lesions was positive in 19 pts(95%) and negative in 1(5%). Among pts negative for CEA at recurrence, CEA staining in metastatic lesions was positive in 14 pts (54%) and negative in 12 (46%). Serum CEA at recurrence was significantly related to CEA staining in metastatic lesions (p=0.0026). Among 33 pts in whom CEA staining was positive at recurrence, serum CEA was negative in 14 (42%). Conclusions: In pts with recurrence of CC, there was no relation between the staining CEA status and serum CEA level at initial diagnosis. In contrast, these variables were significantly related at recurrence. However, 42% of pts with positive staining for CEA in metastatic lesions had negative serum CEA levels. Our findings suggest that factors besides the production of CEA by cancer cells are related to serum CEA levels.
Primary and secondary endpoint analysis of N08C9 (Alliance): A phase III randomized study of sulfasalazine versus placebo in the prevention of acute radiation enteritis.
Authors: Iott Matthew J.
Published: February 2017

562

Background: An interim futility analysis at ASTRO 2013 led to early closure of N08C9 (Alliance), a randomized controlled trial (RCT) comparing sulfasalazine (SSZ) versus placebo (PBO) in the prevention of radiation enteritis during pelvic RT. This is the full analysis of the primary endpoint (PE) and secondary endpoints (SEs) of the trial. Methods: A multi-institutional RCT conducted by the Alliance for Clinical Trials in Oncology assessed the effect of 1000 mg SSZ b.i.d. versus PBO b.i.d. in the treatment of pelvic RT related enteritis. Study participants (SPs) received the study agents during RT and for 4 weeks afterwards. The PEwas the maximal severity of diarrhea toxicity (CTCAE version 4.0) during and up to 6 weeks after RT. SEs, including the maximum severity of diarrhea (MSD) and the duration of MSD, rectal bleeding, abdominal cramping, tenesmus, and constipation, were graded weekly during RT by a health care provider. Bowel function was assessed using a self-administered bowel function questionnaire weekly during RT, afterwards at 6 weeks, and at 12 and 24 months. A two-sided 0.05-level Wilcoxon rank-sum test was used to test the equality of the distributions of MSD grades. The planned study size was 128 SPs. Results: 87 SPs were enrolled in the study between 4/29/2011 and 5/13/2013, with evenly distributed baseline factors. Toxicity data were available in 84 SPs during RT and in 54 SPs in the 6 weeks following RT. There was no significant difference in the distribution of MSD grades between the SSZ and PBO arms (p=0.41 regardless of attribution; p=0.09 at least possibly attributed to the study agent). No significant differences were observed in SEs during RT and after RT, except the abdominal pain occurring after completion of RT was higher in SPs receiving SSZ (p=0.02). More SPs required antidiarrheal agents on the SSZ arm (49% vs. 29%, p=0.06). Conclusions: Despite prior single institution RCT’s suggesting a benefit for SSZ (Kilic 2001; Pal 2013) in this clinical context, the results of this large, multi-institutional trial demonstrate that SSZ does not reduce the risk of enteritis and may worsen acute GI toxicity during pelvic RT. Clinical trial information: NCT01198145.
Improving access to molecularly defined clinical trials for patients with colorectal cancer: The EORTC SPECTAcolor platform.
Authors: Folprecht Gunnar , Aust Daniela Ellen , Roth Arnaud , Messina Carlo G. M. , Lacombe Denis A. , Salgado Roberto , Laurent-Puig Pierre , Bosman Fred , Salazar Ramon , Tabernero Josep , Kohne Claus-Henning , Arnold Dirk , Lordick Florian , Mauer Murielle E. , Tejpar Sabine ,   SPECTAcolor Investigators
Published: February 2017

575

Background: Molecular diagnostics can identify subgroups of colorectal and other cancers that are relevant for the mode of action of new anti-cancer agents. The efficient, GCP-conform and quality assured molecular screening to identify potential study patients is one of the major challenges for targeted drug development. The EORTC has implemented a new collaborative molecular screening platform in order to facilitate these next generation trials. Methods: SPECTAcolor (Screening Patients for Efficient Clinical Trial Access in advanced colorectal cancer) is a pan European network of institutions collaborating in centralized, high-throughput screening of tumor material from patients with colorectal cancer. After informed written consent, patients are screened for molecular alterations. Molecularly annotated patients can be offered so called “downstream” clinical trials. Results: Launched in September 2013, SPECTAcolor is now initiated in 19 clinical centers in 9 countries. As of 12 September 2014, 406 patients were enrolled exceeding the expected accrual target of 300 patients in the first year. Of these 406 patients, 293 patients had their tumor block shipped to the central biobank at the Dresden University Hospital for central quality and pathological review, and core analyses. Tumor samples are being additionally analyzed using next generation sequencing for 360 key cancer alterations in cooperation with the Sanger Institute (Cambridge, UK). In the first year, the blocks were analyzed for 5 baseline biomarkers. KRAS was wild type for exon 2, 3 and 4 in 151/284 pts (53%) and mutated 133 pts (47%; 114 pts in exon 2 (40%), 8 pts in exon 3, and 11 pts in exon 4). NRAS was tested in KRAS wild type pts only; mutations were found in 14 pts (4.9%; 6 pts in exon 2 and 8 pts in exon 3). BRAF mutations, all in exon 15, were found in 18 pts (7%). PI3K mutations occurred in 41 pts (15%; 13 in exon 20 and 28 in exon 9). IHC staining was showing deficient mismatch repair in 16 patients. Conclusions: SPECTAcolor is the first pan-European and EORTC screening platform. Its successful implementation proves that a logistically complex infrastructure to run next generation trials in a multinational setting is feasible.
The safety and tolerability of veliparib (V) plus capecitabine (C) and radiation (RT) in subjects with locally advanced rectal cancer (LARC): Results of a phase 1b study.
Authors: Czito Brian G. , Mulcahy Mary Frances , Deming Dustin A. , Vaghefi Houman , Jameson Gayle S. , Deluca Angela , Xiong Hao , Munasinghe Wijith , Dudley Matthew W. , Komarnitsky Philip , Holen Kyle D. , Michael Michael
Published: February 2017

579

Background: Patients (pts) with LARC treated with neoadjuvant C/RT and then surgery have low rates of pathologic complete response (ypCR) and significant relapse rates. V is a potent, orally bioavailable PARP inhibitor that has been shown to enhance the efficacy of chemotherapy and RT in preclinical models. This study sought to establish the recommended phase 2 dose (RPTD), as well as to assess safety, pharmacokinetics (PK), and preliminary activity of V + RT/C in pts with LARC. Methods: Pts with stage II-III rectal cancer received RT (50.4Gy/1.8Gy/fraction) with C (825 mg/m2 BID) five days per week (W) for 5.5W. Dosing of V (BID, 20mg-400mg) continued from W1D2 to 2 days past RT. Pts underwent surgery 5-10W following RT. Assessments included identification of RPTD with the Exposure Adjusted Continual Reassessment Method, adverse events (AEs), PK, and pathological response (ypCR and tumor downstaging rates). Results: As of August 5, 2014, 30 pts have been enrolled, 24/6 male/female, median age 58 yrs; 1 pt discontinued due to an AE. The most common treatment-emergent AEs possibly or probably related to V (>15% pts, n >4) were nausea (40%), fatigue (37%), diarrhea (30%), vomiting (20%), and dysgeusia (17%). One grade 3/4 event each of anemia and lymphopenia and 2 grade 3/4 events of diarrhea were deemed at least possibly related to V. Two dose limiting toxicities (DLTs) occurred: 1 at 70 mg BID V (radiation skin injury requiring dose interruption); 1 at 400 mg BID (nausea and vomiting requiring discontinuation). The RPTD is 400 mg BID of V in combination with RT/C. PK results from 16 pts suggest that V PK was approximately dose proportional when administered with RT/C and that V had no effect on the PK of C. To date, 18/25 (72%) pts have been downstaged post-surgery; with 7/25 (28%) achieving ypCR. Conclusions: V at 400 mg in combination with RT/C has an acceptable safety profile. 72% of 25 evaluable patients had tumor downstaging post-surgery, including 28% with ypCR. Dose escalation of V resulted in approximately dose-proportional increases in the V PK with no clear effect on C PK. Clinical trial information: NCT01589419.
Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients.
Authors: Giampieri Riccardo , Salvatore Lisa , Del Prete Michela , Prochilo Tiziana , D'Anzeo Marco , Faloppi Luca , Bianconi Maristella , Loretelli Cristian , Loupakis Fotios , Montironi Rodolfo , Scarpelli Marina , Zaniboni Alberto , Falcone Alfredo , Scartozzi Mario , Cascinu Stefano
Published: February 2017

595

Background: The introduction of regorafenib for the treatment of colorectal cancer represented a sure medical achievement though at a cost of relevant toxicity. As a consequence the lack of predictive factors made the use of regorafenib in the clinical practice challenging. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and potentially influence outcome during anti-angiogenesis treatment. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. Methods: From a multicentre experience 138 samples (tumour or blood samples) of colorectal cancer patients receiving regorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients’ progression-free survival (PFS) and overall survival (OS) were analysed. Results: Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS (respectively HR: 0.49, 95% CI: 0.33-0.81, p=0.003 and HR: 0.52, 95% CI: 0.34-0.99, p=0.04). A correlation with disease control rate (DCR) was also observed (DCR 55% vs. 26%, p=0.02). Among clinical factors only ECOG PS was independently correlated with OS (HR: 0.52, 95% CI: 0.21-0.81, p=0.009), whereas no correlation with PFS was evident. Grouping together observations from angiogenesis genotyping and ECOG PS allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. Median OS resulted progressively decreased across these groups (OS not reached, 7.8 and 3.9 months respectively in the favourable, intermediate and unfavourable group, p<0.0001). Conclusions: VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of candidates for regorafenib. This selection opportunity will ultimately improve the therapeutic index of such a treatment approach by limiting treatment to potentially responding patients and sparing unnecessary toxicity to those unlikely to benefit.
Epigenetic regulation and functional roles of SHP1 in gastric carcinoma cell lines.
Authors: Joo Moon Kyung , Park Jong-Jae , Yoo Hyo Soon , Jeoung Yong , Kim Jiwon , Koh Jin Sung , Kim Ho , Choe Jung Wan , Lee Beom Jae , Kim Jae Seon , Bak Young-Tae
Published: February 2017

61

Background: The SH2-containing protein tyrosine phosphatase 1 (SHP1) is an important negative regulator in cytokine-mediated signal transduction and cell cycling. Recent studies demonstrated that promoter methylation of SHP1 is frequently observed in gastric adenocarcinoma tissues. We tried in this in vitrostudy to reveal promoter hypermethylation and to investigate the effects of SHP1 in gastric carcinoma cell lines. Methods: We performed RT-PCR, Western blot, methylation specific PCR (MSP) and bisulfite pyrosequencing to demonstrate promoter hypermethylation of SHP1. To evaluate functional roles of SHP1, we transfected SHP1 plasmid and analyzed WST-1 assay, wound closure assay and Matrigel invasion assay. Results: We observed that both gene and protein expression of SHP1 were negative in 8 of 10 gastric cancer cell lines (SNU-1, SNU-5, SNU-16, SNU-638, SNU-719, MKN-28, MKN-45, AGS). MSP showed methylation-specific band only in all 10 gastric cancer lines. Bisulfite pyrosequencing revealed 96.5% and 97.3% of methylation frequency in AGS and SNU-719 cells. When treating SNU-719, MKN-28 and AGS cells with 5-Aza-2’-deoxycytidine (5-Aza-dc), SHP1 was re-expressed in all three cells. SHP1 expression is known to be correlated with Janus kinase (JAK) and signal transducers and activators of transcription (STAT) signaling pathway in epithelial cells. When introducing exogenous SHP1 in SNU-719 and MKN-28 cells by transient transfection, protein expression of constitutive phospho-JAK2 (Tyr 1007/1008) and phospho-STAT3 (Tyr 705) were substantially down-regulated both, which in turn decreased target gene expression of STAT3, including cyclin D1, MMP-9, VEGF and survivin. Induction of SHP1 significantly inhibited cell proliferation, migration and invasion in SNU-719 and MKN-28 cells. Conclusions: Epigenetic silencing of SHP1 is frequently caused by promoter hypermethylation in gastric carcinoma cell lines. Overexpression of SHP1 down-regulates JAK2/STAT3 pathway to modulate various target genes and inhibit cell proliferation, migration and invasion in gastric cancer cells.
EGFR ligands and ERCC1 mRNA expression to predict clinical outcome in Japanese (JPN) patients (pts) with metastatic colorectal cancer (mCRC) harboring overexpressed EGFR and KRAS exon 2 wild-type (KRAS wt) treated with cetuximab (cet) plus oxaliplatin-based chemotherapy (JACCRO CC-05/06 AR).
Authors: Sunakawa Yu , Ichikawa Wataru , Tsuji Akihito , Moran Miriana , Astrow Stephanie H. , Yang Dongyun , Zhang Wu , Takahashi Takehiro , Denda Tadamichi , Shimada Ken , Kochi Mitsugu , Nakamura Masato , Kotaka Masahito , Segawa Yoshihiko , Takeuchi Masahiro , Lenz Heinz-Josef , Fujii Masashi , Nakajima Toshifusa
Published: February 2017

618

Background: Previous studies have reported that EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), are potential predictive markers for cet and high ERCC1 expression is associated with resistance to platinum-containing chemotherapy. However, there are still few studies to assess predictive values of these expression levels in JPN mCRC pts. The aim of this study was to evaluate the values in JPN mCRC pts treated with cet. Methods: This study enrolled 77 pts with tissue available from 2 prospective clinical trials evaluating combination of cet with oxaliplatin-based chemotherapy as first-line treatment in pts with KRAS wt and EGFR-expressing tumors, modified FOLFOX6 (n=28/57, UMIN000004197) and SOX (n=49/67, UMIN000007022). Total RNA isolated by macro-dissection from tissue was screened by RT-PCR for mRNA expression levels of AREG, EREG, and ERCC1, the cut-off values of which were based on the optimal cut-off value using the maximal chi-square approach on tumor response with adjusted p values. The same cut-off values were used to evaluate associations with progression-free survival (PFS) and overall survival (OS). Results: Median age and follow-up time were 63 (range: 39-79) years old and 24.7 (range: 5.5-39.3) months, respectively. In 73 evaluable pts, response rate (RR) was 77 % (95% CI, 67 to 86), but no significant association was seen in RR. Pts with high AREG expression (>1.59) had significantly longer PFS (11.6 vs. 6.6 months, HR: 0.53, logrank p=0.047) but not OS in 67 assessable pts. Pts with low ERCC1 expression (≤1.35) had significantly longer OS (42.8 vs. 22.0 months, HR: 2.46, logrank p=0.014) but a trend toward longer PFS (11.6 vs. 8.9 months, HR: 1.63, logrank p=0.092) in 68 assessable pts. On the other hand, high EREG expression (>3.21) was not associated with clinical outcome in 64 assessable pts. Conclusions: Our study identified predictive roles for AREG and ERCC1 mRNA expression in JPN mCRC pts treated with cet plus oxaliplatin. However, extended RAS mutations analysis is warranted (UMIN000010635).
Prognostic and predictive effect of microsatellite instability (MSI) in MAGIC.
Authors: Smyth Elizabeth Catherine , Hulkki Wilson Sanna , Nankivell Matthew Guy , Gonzalez de Castro David , Wotherspoon Andrew , Okines Alicia Frances Clare , Langley Ruth E , Stenning Sally Patricia , Cunningham David
Published: February 2017

62

Background: MSI is prognostic for survival in diverse cancers and predicts resistance to fluoropyrimidine chemotherapy in colon cancer. We examined the interaction between MSI and patient (pt) characteristics and survival for pts randomised to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. Methods: Tumor and normal control DNA was extracted from resection FFPE. MSI status was determined using the Promega MSI Analysis System (NR-21, BAT-26, BAT-25, NR-24, MONO-27). Tumors were classified as MSS when all markers were stable, MSI-L when only one marker was unstable and MSI-H with minimum of instability in two markers. MSI status was correlated with pt characteristics and survival. Results: MSI results were available for 303 pts (66% resected pts). Twenty (6.6%) and 2 (0.6%) pts were MSI-H and MSI-L. All pts with MSI-H had stomach tumors (vs.GEJ/esophagus). KRAS mutation was more common in MSI-H tumours (30% vs. 4%, p-value <0.001); rates of BRAF, PIK3CA and TP53 mutations were comparable. Median overall survival (OS) from surgery was greater for pts with MSI-H tumours treated with surgery alone (1.69y for MSS vs. not reached for MSI-H) (Table 1), whereas patients with MSI-H tumors treated with chemotherapy plus surgery had inferior outcomes compared to MSS stable pts (median OS 0.8y vs. 1.89y respectively). An interaction test for MSI-H vs. MSS status and treatment arm was positive (p=0.007). Conclusions: In MAGIC, MSI-H status is associated with a positive prognostic effect in pts treated with surgery alone, and a negative predictive effect in pts treated with chemotherapy. As pt selection biomarkers for perioperative chemotherapy are lacking, validation of this finding in an independent dataset is warranted. [Table: see text]
Association of the apoptotic effect of the coffee deterpene kahweol on human colon cancer cell with the expression of heat shock proteins (HSPs).
Authors: Park Sung Chul , Choi Dong Wook , Park Jin Myung , Choi Dae Hee , Kang Chang Don , Lee Sung Joon , Chun Wan Joo
Published: February 2017

622

Background: It has been reported that coffee has a preventative effect in several cancers because of its anti-oxidant, anti-inflammatory, and anti-tumor properties. However, there have been few reports about the effect and mechanism of coffee compounds in colorectal cancer. Heat shock proteins (HSPs) are molecular chaperones that prevent cell death. Their expression is significantly elevated in many tumors and is accompanied by increased cell proliferation, metastasis, and poor response to chemotherapy. Methods: We investigated the apoptotic effect of major components of coffee in the HT-29 human colon adenocarcinoma cells and evaluated the antitumor mechanism via the regulation of HSPs expression. HT-29 cells were cultured with bioactive compounds of coffee such as caffeine, chlorogenic acid, caffeic acid, and kahweol. Cell viability was determined by MTT and LDH assay according to the concentration of each component. Western blot assay was taken for evaluation of the apoptosis-related signals such as cleaved caspase-3, cleaved PAPR, Bcl-2, phospho-AKT(p-AKT), and HSPs including HSP40, HSP70, and HSP90. Results: Among the various coffee compounds, only kahweol showed significant anti-tumor cell activity, and cell death was observed in a concentration-dependent manner on MTT and LDH assay. Kahweol induced an increase in expression of cleaved caspase-3 and PAPR. In contrast, the reduction of anti-apoptotic proteins such as Bcl-2 and p-AKT was derived. HSPs including HSP40, HSP70, and HSP90 were decreased by kahweol treatment. HSP70 inhibitor such as quercetin and triptolide showed the significantly decreased viability of HT-29 cells. Conclusions: Kahweol had a cytotoxic effect on HT-29 cells via the apoptotic signal pathway in a concentration-dependent manner and inhibited the expressions of HSPs. HSP70 inhibitors showed tumor cell cytotoxicity, suggesting that HSP might play a significant role in the proliferation of cancer cells.
Somatic mutations in young-onset colorectal cancer unrelated to hereditary syndromes: A comparative study using high-depth targeted exome sequencing.
Authors: You Y. Nancy , Chang Kyle , Chen Ken , Mehdizadeh Amir , Cuddy Amanda , Lieu Christopher Hanyoung , Shaw Kenna Rael , Vilar Sanchez Eduardo , Eng Cathy
Published: February 2017

623

Background: Colorectal cancer (CRC) is being increasingly diagnosed among young adults, but known hereditary syndromes do not account for the majority of these cases. Young patients often present with metastatic disease and exhibit aggressive clinical courses. We aimed to elucidate the potentially unique biology of young-onset CRC. Methods: Patients diagnosed with metastatic CRC prior to age 40 without a known predisposing syndrome (young-onset) were compared to similar patients diagnosed after age 60 (later-onset). Primary and/or metastatic tumor tissues from 19 young- and 51 later-onset patients underwent targeted exome sequencing on a panel of 200 genes using Illumina HiSeq2000 performed by the Institute of Personalized Cancer Therapeutics of MD Anderson Cancer Center. Sequencing was to an average depth of 800x; single nucleotide variations (SNVs) were called according to in-house algorithms. Results: The median age of patients with young-onset CRCs was 34 years (interquartile range: 31-37), while that of later-onset CRCs was 66 years (IQR: 62- 72). The primary CRC was in the rectum in 30% of the young- vs. 16% of the later-onset cases. The overall mutational rate as measured by the number of SNVs per patient (median: 7 vs. 9) did not differ significantly between the groups. However, the median allelic frequency of SNVs was higher in the young-onset group (0.34 vs. 0.17%), suggesting differing patterns of tumor heterogeneity. Genes known to be associated with CRC carcinogenesis were mutated at different proportions (Table); SMAD4, mismatch repair genes (MSH6, MLH1, MSH2), ARID1A, IGF1R and KITappear to be more frequently mutated among the young. Conclusions: This exploratory study suggests that the somatic mutation profiles are distinct between young- vs. later-onset CRCs. More in-depth analysis of the genomic landscape of young-onset CRCs may reveal distinct and novel therapeutic avenues. [Table: see text]