bluuebunny/crossref_metadata_2025 huggingface dataset:
C-reactive protein on postoperative day 3 as a predictor of infectious complications following gastric cancer resection.
Authors: Fujitani Kazumasa , Shishido Yuji , Yamamoto Kazuyoshi , Hirao Motohiro , Tsujinaka Toshimasa , Sekimoto Mitsugu
Published: February 2017

26

Background: Postoperative infectious complications (PICs) after gastric cancer resection remain a clinically relevant problem. Early detection of PICs, before critical illness develops, may be of considerable clinical benefit. The aims of this study were to investigate the predictive factors for PICs and to define the clinical parameters for their early detection in patients with gastric cancer resection. Methods: Clinical data of 417 consecutive patients undergoing elective gastrectomy for primary gastric cancer between 2009 and 2012 were retrospectively analyzed. Diagnostic accuracy was determined by the area under the receiver operating characteristic curve (AUC). Univariate and multivariate logistic regression analyses identified clinical factors predicting PICs of grade III or more according to the Clavien-Dindo classification. Results: Forty-four patients developed PICs of grade ≥ III (10.6%, 95% confidence interval [CI] 7.6–13.5%). As a systemic inflammatory marker, C-reactive protein (CRP) on postoperative day (POD) 3 had superior diagnostic accuracy for PICs (AUC 0.802, 95% CI 0.735–0.870) with a calculated cut-off value of 17.7 mg/dl, yielding a sensitivity of 0.66 (95% CI 0.524–0.774) and a specificity of 0.84 (95% CI 0.821–0.850). Multivariate analysis identified CRP on POD 3 of 17.7 mg/dl or greater (odds ratio [OR] 8.094, 95% CI 3.568–19.342) as well as clinical stage ≥ II (OR 4.445, 95% CI 1.478–15.881) and operation time ≥ 250 min (OR 3.638, 95% CI 1.449–10.137) as significant predictive factors for PICs after gastrectomy. Conclusions: Elevated CRP levels on POD 3 will help physicians predict postoperative course and facilitate decision-making regarding the prompt, comprehensive clinical search and therapeutic approach for PICs.
Tumor profiling of biliary tract carcinomas to reveal distinct molecular alterations and potential therapeutic targets.
Authors: Holcombe Randall F. , Xiu Joanne , Pishvaian Michael J. , Millis Sherri Z. , Gatalica Zoran , Reddy Sandeep K. , Sicklick Jason K. , Fanta Paul T. , Kesari Santosh , Morse Michael
Published: February 2017

285

Background: Extrahepatic cholangiocarcinoma (EHCC), intrahepatic cholangiocarcinoma (IHCC), and gallbladder carcinoma (GBCA) are rare tumors with poor prognosis that tend to be chemo-resistant. The underlying molecular alterations and their correlation with altered responses to therapies are not well understood. We hypothesized that delineation of different molecular alterations in the cancer types might potentially yield different therapeutic options. Methods: 815 cases (126 EHCC, 434 IHCC, 244 GBCA, 11 NOS) were tested by a commercial multiplatform profiling service (Caris Life Sciences, Phoenix, AZ). Tests included sequencing (Sanger, NGS), gene amplification (CISH/FISH), and protein expression (IHC). Results: 24 of 47 genes tested had mutations, with the highest rates in TP53 (28%), KRAS (18%), IDH1 (9%), and SMAD4 (6%). BRCA1/2 mutations were seen in 3/41 (7.3%) and 5/40 (12.5%) cases. Overall,IHC showed high TOPO1, TOP2A, PD-1, SPARC and PD-L1 in 56%, 49%, 40%, 39% and 15% of cases and low RRM1, ERCC1 and TS in 82%, 72% and 79%, respectively, suggesting potential utility of chemotherapeutic and immunomodulatory agents targeting these alterations in selected cases. Mutually exclusive protein loss of chromatin modifiers BAP1 and PBRM1 were seen in 17% and 27%. ROS1 break-apart FISH showed negative results in 16 cases tested. Comparing the three carcinomas (EHCC, IHCC and GBCA, Table), EHCC had the highest KRAS mutation rate; IHCC had the highest IDH1 mutation; GBCA and EHCC had significantly higher TP53 mutation and HER2 amplification than IHCC.IDH1 and TP53 mutations were mutually exclusive, and IDH1-mutated IHCC had higher P-glycoprotein expression than TP53-mutated IHCC (82% vs. 37%). GBCA had high TOP2A by FISH and IHC, and a high loss of PBRM1(all p<0.05). Conclusions: Multiplatform cancer profiling reveals distinctbiomarker characteristics of biliary tract carcinomas, offering insights into disease biology and suggests potential sensitivity to novel and conventional therapies. Further analyses with clinical correlation are warranted. [Table: see text]
Influence of IP-10/CXCL10 induction in human pancreatic cancer stroma on lymphocytes recruitment and correlation with survival.
Authors: Brunner Thomas B , Lunardi Serena , Jamieson Nigel B , Lim Su Yin , Griffiths Kristin L , Carvalho-Gaspar Manuela Maria , Al-Assar Osama , Carter Ross , McKay Colin J , Spoletini Gabriele , D'Ugo Stefano , Silva Michael A , Samson Owen J , Janssen Klaus Peter , Muschel Ruth J
Published: February 2017

290

Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3+ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.
Prognostic value of tumor-infiltrating lymphocytes (TILs) and expression of PD-L1 in cholangiocarcinoma.
Authors: Suleiman Yaman , Coppola Domenico , Zibadi Sherma , Dalia Samir , Juan TzuHua , Lee Jae K , Malafa Mokenge Peter , Soliman Hatem Hussein , Kim Richard D.
Published: February 2017

294

Background: Cholangiocarcinoma is a malignancy arising from the epithelial cells of the biliary tract with poor prognosis. Tumor-infiltrating lymphocytes (TILs) have a prognostic impact in various solid tumors. We aimed to investigate TIL expression and programmed cell death ligand PD-L1 and their clinical relevance in cholangiocarcinoma. Methods: Formalin-fixed paraffin-embedded tumor samples from thirty seven patients with resected and histologically verified cholangiocarcinoma between 1990 and 2011 were identified and immunohistochemically (IHC) stained with anti CD8, anti CD45RO and the anti-PDL1 mouseIgG1 (clone 5H1; Thompson) antibodies on a Leica automated IHC platform. The stains were semiquantitatively analyzed using the AllRed score system (range 1 to 8). Cases with IHC score > 3 were considered positive. The association between PDL1, CD45R0, overall survival (OS) and progressive free survival (PFS) was investigated using Kaplan-Meier survival and COX proportional hazard regression analyses. Results: The median age of patients was 64 (41-85) with 51% male. 25%, 59%, 10% and 5% were stage I, II, III, and IV respectively. CD8 was positive in 10/37 (27%) with median IHC of 5, CD45R0 (specimen with lymph node like structure) was positive in 16/37 (43%) with median IHC score of 4, PD-L1 was positive in 35/37 (94 %) with median IHC score of 8. Pts with tumors exhibiting lymph node (LN) like structures (CD45RO+) has better median OS (63 months vs 18 months, P = 0.0065) and median PFS (29 months vs 14.6 months, P = 0.05) than patients lacking LN like structures (CD45RO-). 5 yrs. OS in CD45RO+ was 64% vs 20% in CD45RO- (P 0.006) whereas 5 yrs. PFS in CD45RO+ was 41% vs. 8% in in CD45RO- pts (P value 0.05). Correlating PDL1 with OS and PFS was not done due to high expression of PD-L1 in most of the samples (94%). Conclusions: Presence of lymph node like structures (CD45RO+) was associated with significant better outcome reflecting the immune-mediated killing of tumor cells. The high expression of PD-L1 on cholangiocarcinoma cells represents a potential therapeutic target which may improve the prognosis for this dismal cancer. Future trials involving PD-L1 inhibitors in cholangiocarcinoma are warranted.
Clinical activity and correlative DCE-MRI imaging of G-202, a thapsigargin-based prostate-specific membrane antigen-activated prodrug, in progressive hepatocellular cancer.
Authors: Mahalingam Devalingam , Tubb Benjamin , Nemunaitis John J. , Cen Putao , Rowe Julie Haewon , Sarantopoulos John , Kurman Michael R. , Allgood Victoria , Campos Luis T.
Published: February 2017

301

Background: G-202 is a thapsigargin-based prodrug whose cytotoxic activity is blocked by a masking peptide that is cleaved by prostate-specific membrane antigen (PSMA), a membrane-bound protease expressed in prostate cancer and the endothelium of tumor vasculature but not in most other tissues or normal tissue vasculature. In a Phase I study of G-202, prolonged disease stabilization was observed in the subset of patients with hepatocellular carcinoma (HCC) and prompted development of a Phase II study to further evaluate activity of G-202 in patients with HCC who have progressed on sorafenib. Methods: G-202 is administered by iv infusion on Days 1, 2 and 3 of a 28-day cycle; prophylactic hydration is administered with infusion to ameliorate incidence of creatinine elevations. HCC is typically highly-vascularized, and DCE-MRI is performed in consenting patients at baseline and after treatment on approximately Day 6 of Cycle 2 to evaluate possible effects of G-202 on blood flow metrics in hepatic lesions. DCE-MRI is a non-invasive method of investigating vascular structure and function and is sensitive to alterations in vascular permeability and blood flow. DCE-MRI measurements were made on 1.5 Tesla MRI and the volume transfer coefficients, Ktrans, of HCC tumor lesions were calculated using arterial input function derived from signal in abdominal aorta. Results: Among the 22 patients treated to date, G-202 related SAEs in this patient population have been creatinine increase/acute renal failure/acute kidney injury (3 pts) and congestive heart failure (1 pt). While objective responses (CR, PR) have not been observed in these patients with advanced disease, the rate of disease stabilization has been remarkable, with >70% of patients exhibiting SD. In patients undergoing DCE-MRI, an average 56% decrease in Ktranshas been observed after administration of G-202. Conclusions: G-202 is generally well-tolerated and promotes disease stabilization in patients with advanced HCC who have progressed on sorafenib. DCE-MRI findings of decreased tumor Ktrans values suggests that G-202 reduces early arterial blood flow in hepatic lesions. Clinical trial information: NCT01777594.
Evolution of phase 1 trials for patients with advanced pancreatic cancer: An update on the experience from MD Anderson Cancer Center.
Authors: Goldstein Jennifer Brooke , Tang Chad , Hong David S. , Subbiah Vivek , Janku Filip , Hess Kenneth R. , Fu Siqing , Karp Daniel D. , Naing Aung , Tsimberidou Apostolia Maria , Wheler Jennifer J. , Zinner Ralph , Javle Milind M. , Varadhachary Gauri R. , Wolff Robert A. , Fogelman David R. , Meric-Bernstam Funda , Piha-Paul Sarina Anne
Published: February 2017

320

Background: Pancreatic cancer is a disease that generally presents in advanced stage and is nearly fatal in all cases. In 2011, we reported our experience with pancreatic cancer patients enrolled on phase 1 clinical trials from 2004-2009. At the time, gemcitabine and erlotinib were the only US FDA approved drugs for pancreatic cancer. Median overall survival from presentation in the phase 1 clinic was 5 months. After an additional 5 years of progress, we queried the impact of novel cancer therapeutics, evolving molecular profiling, and targeted therapy on pancreatic cancer patient outcomes in the phase 1 setting. Methods: A retrospective review of advanced pancreatic adenocarcinoma patients from the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, was conducted for patients treated from 1/2009 to 1/2014. Statistical analyses utilized the Kaplan-Meier method. Results: A total of 90 patients were identified in 50 trials reviewed. Median age was 62 years (40-84), 57% were male, and 40% had stage IV disease at presentation. Median documented PS was 1 (range 0-3). The median time from diagnosis to treatment on a phase I protocol was 15 months (0.2-119). Patients were treated with an average of 4 prior regimens prior to Phase 1 referral (0-10) with 8% having undergone >5 treatments. The median overall survival from the first phase I treatment was 5.2 months, 95% CI = (4.4-6.3) and the 1 year overall survival from the first phase 1 treatment was 15% (9%- 25%). The median duration on regimen with best phase I response was 1.9 months (0.2-21.3). Of 88 evaluable, the best responses were PR in 1 patient and SD (> 6 months) in 5 patients. Although 47 patients had biomarker profiling performed and 61 patients were treated with targeted therapy alone or in combination with cytotoxic therapy, only 6 patients (5 PD, 1 SD currently on protocol) were placed on trials based on biomarker testing results. Conclusions: Pancreatic cancer remains a difficult disease to treat with poor outcome. Referral to phase 1 occurs late in the disease course. Biomarker based therapies may be more successful with more stringent patient selection and when referred earlier or used prior to cytotoxic treatment.
Prognostic and predictive potential of omics studies from blood in pancreatic cancer patients treated with concurrent radiotherapy, gemcitabine, and cetuximab.
Authors: Huber Peter E , Timke Carmen , Nicolay Nils H , Lopez Ramon
Published: February 2017

326

Background: Pancreatic cancer is a cancer with dismal prognosis. Multimodal therapy approaches integrating targeted drugs into radiochemotherapy regimens may be promising concepts for patients with locally advanced disease. It would be desirable to better understand patterns of therapy response, clinical outcome and side effect spectra by performing gene expression and protein analyses from blood samples before, during and after actual treatments. Methods: At defined time points before, during and after neoadjuvant triple therapy consisting of IMRT +/-gemcitabine chemotherapy +/-cetuximab EGFR antibodies, blood samples were collected from 21 patients with advanced pancreatic cancer. Whole blood transcriptomics was performed using Agilent’s human genome wide microarray platform. Quantitative serum protein analysis was performed using the ‘FastQuant’ (sandwich antibody) system on 20 selected proteins with a focus on cytokines and angiogenesis related proteins. Cluster analyses were performed and array data were correlated to local control, survival, CA19-9 response, and side effects e.g. acne grading and hematotoxicity. Results: Whole blood transcriptomics was feasible and showed statistically significant prognostic and predictive value for therapy specific and patient specific expression signatures. RNA expression signatures obtained before and during treatment course appeared to have significant statistical power to predict CA19-9 response, clinical outcome and side effect parameters. Similarly, the serum proteomic time course correlated with clinical outcome. Moreover, cetuximab increased e.g. PDGF, MCP-1, Rantes, Il-6, Angiopoietin, serum and downregulated TIMP-1, Il-8, and Angiogenin levels while radiochemotherapy had primarily the respective opposite effects. Conclusions: Whole blood analyses provides a promising tool to monitor pancreatic cancer patients undergoing radiotherapy+gemcitabine+cetuximab, and the protein and gene expression “signatures” from blood may be prognostic and predictive for clinical endpoints.
Exploring phosphatase and tensin homolog (PTEN) loss via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) as a potential predictive marker for response to everolimus in patients (pts) with neuroendocrine tumors (NET).
Authors: Khushman Moh'd M. , Gomez Arteaga Alexandra , Diaz Liege , Tinoco Gabriel , Dawar Richa , Bustinza Ernesto , Garcia Monica T. , Fan Yao-Shan , Restrepo Maria , Merchan Jaime R. , Sussman Daniel A. , Slingerland Joyce , Rocha Lima Caio Max S. , Hosein Peter Joel
Published: February 2017

333

Background: Identification of pts with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Exceptional responders to everolimus in NET including pancreatic (PNET) were observed in our cohort of pts. PTEN is a key negative regulator of the phosphatidylinositol 3-kinase(PI3K)/Akt and mammalian target of rapamycin (mTOR) pathway. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to PI3K/Akt/mTOR pathway activation. Inthis study, we explored the role of PTEN as a potential predictive marker of everolimus in pts with NET including PNET. Methods: Between 2010 and 2014, pts with well-differentiated unresectable and metastatic gastrointestinal NET treated at our institution with everolimus were identified. 17 patients had pathology specimens available for testing. PTEN loss detection by FISH was carried out using a commercially available probe for cytoband 10q23, and by IHC using a commercially available antibody. Patients’ response to everolimus was evaluated through August 2014. The primary outcome was PFS and PTEN status was correlated with PFS for any potential association. Results: The median age was 59 years (range 45-78); 7 were male; 8 had PNET (2 gastrinomas, 1 insulinoma and 5 non-functional); 7 had small bowel NET and 2 unknown primary. All pts received everolimus starting at 10mg daily and octreotide LAR. Of the pts with PNETs, 3 had PTEN loss by FISH. Of those, one did not tolerate everolimus. The PFS for the other two pts was 8 and 24 months respectively. Among the 4 pts with intact PTEN; PFS was 14, 26, 3 and 12 months. 1 patient had insufficient tumor for testing. PTEN FISH is ongoing in the 9 non-pancreatic NET pts. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusions: Testing for PTEN loss by FISH is feasible. Due to the small sample size, the role of PTEN loss could not be defined as a predictive marker in PNET. Testing on additional cases is ongoing and will be presented at the meeting.
Outcomes of therasphere radioembolization for neuroendocrine metastases.
Authors: Abbott Andrea M. , Hoffe Sarah E. , Strosberg Jonathan R. , Almhanna Khaldoun , Biebel Benjamin , Choi Junsung , El-Haddad Ghassan , Kis Bela , Sweeney Jennifer , Fulp William J. , Shridhar Ravi
Published: February 2017

371

Background: Neuroendocrine tumors (NET) are a rare group of tumors with variable biologic activity that have a propensity for hepatic metastases. Complete surgical resection or debulking is the standard of care while chemotherapy is reserved for unresectable disease. However, liver directed therapy utilizing radioembolization with yttrium-90 (y90) may offer an alternative modality of treatment to patients with unresectable hepatic disease while minimizing systemic toxicity and providing acceptable overall survival (OS). Methods: A retrospective review of all patients undergoing y90 microsphere treatment for metastatic NET (mNET) from 2009-2013 was conducted. Patient, treatment, and post-treatment variables from initial diagnosis and y90 treatment were collected. Multivariable analysis (MVA) of factors related to OS and treatment toxicity was performed by the Cox proportional hazard model using Wald test and OS estimates were calculated using the Kaplan-Meier method. Results: We identified 74 patients with a median follow-up of 21 months. Median and 2 year OS was 26 months and 56%. Tumor burden was a significant predictor of survival. Two year OS for patients with ≤ 25%, 25-50%, 50-75%, and >75% tumor burden was 63%, 59%, 40%, and 34%, respectively (log-rank p = 0.027). MVA revealed that female gender and higher disease burden were associated with increased mortality; age, location of primary tumor, resection status of the primary tumor, prior chemotherapy, and presence of extrahepatic metastases at the time of treatment were not significant predictors of OS. The majority of patients (88%) experienced a treatment related toxicity; however 72% were Grade 1/2 and only 16% were Grade 3/4. Male gender and prior liver therapy were associated with higher rates of toxicity. Conclusions: Y90 was associated with acceptable OS with minimal severe morbidity in this series of patients with mNET. Lower tumor burden and male gender were associated with better OS. These results suggest that y90 may be a potential treatment alternative for patients with unresectable mNET. Prospective studies evaluating y90 in the treatment of unresectable chemo-refractory mNET are needed.
Phase II study evaluating the association of gemcitabine, trastuzumab, and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1).
Authors: Assenat Eric , Mineur Laurent , Mollevi Caroline , Lombard-Bohas Catherine , Mazard Thibault , Samalin Emmanuelle , Portales Fabienne , Walter Thomas , Ychou Marc
Published: February 2017

379

Background: This study aimed to assess the efficacy and tolerance of the combinationof chemotherapy and two targeted therapies as a first-line treatment in metastatic pancreatic cancer patients. Methods: We designed a phase 2 open-label, non-comparative, multicenter study (NCT01204372). Patients received weekly 1000 mg/m² gemcitabine (3 weeks out of 4), weekly trastuzumab (4 mg/kg the first week, 2 mg/kg afterwards) and erlotinib 100 mg/day per os. The primary endpoint was the disease control rate (DCR) according to RECIST. Using a Fleming’s single-stage procedure, the trial was considered positive if 29 patients had a controlled disease (out of 57 evaluable patients). Secondary endpoints included the safety, the progression-free survival (PFS) and the overall survival (OS). An ancillary study addressed the EGFR, HER2 and KRAS status of the patients. Results: Between June 2010 and July 2013, 62 patients were recruited (37 men). The median age was 62 years (range 35-77). Performance status was 0 (n=27) and 1 (n=35). 10 patients had had a surgery of the primary tumor (PT), of whom 6 had been treated with a gemcitabine-based adjuvant chemotherapy (> 6-month delay). PT were localized in the head (n=25), corpus (n=22) and tail (n=15) of pancreas. The number of metastatic sites varied from 1 (n=25) to ≥ 3 (n=15). The baseline median left ventricular ejection fraction was 65% (range 51-86%). All patients were evaluable for safety and 59 patients for efficacy. Main first cycle treatment-related toxicities included: grade 3 anorexia (27%), asthenia (13%), diarrhea (10%), anemia (6%), and thrombocytopenia (3%); grade 3-4 neutropenia (24%), and mucositis (6%); grade 2-3 cutaneous events (35%). No complete responses were observed. 11 patients had a partial response, 33 a stable disease and 15 a disease progression. Therefore, the DCR was 74.6% (95%CI: 61.6-85.0%). Definitive results for the secondary endpoints will be presented at the meeting. Conclusions: Our results showed that combining gemcitabine, trastuzumab and erlotinib is efficient in terms of DCR. A further study is necessary to investigate this promising association. Funding (Roche SAS). Clinical trial information: NCT01204372.
Neoadjuvant chemoradiation (NACRT) and the prognostic effect of surgical margin (SM) status in pancreatic adenocarcinoma (PAC).
Authors: Wang Lora S , Hoffman John Parker , Handorf Elizabeth , Murphy Colin T. , Cooper Harry S. , Cohen Steven J. , Meyer Joshua E.
Published: February 2017

407

Background: Many studies have associated a R0 resection to have significantly improved survival compared with a R1 resection in PAC. Patients (pts) who undergo NACRT often go to surgery 4-8 weeks after the end of therapy, before the effects of NACRT can be fully manifested. The goal of this study is to evaluate if a positive SM (+SM) after NACRT has the same poor prognosis as a +SM after upfront surgery. Methods: After IRB approval, we retrospectively reviewed all cases of surgically resected PAC at a single institution from Dec 1996 to Jan 2014. Pts were stratified by receipt of NACRT as well as by SM status. We excluded pts treated with palliative intent, metastatic disease at presentation, death within 90 days of surgery, and biliary or ampullary tumors. The primary endpoint was overall survival (OS). We assessed the relationship between pt and tumor variables with treatment/margin combination using Chi-squared tests. OS was examined using Kaplan-Meier curves, and we tested association with treatment/margin using log-rank tests. Results: A total of 213 pts met inclusion criteria; 111 received upfront surgery (group I) with 94 (85%) receiving adjuvant chemotherapy or CRT and 102 received NACRT (group II) with either concurrent 5-fluorouracil (n=18) or gemcitabine (n=84). There were 31 pts with +SM in group I and 29 pts in group II. Pt demographics were balanced. There was more vessel involvement in group II (81%) at diagnosis than group I (11%) (p<0.01) with a trend towards improved OS in group II vs group I (p=0.09). Pathological evaluation revealed more PNI (61% vs 42%, p<0.01) and more lymph node positivity (71% vs 33%, p<0.01) in group I vs group II, respectively. Median OS for group I SM+/SM- and group II SM+/SM- were 15/25 months and 26/32 months respectively. OS is significantly improved with a negative SM (-SM) compared with a +SM (p<0.01). If the SM is positive, pts in group II had improved OS compared with group I (p=0.02). OS was not significantly different for group II +SM vs group I –SM (p=0.34). Conclusions: The negative impact of a +SM on survival is partially mitigated by NACRT. This data further supports the use of NACRT, although it is limited by its retrospective nature and small sample size.
Prognosis of gastric cancer (GC) patients with positive peritoneal cytology.
Authors: Shiozaki Hironori , Elimova Elena , Slack Rebecca , Chen Hsiang-Chun , Staerkel Gregg A , Sneige Nour , Planjery Venkatram , Charalampakis Nikolaos , Wadhwa Roopma , Sudo Kazuki , Matamoros Aurelio , Lee Jeffrey H. , Weston Brian , Bhutani Manoop S. , Blum Mariela A. , Estrella Jeannelyn , Das Prajnan , Mansfield Paul F. , Badgwell Brian D. , Ajani Jaffer A.
Published: February 2017

41

Background: Laparoscopic staging of patients with GC can disclose peritoneal metastases. Although this finding is associated with a poor prognosis, some patients achieve a long-term survival. In an attempt to provide explanation we compared the overall survival (OS) of patients with GC peritoneal metastases from two settings: cytology positive only (Cy+) and grossly positive (Gross+). Methods: 146 GC patients with peritoneal metastases were identified between 2000 and 2014. Cox-model regression was used for overall survival (OS) analyses. Results: Patient/treatment characteristics were as follows: males (66%), good ECOG scores (0-1; 89%), metastases confirmed by a diagnostic laparoscopy (84%), poorly differentiated histology(92%), received chemotherapy (89%), received chemoradiation (22%), and received surgery (10%). The median follow-up time for all patients was 12.9 months and median OS was 15 months. Patients with Gross+ were at higher risk of death compared to Cy+ patients (50% vs. 83%1-year OS, respectively). Only diagnostic laparoscopy and metastasis type (Gross+ vs. Cy+) were significant in both univariate and multivariate OS models. With both factors in the same model, patients with Gross+ were more than twice as likely to die when compared to those with Cy+ (HR=2.23; p=0.001) while patients having a diagnostic laparoscopy were half as likely to die (HR=0.52; p=0.01). Conclusions: The one-year OS of patients with Cy+ peritoneal metastases is significantly longer than those with Gross+ findings. As such, novel strategies for Cy+ patients may further prolong their survival. From U. T. M. D. Anderson Cancer Center (UTMDACC), Houston, Texas, USA. (Supported in part by UTMDACC, and CA 138671 and CA172741 from the NCI).
Impact of FOLFOXIRI regimen on early “conversion” and long-term outcome in patients with initially unresectable colorectal liver metastases.
Authors: Shimada Mitsuo , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Arakawa Yusuke , Iwahashi Shuichi , Saito Yu , Yamada Shinichiro , Higashijima Jun , Takasu Chie
Published: February 2017

416

Background: In our principle, hepatectomy is the first choice for liver metastases (mets) from colorectal cancer whenever future remnant liver is over 40% in volume. Recently, FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab (Bev) regimen was reported to be high rates of pathologic responses and necrosis of colorectal liver metastases (CLMs) without increasing liver toxicity (Br J Cancer 2013). The aim of this retrospective study is to clarify impact of FOLFXIRI plus molecular targeted drugs on initially unresectable CLMs. Methods: Among 81 patients with initially unresectable liver mets, 59 had chemotherapy (CTx), including 10 old CTx (-2003) and 49 new CTx (2004- ) using new drugs such as oxaliplatin. Regimen of FOLFOXIRI + molecular target drugs, consisting of Bev in 12 and C/P-mab in 2, was applied to 14 patients. “Conversion” rate and the period until “Conversion”, and overall survival (OS) were compared between FOLOFOXIRI group and other regimen group. Pathological and morphological responses were also examined. Results: “Conversion” was not obtained in old CTx group. In new CTx group, “Conversion” was achieved in 21 patients (43%). OS in “Convresion” group was better than “non-conversion” group (3-year survival: 70 % vs. 15 %). “Conversion” rate in FOLFOXIRI group was higher than that in other regimen group (64% vs. 34%). The period until “Conversion” in FOLFOXIRI group was shorter than that in other regimen group (6.2 cycles vs. 16.1 cycles). Furthermore, tumor necrosis rate in FOLFOXIRI group (80 %) was higher than that in other regimen group (47 %), and morphologic response (optimal/partial) in FOLFOXIRI group (33 % / 44 %) was higher than in other regimen group (8 % / 33 %). Prognosis after “Conversion” in FOLFOXIRI group was better than that in other regimen group (3-year survival: 80 % vs. 33 %). In addition, time to surgical failure (TSF) in FOLFOXIRI group tended to be better than that in other regimen group. Conclusions: FOLFOXIRI + molecular target drugs is highly effective in order to obtain early conversion and better long-term outcome after ”Conversion” for initially unresectable CLMs.
Nab-paclitaxel as second-line treatment in advanced biliary cancer.
Authors: Prager Gerald W. , Kornek Gabriela , Scheithauer Werner , Steger Guenther G. , Zielinski Christoph , Unseld Matthias
Published: February 2017

463

Background: Addition of nab-paclitaxel to gemcitabine has recently been demonstrated in the clinical phase III trial MPACT to be beneficial for progression free survival, overall response rate, and overall survival in advanced pancreatic cancer patients. Any potential biologic activity of nab-paclitaxel in biliary cancer is hitherto unknown. Methods: A retrospective analysis of patients with advanced biliary cancer was undertaken to determine the disease control rate (CR+PR+SD), progression-free survival and overall survival in patients who had received nab-paclitaxel-based chemotherapy after failure of a platinum-containing first-line combination chemotherapy. Results: Eleven patients were identified. 4 of 11 patients received nab-paclitaxel as second line, 7 of 11 patients as a third-line treatment. 7 of 11 patients received nab-paclitaxel in combination with gemcitabine, while in 4 of 11 patients nab-paclitaxel was combined with fluoropyrimidine. The disease control rate seen with nab-paclitaxel was 81% (nine of eleven patients). Disease was progressive in one patient, and in one patient the response status is unknown yet. One patient received partial remission and 8 patients had stable disease. As of September 13th, 2014, three patients are still undergoing nab-paclitaxel combination therapy, but were censored by this date for analysis. The median time to progression was 4.9 months (2.3 – 18.9 months) for all patients (11/11 pts.), and 9.5 months for patients completed nab-paclitaxel treatment (8/11 pts.). Median overall survival for all eleven patients after initiation of nab-paclitaxel treatment was 7.3 month (2.6 – 21.8 month). The mean time of survival after diagnosis of advanced disease was 21.3 month, whereby 5 patients were alive at date of censoring. Conclusions: Nab-paclitaxel based chemotherapy can be an effective second-line regimen after platinum-failure in patients with advanced biliary cancer. In this small series, nab-paclitaxel appears to have a biological activity by controlling the disease and positively affecting survival. Randomized trials in this group of patients are urged.
Investigation of the tolerability of FOLFIRINOX in patients with unresectable advanced pancreatic cancer: Single-institution experience in Japan.
Authors: Miyashita Kouichirou , Sekikawa Takashi , Shimada Ken , Yamamoto Taikan , Kaga Yasuhiro , Nunoue Toshikazu , Uto Yu , Kitahara Yu , Hisamatsu Atsushi , Saito Yusuke , Kobayashi Kouji , Takinishi Yasutaka , Kinugasa Eriko
Published: February 2017

487

Background: FOLFIRINOX therapy has contributed to the overall survival extension of unresectable advanced pancreatic cancer. This regimen is however associated with significant toxicity. And doing the treatment, while careful to toxicity at our institution. We investigated the tolerability of FOLFIRINOX for the treatment of unresectable advanced pancreatic cancer in clinical practice. Methods: We conducted a retrospective analysis of patients with unresectable advanced pancreatic cancer who received FOLFIRINOX between November 2012 and August 2014. FOLFIRINOX is as follows: irinotecan at 150 mg/m2; oxaliplatin at 85 mg/m2; 5-fluorouracil (5FU) at 400mg/m2 bolus, 2,400mg/m2 continuous infusion. Patients' characteristics, objective response, survival and toxicities were collected. Response were evaluated with RECIST version 1.1 and toxicities with NCI-CTCAE version 4.0. Results: 13 patients were includes (8 males and 5 females). Treatment eligibility criteria in our institution were Performance Status 0 or 1, and UGT1A1 polymorphisms were excluded. Median age was 58.6 years (41-74). Clinical stage IVa/IVb was 3/10. The mean number therapy was 7.7 (3-15) cycles. The toxicity of all grade was 100% and grade 3 was 80%. The non-hematological toxicities included nausea in 8 patients (61.5%) and anorexia in 9 (69.2%). The hematological toxicities included neutropenia in 12 patients (92.3%), of which 11 (84.6%) presented a grade 3/4 neutropenia. In patients who developed grade 3 neutropenia, the treatment of FOLFIRINOX could be continued once every three weeks (triweekly) without reducing the dose. Response rate was 38.5% (CR: 0, PR: 5, SD: 6, PD: 2) and disease control rate was 84.6%. Time to treatment failure was 175 days. Relative dose intensity was 95.0% for oxaliplatin, 88.9% for irinotecan, 81.9% for 5FU (bolus), and 95.6% for 5FU (continuous). Conclusions: In clinical practice, it is expected that FOLFIRINOX is an effective, well-tolerated regimen by reducing the dose or determining the appropriate dosing interval.
Organ preservation in patients with rectal cancer with clinical complete response after neoadjuvant therapy.
Authors: Smith Jesse Joshua , Chow Oliver S , Eaton Anne , Widmar Maria , Nash Garrett Michael , Temple Larissa K. F. , Guillem Jose G. , Weiser Martin R. , Goodman Karyn A. , Cercek Andrea , Saltz Leonard , Gollub Marc J. , Gonen Mithat , Garcia-Aguilar Julio , Paty Philip
Published: February 2017

509

Background: Nonoperative management (NOM) of rectal cancer following a clinical complete response (cCR) to neoadjuvant therapy is a non-standard approach. We review our experience with NOM to evaluate safety and efficacy. Methods: A retrospective review of prospectively collected data between 2006 and 2014 was conducted. We compared patients completing neoadjuvant therapy for stage I to III rectal cancers who: a) achieved cCR and were treated with NOM, or b) underwent standard total mesorectal excision (TME) and achieved a pathologic complete response (pCR). Kaplan-Meier estimates and the log-rank test were used. Results: Seventy-three patients underwent NOM after cCR. From 369 rectal resections performed, 72 (20%) achieved pCR and form the comparison group. Median follow-up across both groups was 3.3 years. Rectal preservation was achieved in 56 (77%) of the patients treated with NOM. Of the 19 NOM patients with local regrowth, 18 were salvaged successfully with standard TME (n=16) or local excision (n=2), with one patient pending a salvage operation (n=1). No significant differences were noted in the number of distant recurrences between the NOM and pCR groups. Four-year disease-specific survival and overall survival between the two groups were not significantly different. Conclusions: In this highly selected group of patients with cCR to neoadjuvant treatment, NOM with surgical salvage of local tumor regrowth achieved local control in all patients. The oncologic outcome for NOM patients at 4 years was comparable to patients with pCR after rectal resection. These data continue to suggest that NOM does not compromise oncologic outcome, and that preservation of the rectum is achieved in a majority of patients. [Table: see text]
RAISE: A randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab (RAM) or placebo (PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a fluoropyrimidine (fp).
Authors: Tabernero Josep , Cohn Allen Lee , Obermannova Radka , Bodoky Gyorgy , Garcia-Carbonero Rocio , Ciuleanu Tudor-Eliade , Portnoy David Craig , Van Cutsem Eric , Grothey Axel , Prausová Jana , Garcia-Alfonso Pilar , Yamazaki Kentaro , Clingan Philip R. , Zagonel Vittorina , Kim Tae Won , Simms Lorinda , Chang Shao-Chun , Nasroulah Federico , Yoshino Takayuki ,   The RAISE Study Investigators
Published: February 2017

512

Background: Angiogenesis is an important therapeutic target in CRC; VEGF plays a key role in angiogenesis. RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The RAISE study evaluated the efficacy and safety of adding RAM to standard second-line treatment FOLFIRI. Methods: Eligible pts with mCRC who progressed on or after first-line combination therapy with bev, ox, and fp, had an ECOG PS of 0 or 1, and adequate organ function were randomized 1:1 (stratified by region, KRAS mutation status, and time to progressive disease [PD] after beginning first-line treatment) to receive RAM (8 mg/kg IV) plus FOLFIRI or PBO plus FOLFIRI every 2 weeks until PD, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Planned sample size of 1,050 pts ensured 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.8. Results: Between Dec 2010 and Aug 2013, 1,072 eligible pts were randomized (RAM 536; PBO 536). Baseline pt characteristics were similar between treatment arms. The OS HR was 0.84 (95% CI: 0.73, 0.98; log-rank p=0.0219). Median OS was 13.3months (m) for RAM vs 11.7m for PBO. The PFS HR was 0.79 (95% CI: 0.70, 0.90; log-rank p = 0.0005). Median PFS with RAM was 5.7m and 4.5m for PBO. ORR was 13.4% RAM; 12.5% PBO (p = 0.6336). Subgroup results were consistent with the OS and PFS results. Grade ≥3 adverse events (AEs) occurring in >5% of pts in RAM+FOLFIRI were: neutropenia (RAM 38.4% vs PBO 23.3% ), hypertension (11.2% vs 2.8%), diarrhea (10.8% vs 9.7%), and fatigue (11.5% vs 7.8%). Conclusions: RAISE met its primary end-point, demonstrating a statistically significant improvement in OS for RAM and FOLFIRI vs PBO and FOLFIRI in second-line mCRC pts. Benefits were similar across important clinical subgroups and no unexpected AEs were identified. Clinical trial information: NCT01183780.
A randomized, double-blind, parallel-group, placebo-controlled, multicenter, phase II clinical study of famitinib in the treatment of advanced metastatic colorectal cancer.
Authors: Xu Rui-hua , Shen Lin , Wang Keming , Wu Gang , Shi Chunmei , Ding Kefeng , Lin Lizhu , Wang Jinwan , Xiong Jianping , Wu Changping , Li Jin , Liu Yunpeng , Wang Dong , Ba Yi , Feng Jueping , Bai Yuxian , Bi JingWang , MA Liwen , Lei Jian , Yu Hao
Published: February 2017

513

Background: Colorectal cancer (CRC) is the third most frequently diagnosed cancer and is the fifth leading cause of cancer death in China. No standard care is available for patients with advanced CRC who failed the second-line treatment. Famitinib is a small-molecular, multi-target receptor tyrosine kinase inhibitor which primarily acts against angiogenesis. This phase II study was designed to evaluate the efficacy and safety of famitinib in the treatment of advanced colorectal cancer. Methods: This is a multi-center, randomized, double-blind, placebo-controlled, phase II clinical study (ClinicalTrials.gov Registration No.: NCT01762293). Totally 154 patients with advanced colorectal cancer who failed second or later-line treatments were randomized in a 2:1 ratio to receive either famitinib or placebo at 25 mg each day in each treatment cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and safety. The statistical analyses of endpoints were using intent-to-treat population. Results: Of 154 patients randomized, the mPFS was 2.8 and 1.5 months in the treatment group and control group, respectively (p=0.0034; HR=0.58). The ORR was 2.02% and 0.00% (p=0.54) and the DCR was 57.58% and 30.91% (p=0.0023) in the treatment group and control group, respectively. Analysis of OS data is ongoing. The frequently reported adverse events (AEs) include neutropenia, thrombocytopenia, hypertension, proteinuria, and hand-foot syndrome and were most grade 1/2. The incidences of serious adverse events (SAEs) for the famitinib and placebo groups were 11.11% and 9.09%, respectively (p=0.7884). Overall, famitinib was well tolerated and toxicities were manageable. Conclusions: Famitinib improved the PFS in patients with advanced metastatic colorectal cancer resulting in higher ORR and DCR in the treatment group with good safety and tolerability. Clinical trial information: NCT01762293.
MicroRNA targeting for the therapy of colitis-associated colon cancer.
Authors: Polytarchou Christos , Hommes Daniel W. , Palumbo Tiziana , Hatziapostolou Maria , Koukos Georgios , van der Meulen-de Jong Andrea E. , Oikonomopoulos Angelos , van Deen Welmoed K. , Vorvis Christina , Koutsioumpa Marina , Birli Eleni , Choi Jennifer , Chang Lin , Anton Peter A. , Pothoulakis Charalabos , Verspaget Hein W. , Iliopoulos Dimitrios
Published: February 2017

571

Background: Inflammatory Bowel Diseases (IBD) consist of ulcerative colitis (UC) and Crohn’s Disease (CD), which are characterized by activation of inflammatory responses. Patients with longstanding UC are at high risk of developing colorectal cancer. The identification of novel molecular targets with therapeutic potential for UC and UC-related dysplasia are of major importance. Methods: Using a high throughput functional suppressor screen of the human microRNAome, we identified microRNAs involved in the regulation nuclear factor kappa beta (NF-κB). We correlated microRNA expression levels with different clinicopathological parameters in 401 colonic specimens derived from patients with UC, CD, irritable bowel syndrome (IBS), sporadic colon cancer (CRC), colitis-associated cancer (CAC) and control subjects. Bioinformatic and molecular analyses were employed for the study of micoRNA-regulated signaling pathways. A microRNA specific chemical inhibitor was used to treat colonic biopsies ex vivo and murine CAC development in vivo. Results: The microRNA screen identified miR-214 as master regulator of NF-κB. MiR-214 levels are increased in colonic tissues from UC and CAC, but not from CD, IBS and CRC patients and positively correlate with UC disease activity and duration. STAT3 regulates miR-214 expression in colonocytes in vitro and STAT3 and miR-214 levels positively correlate in UC and CAC. MiR-214 regulates the expression of phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2) and both are decreased in colonic tissues of UC and CAC patients. MiR-214 is amplified through a feedback loop circuit and its overexpression increases the tumorigenic and invasive phenotype of colon cancer cells. A chemical miR-214 inhibitor perturbs this circuit in colonic biopsies from UC patients ex vivo while intracolonic delivery suppresses CAC growth in mice. Conclusions: Our findings demonstrate a gene controlling the inflammatory response specifically in UC and CAC. The miR-214 molecular circuit activity correlates with UC disease activity and duration. Activation of this circuit contributes to colitis-associated colon carcinogenesis, and its suppression has therapeutic potential for patients with UC-related dysplasia.