bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of anti-CD3 x anti-EGFR–armed activated T-cells for treatment of advanced colorectal or pancreatic cancer.
Authors: Choi Minsig , Dyson Greg , Thakur Archana , Mahaseth Hemchandra , Philip Philip Agop , Shields Anthony Frank , Deol Abhinav , Lum Lawrence G. 
Published: February 2017

698 Background: Advanced colorectal cancer (CRC) and pancreatic cancer (PC) are common gastrointestinal cancers with poor prognosis. Novel therapy with less toxicity using immune system is an attractive avenue for treatment. Preclinical studies have shown targeted tumor cell killing when anti-CD3 and anti-EGFR were heteroconjugated (EGFRBi) and added to cell cultures of colon cancer, lung cancer and breast cancer including tumor-xenograft models. Methods: Patients who have no standard treatment options with advanced CRC and PC were treated with immunotherapy. Peripheral blood mononuclear cells (PBMC) for the generation of armed activated T cells (ATC) was collected using 1 leukapheresis to obtain 8-20 x 109 PBMC for T cell expansion. The PBMC was activated with anti-CD3 monoclonal antibody (anti-CD3) and expanded in IL-2. ATC was harvested, armed with EGFRBi, and cryopreserved in aliquots for 4 infusions. The primary objective of the study was to determine the feasibility and safety of immunotherapy. Secondary endpoints were immune response, tumor response and overall survival. Results: The study accrued 13 patients with 10 patients receiving at least 3 weekly immunotherapy. In two patients (age 73 and 78) no viable cells were grown and one patient developed symptomatic brain metastasis after leukapharesis. Median age was 58 (50-78) and 8 patients had CRC and 5 patients had PC. Total of 34 billion activated T cells ( range 0-50 billions) were infused with no significant toxicity. Infusion related headache, fever, chills and blood pressure changes was most common adverse events and most of the symptoms resolved within 48 hours of infusion. No objective tumor regression was noted but stable disease was noted lasting 2.5 to 7.6 months. Among 10 patients treated with immunotherapy OS was 13.4 months while 3 patients who did not receive therapy was 5.4 months. Overall survival for all patients (n=13) was 11.4 months. Conclusions: Activated T-cells armed with anti-CD3 x anti-EGFR can be produced and infused in patients with advanced CRC and PC with minimal toxicity. Further studies in larger number of patient will test efficacy of this immunotherapy strategy (clinical trial info NCT01420874). Clinical trial information: NCT01420874.
Comprehensive genomic profiling (CGP) of advanced stage esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) to reveal similarities and differences.
Authors: Wang Kai , Chmielecki Juliann , Ali Siraj M. , Elvin Julia Andrea , Yelensky Roman , Lipson Doron , Miller Vincent A. , Stephens Philip J. , Ross Jeffrey S. 
Published: February 2017

7 Background: ESCC and EAC are relatively rare malignancies in the US with EAC more common than ESCC. Using a sensitive CGP assay, we compared the genomic profiles of ESCC and EAC focused on the search for therapy targets. Methods: DNA was extracted from 40u of FFPE sections from 54 clinically advanced ESCC and 234 EAC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a median coverage depth of 652X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alterations (GA) including point mutations, short INDELs, copy number alterations and fusions/rearrangements. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: All ESCC and EAC were at an advanced stage (Stage III/IV) at the time of CGP and had similar gender and age (median 63 yrs) distribution. 54 (100%) of ESCC and 233 (99.6%) of EAC featured GA on profiling with 397 GA in ESCC (7.4/sample) and 1,317 GA (5.6/sample) in EAC. The frequency of clinically relevant GA in ESCC (2.7/sample; 93% of cases) and EAC (2.7/sample; 92% of cases) were identical. EAC featured a greater number of CRGA (72) than ESCC (46). CRGA more frequently altered in EAC than ESCC included KRAS (23% vs 7%) and ERBB2 (23% vs 4%). CRGA more frequently identified in ESCC than EAC included PIK3CA (28% vs 10%), PTEN (13% vs 4%) and NOTCH1 (22% vs 3%). Other GA that were significantly different in the 2 tumor types included SMAD4 (14% EAC vs 0% ESCC), RB1 (19% ESCC vs 2% EAC), SOX2 (17% ESCC vs 1% EAC) and NFE2L2(19% ESCC vs 0% EAC). HPV-16 was detected in 2 (4%) and HPV-18 in 1 (2%) of ESCC. HPV was not detected in EAC. Conclusions: ESCC and EAC share high frequencies of total GA and CRGA. However, KRAS and ERBB2 are far more frequently altered in EAC than ESCC and mTOR pathway genes (PIK3CA and PTEN) more frequently altered in ESCC than EAC. CGP shows significant promise to identify CRGA in both ESCC and EAC and drive the potential use of clinical outcome altering targeted therapies in both major types of esophageal cancer.
siRNA library screening to define esophageal adenocarcinoma cell survival factors.
Authors: Duggan Shane P , Garry Catherine , Behan Fiona , Kirca Murat , MacGarrigle Sarah , Kudo Hiromi , Goldin Robert D , Botto Marina , Long Aideen , Kelleher Dermot P 
Published: February 2017

70 Background: There is a pressing need to identify new therapeutic targets for esophageal adenocarcinoma (EAC). Hence, we utilized siRNA-screening libraries to identify genes impacting on EAC cancer cell growth to identify potential therapeutic targets. Methods: A “druggable genome” library (6,022 individual siRNAs) was utilized to examine EAC cell survival using the MTT assay. Statistical analysis combined the use of Z-factor, t-test and SSMD. EAC cell lines GohTRT, SKGT4 and OE33 were utilized. Functional validation of the resulting siRNAs utilized RT-PCR, Western Blot, ELISA and TOPFLASH assays. Results: siRNA library screening resulted in positive quality metrics (Z-factor>0.5) confirming its validity and further identifying 118 high confidence gene targets affecting EAC cell growth. Verification of these siRNA targets in multiple cell lines indicated a good level of concordance with the primary screening data. Bioinformatic and pathway mapping approaches of these targets emphasized links between EAC cell proliferation and regulators of inflammation and “immune cell processes” (LIF, C1Qa, C1r, C1s, GDF15, IL9R and TREM2). Pathological and transcriptomic studies demonstrated that LIF (FC=96.7; P<0.0001), GDF15 (EAC: FC=74; P<0.0001), C1Qa and TREM2 may be up-regulated in EAC biopsies. In functional work, exposure of EAC cell lines to recombinant or native proteins of C1q, LIF and GDF15 rescued the observed effects of their respective silencing in EAC cells (>90%,p0.001) and acted as potential growth promoters (>40%, p0.01). Auto-regulatory feedback loops were discovered in response to treatment with exogenous C1q and LIF in EAC cells. Signal transduction could be induced through b-catenin stabilization and STAT3 pathways in response to C1q and LIF treatment respectively. GDF15 was observed to act in a similar fashion to TGFb in scratch wound assays and additionally regulate Th17 type T-cell differentiation. Conclusions: Genes regulating EAC proliferation have been defined by siRNA library screening. We have identified secreted immune factors, not previously associated with EAC biology, capable of regulating EAC cell survival.
Benefit of adjuvant chemotherapy in patients with T4, UICC II colon cancer.
Authors: Teufel Andreas , Gerken Michael , Hartl Janine , Itzel Timo , Fichtner-Feigl Stefan , Stroszczynski Christian , Schlitt Hans J. , Hofstaedter Ferdinand , Klinkhammer-Schalke Monika 
Published: February 2017

700 Background: Colorectal cancer is the third most common cancer and a major cause of morbidity and mortality worldwide. Adjuvant chemotherapy is considered standard of care in patients with UICC stage III colon cancer after R0-resection. For patients with UICC stage II colon cancer, a benefit of adjuvant therapy was not demonstrated. However, there is an ongoing discussion whether adjuvant chemotherapy may be beneficial for a subgroup of UICC II patients with "high-risk situation" (e.g., T4 situation). Methods: We investigated our Bavarian, population based (2.1 million inhabitants) cohort of 1,937 patients with UICC II CRC for a benefit of adjuvant chemotherapy in patients with larger (T4) tumors. Patients over 80 years were excluded. Of these patients, 240 patients had a T4 tumor (12%). 77 of all T4 patients received postoperative chemotherapy (33%). Survival analyses were performed using Kaplan Meier analysis and Cox regression models. Results: Patients with a T4 tumor who received postoperative chemotherapy had a highly significant survival benefit with respect to overall survival (p<0.001) and recurrence free survival (p=0.008). However, no difference was seen between oxaliplatin containing or non-oxaliplatin containing treatment regimens. Finally, G2 and G3 tumors were demonstrated to particularly benefit from adjuvant treatment. Chemotherapy, age at diagnosis and tumor grading remained independent risk factors in multivariable cox regression analysis. Conclusions: Overall, our retrospective study demonstrated a significant benefit of an adjuvant chemotherapy in the T4 UICC II subgroup of patients with colon cancer. Based on our data adjuvant chemotherapy should strongly be considered in these patients.
Phase I/II trial of IMMU-132 (isactuzumab govitecan), an anti-Trop-2-SN-38 antibody drug conjugate (ADC): Results in patients with metastatic gastrointestinal (GI) cancers.
Authors: Starodub Alexander , Ocean Allyson J. , Messersmith Wells A. , Picozzi Vincent J. , Guarino Michael J. , Thomas Sajeve Samuel , Bardia Aditya , Shah Manish A. , Govindan Serengulam V. , Maliakal Pius P , Wegener William A. , Hamburger Steven A. , Sharkey Robert M. , Goldenberg David M. 
Published: February 2017

703 Background: Trop-2 is a tumor-associated glycoprotein highly expressed in many epithelial cancers. Elevated expression has been linked to more aggressive disease and a poorer prognosis. IMMU-132 is an ADC comprising a humanized mAb binding to Trop-2 and conjugated to SN-38 (drug: Ab ratio = 7.6), the active metabolite of irinotecan. After finding potent activity in human tumor xenografts, a phase I/II trial was undertaken (NCT01631552). Methods: Pts with relapsed/refractory metastatic cancers were enrolled, starting at a dose of 8 mg/kg given on days 1 and 8 of a 3-week cycle. Dose levels of 8 and 10 mg/kg were chosen for phase II (N=47). Results: Sixty pts with advanced GI cancers were enrolled in phase I/II. Neutropenia was the principal dose-limiting toxicity, with fatigue, diarrhea, nausea, and vomiting as other reported toxicities. In the phase II pts with median prior therapies of 3 (range 1-7), the following moderate/severe drug-related toxicities occurred: neutropenia (Gr 3, 18.8%; Gr 4, 10.4%); fatigue (Gr 3, 14.6%; Gr 4, 0%), anemia (Gr 3, 10.4%; Gr 4, 0%); diarrhea (Gr 3, 4.2%; Gr 4, 0%). Of 29 CRC pts (10 mg/kg [N=9], 8 mg/kg [N=20]), 1 had a PR and 14 had SD as the best response by RECIST, with a time to progression (TTP) of 11.5+ months (mo) for the PR (65% shrinkage) and a median of 4.8+ mo for the SD pts (5 ongoing). This is a disease control rate (DCR) of 51.7%. Thirteen CRC pts had KRAS mutations, 7 with SD (median TTP = 4.4+ mo [range, 2.8-7.8 mo; 3 ongoing]). Of 15 pts with pancreatic ca, 8 had SD as best RECIST response (median TTP = 3.4 mo); DCR=53.3%. Among 11 pts with esophageal ca, 7 had CT assessments with 1 PR (TTP, 6.9+ mo), and 4 SD (TTP, 4.0+, 5.0, 6.0, and 6.9 mo) as best response; DCR=62.5%. Of 5 gastric ca pts, only 3 had post-baseline CT assessments, all with SD (1 with 19% target lesion reduction and an ongoing TTP of 6.7+ mo). Conclusions: IMMU-132 is a novel anti-cancer therapeutic, conjugating a topoisomerase I inhibitor to an internalizing, cancer-selective mAb. This ADC can be given safely and repeatedly over many months to heavily pretreated patients. Encouraging activity in pts with several metastatic gastrointestinal tumors has been observed. Clinical trial information: NCT01631552.
Multicenter phase II trial of neoadjuvant chemotherapy with mFOLFOX6 for stage II/III rectal cancer with a T3/T4 tumor FACT trial.
Authors: Enomoto Toshiyuki , Saida Yoshihisa , Takabayashi Kazuhiro , Nagao Jiro , Koike Junichi , Funahashi Kimihiko , Yoshimatsu Kazuhiko , Yokomizo Hajime , Kan Hayato , Yamada Takeshi , Ishida Hideyuki , Ishibashi Keiichiro , Katsumata Kenji , Hasegawa Hirotoshi , Koda Keiji , Ochiai Takumi , Sakamoto Kazuhiro , Ogawa Shimpei , Itabashi Michio , Kameoka Shingo 
Published: February 2017

713 Background: The efficacy and safety of neoadjuvant chemotherapy with mFOLFOX6 for stage II/III rectal cancer patients with a T3/T4 tumor is still unknown. Methods: Inclusion criteriain this study are as follows: Stage II/III (Ra/Rb) rectal cancer patients with a T3/T4 tumor. The primary endpoint is preoperative response rate, and the secondary endpoints are histological effect, R0 resection rate, pCR rate, down-staging rate, neoadjuvant therapy completion rate, toxicity, the incidence of postoperative complications, and 3-year disease-free survival. Computed tomography was performed after 4 courses of mFOLFOX6. Patients with disease progression (DP) underwent resection of the primary lesion, while those without DP received another 2 courses of treatment. Treatment was discontinued when resection was not possible in patients with DP. Results: Registered patients totaled 53 with a mean age of 60 (38–77). The number of patients with T3 and T4 tumors was 42 and 10, and patients at stages II and III were 10 and 42, respectively. One patient withdrew due to consent retraction. Median relative dose intensity of mFOLFOX6 therapy was 93.2% for L-OHP, 5-FU, and l-LV. Treatment completion was achieved in 96.2% and 84.6% for 4 and 6 courses, respectively, and withdrawal was due to patient’s discretion, not adverse events. Preoperative response rate was 51%. Surgery was performed in 78.8% of patients. Serious (grade ≥3) toxicity included neutropenia (n=5), leukopenia (n=1), thrombocytopenia (n=1), febrile neutropenia (n=1), nausea (n=1), vomiting (n=1), and peripheral neuropathy (n=2). The rates of R0 resection, pCR, and sphincter preservation were 91.0%, 10.3%, and 82.9%. The down staging rate was calculated as 2%. The median follow-up after surgery was 18.0 months. Median DFS was 17.3 months, and 1-year disease-free survival was 78.8%. Median OS was 22.0 months, and 1-year overall survival was 95.7%. Postoperative complications included suture failure (n=3), wound infection (n=2), pneumonia (n=1), and intestinal obstruction (n=1). Conclusions: Neoadjuvant chemotherapy using mFOLFOX6 is a safe and efficacious treatment option for rectal cancer, especially locally advanced disease. Clinical trial information: UMIN000006583.
Risk factors for postoperative complications of a randomized clinical trial: Laparoscopic versus open surgery with D3 lymphadenectomy for stage II/III colon cancer (JCOG0404).
Authors: Nishizawa Yusuke , Ito Masaaki , Saito Norio , Katayama Hiroshi , Mizusawa Junki , Yamaguchi Takashi , Masaki Tadahiko , Fukunaga Yosuke , Murata Kohei , Akagi Tomonori , Inomata Masafumi , Kitano Seigo 
Published: February 2017

717 Background: A randomized controlled trial to confirm the non-inferiority of laparoscopic surgery to open surgery for clinical stage II/III colon cancers in terms of overall survival was conducted. In this ancillary study, we explored the risk factors for postoperative complications of laparoscopic surgery and open surgery. Methods: Eligibility criteria included colon cancer; tumor located in the cecum, ascending, sigmoid, or rectosigmoid colon; T3 or T4 without involvement of other organs; N0-2; and M0. Postoperative complications which were observed from the end of the operation to discharge were graded according to the CTCAE 3.0. Multivariate analysis was performed using logistic regression model. Results: Between October 2004 and March 2009, a total of 1,057 patients from 30 Japanese centers were registered. By per-protocol set, 524 patients underwent open surgery (OPEN) and 533 patients underwent laparoscopic surgery (LAP). Proportion of any grade (G) complication was 18.3% (OPEN 22.3%, LAP 14.3%), G2–G3 was 12.9% (OPEN 13.9%, LAP 11.8%), G3 was 5.3% (OPEN 6.9%, LAP 3.8%) and G4 was none. Postoperative complications (G2-G3) included leakage (OPEN 2.1%, LAP 1.9%), ileus (OPEN:1.5%, LAP:0.9%), and wound complication (OPEN: 0.2%, LAP: none). Multivariate analysis revealed that risk factors for postoperative complications were operation times 240 min or more (p=0.0019, odds ratio [OR] 2.01 [95% CI: 1.30-3.13]) and open surgery (p=0.0001, OR 2.05 [95% CI: 1.41-2.98]). Conclusions: Operation times more than 240 min and open surgery were considered to be the risk factors for postoperative complications for clinical stage II/III colon cancers. Clinical trial information: C000000105.
Possible predictive clinical factors for chemotherapy holiday in metastatic colorectal cancer: A single institution–based retrospective data analysis.
Authors: Tumula Praveen Kumar , Tapan Umit , Hartshorn Kevan L. 
Published: February 2017

720 Background: During the last decade, numerous new agents were introduced into the therapy of metastatic colorectal cancer. For those patients who are not curable by resection, life can be extended with chemotherapy. However, it is not possible to predict who can safely take breaks without compromising survival. We sought to evaluate the relationship between various possible predictive factors and the duration of break from chemotherapy in patients with metastatic colorectal cancer. Methods: The hospital’s cancer registry was used to identify metastatic colon cancer cases diagnosed from January 2008 to December 2012. To be included in the study, the patient must have been diagnosed with colorectal adenocarcinoma, treated with a fluoropyrimidine based chemotherapy regimen and had planned treatment breaks. Retrospective chart review of electronic medical records was used to collect patient characteristics, including age, performance status (ECOG), comorbidities, disease burden (number of metastasis), and response to the initial treatment. Multivariate regression analysis was performed to observe impact of various variables on the duration of break from chemotherapy. Results: A total of 110 patients were diagnosed with metastatic colorectal cancer between 2008 to 2012 and 27 (24.5%) subjects in the initial analysis met the inclusion criteria, with a mean age of 56 years. The percentage of male and female patients was 37% and 63%, respectively. Patients who had a complete response to the initial chemotherapy (n=6) had 69±23 week breaks which was significantly longer (p<0.01) than the 17±2 and 13±5 week breaks of those with partial response or stable disease. In multivariate regression analysis, degree of response was a significant predictor for chemotherapy breaks (CI 0.36 – 1.77, p=0.005). No statistical difference was noted in other variables. Conclusions: These preliminary findings suggest that complete response to initial chemotherapy may be a strong predictor of patients who can safely undergo chemotherapy breaks. This study also raises the possibility that various factors could influence break from chemotherapy.
Tumor necrosis as prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer.
Authors: Jung Ji Han , Kim Hyung Jin , An Ho Jung , Kim Sung Whan , Cho Hyun Min , Shim Byoungyong 
Published: February 2017

722 Background: Association between treatment response on the basis of pathologic stage evaluated after radical tumor resection and patient prognosis was well established. The object of this study is that tumor necrosis factor after CRT is also important as treatment response. Methods: A total of 243 patients with locally advanced rectal cancer that underwent neoadjuvant CRT was included. Three treatment response groups were classified by their pathologic stage results: complete treatment response (CTR), intermediate treatment response (ITR), and poor treatment response (PTR). Three tissue necrosis groups were classified by tissue pathologic results: complete necrosis response (CNR), intermediate necrosis response (INR), and poor necrosis response (PNR). Results: Overall survival (OS) and recurrence free survival (RFS) rate at 3 years were 74.5% and 61.3%, respectively. The 3-year OS rates of the CTR, ITR, and PTR were 83.7%, 75.9%, and 69.7%, respectively (p<0.001); the 3-year RFS rates were 76.7%, 69.0%, and 52.1%, respectively (p<0.001). The 3-year OS rates of the CNR, INR, and PNR were 83.7%, 80.6%, and 61.8%, respectively (p<0.001); the 3-year RFS rates were 76.7%, 68.9%, and 44.3%, respectively (p<0.001). When compared to CTR / CNR, PTR / PNR was strongly related to an increased risk of recurrence (hazard ratio, 5.53; 95% CI, 2.01 to 15.23 / 6.37; 95% CI, 2.29 to 17.74) respectively in the univariate Cox regression. Therefore in the two models using multivariate Cox regression, both PTR and PNR were strongly associated to RFS and OS compared with CTR and CNR. Conclusions: The tissue response factor to neoadjuvant CRT is one surrogate marker for recurrence and oncologic outcomes and almost as important as the treatment response factor in rectal cancer patients treated with neo-adjuvant CRT.
Effect of neoadjuvant pelvic perfusion on symptom control and resection of pelvic recurrent rectal cancer.
Authors: Wanebo Harold J. , Begossi Giovanni J. , Gustafson Eric , Belliveau James 
Published: February 2017

723 Background: Isolated pelvic perfusion (IPP) may improve disease control and facilitate pelvic resection in selected high-risk patients with advanced recurrent rectal cancer by reducing painful tumor burden and lessening chances of recurrence. Methods: IPP was done in 42 patients with locally advanced previously irradiated rectal cancer, 26 as preoperative therapy and 16 for palliation. A comparative larger non-perfused group included 63 patients with pelvic resection only via abdominal sacral resection (ABSR) for recurrent rectal cancer. Isolated pelvic perfusion (IPP) with a pump oxygenator, (temp > 41ºc), delivered sequential (q 10 minutes) chemotherapy:– 5FU (5fluorouracil) 1,500 mg/m2, cisplatin/oxaliplatin 100/150 mg/m2, mitomycin 10mg/m2, for 60 minutes in 42 patients. Results: Palliative IPP in 16 advanced rectal cancer patients resulted in significant relief (1–4 months) of narcotic resistant pain (in 70%). Pre-operative IPP in 26 locally advanced rectal cancer patients achieved a clinical path (CR) in 2 patients, and significant regression in 11 patients rendering them resectable. Seven had RO pelvic resections. Of 6 other patients, 4 refused surgery, 2 were medically excluded. Median survival was 30 months in 7 resected patients (all had RO resections) and 2 were 5-year survivors. This is compared to outcome in 63 patients having pelvic resection alone for recurrence: 57 % had RO resection (median OS = 36 months), 28% had R1 resection (median OS = 15 months) and 15% had R2 resection (marrow invasion) (median OS = 21 months). Conclusions: Neoadjuvant IPP may facilitate resection of advanced or (borderline resectable) recurrent rectal cancer by reducing tumor bulk and identifying therapeutic responders likely to benefit from major pelvic resection while excluding non-responders mostly likely to benefit from non-surgical therapy. The potential to induce regression and facilitate RO resection merits further exploration