bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of metastatic pancreatic cancer patients’ survival using both host immunity and tumor metabolic activity.
Authors: Choi Younak , Oh Do-Youn , Park Hyunkyung , Kim Tae Yong , Lee Kyung-Hun , Han Sae-Won , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue
Published: February 2017

411

Background: Host antitumor immunity measured by neutrophil-lymphocyte ratio (NLR) is reported to be associated with prognosis of cancer patients. Standard uptake value (SUV)by18F-FDG PET represents the metabolic activity of tumor itself. The correlation of host immunity and tumor metabolic activity has not been studied. We investigate the association of these two factors and evaluate their roles in prediction of overall survival (OS) in metastatic pancreatic cancer (MPC) patients who receive palliative chemotherapy. Methods: We reviewed 396 MPC patients receivingpalliative chemotherapy. NLR was obtained before initiation of chemotherapy and after 1st cycle of chemotherapy. In 118 patients who were evaluated with 18F-FDG PET before initiation of chemotherapy (PET cohort), maximum SUV (SUVmax) was collected. Cut-offs for each variable were determined by ROC curve. Results: In multivariate analysis, higher NLR was associated with worse OS ( < 2.5, 9.0 m; 2.5-4.4, 7.2 m; ≥ 4.5, 3.9 m; p< 0.001). Reduction of NLR after 1st cycle of chemotherapywas associated with betterOS (8.0 m vs 6.1 m; HR 0.653; p< 0.001). We made the risk scoring model considering both NLR (score 0, NLR < 2.5; score 1, 2.5 ≤ NLR < 4.5; score 2, NLR ≥ 4.5) and ΔNLR(score 0:ΔNLR < 0; score 1: ΔNLR ≥ 0), which identified 4 risk groups with different prognosis (group with risk score 0 vs 1 vs 2 vs 3: OS 9.7 vs 7.9 vs 5.7 vs 2.6 months; HR 1 vs 1.329 vs 2.137 vs 7.915, respectively; P < 0.001). In PET cohort (118 patients), NLR and SUVmax were independent prognostic factors for OS. The risk model considering both NLR (score 0, NLR < 2.5; score 1, 2.5 ≤ NLR < 4.5; score 2, NLR ≥ 4.5) and SUVmax (score 0:SUVmax < 4.5; score 1: SUVmax ≥ 4.5), which define 4 risk groups with different OS. (group with risk score 0 vs 1 vs 2 vs 3: OS 11.8 vs 9.8 vs 7.2 vs 4.6 months; HR 1 vs 1.536 vs 2.958 vs 5.336, respectively; P < 0.001). Conclusions: NLR and SUVmax as simple parameters of host antitumor immunity and tumor metabolic activity, respectively, have significant impacts on the survival of metastatic pancreatic cancer patients independently. Consideration of both aspects allows more precise prediction of patients’ prognosis.
Perioperative outcomes following composite resections for colorectal cancer with liver metastases: Can we do better?
Authors: Hui Jane Yuet Ching , Li Tianyu , Ross Eric A. , Esnaola Nestor F.
Published: February 2017

412

Background: Curative resection for synchronous colorectal cancer and liver metastases (CRC/LM) can be performed simultaneously as composite resections or in isolation as staged resections. Composite resections expedite care and may be more cost-effective, but there is persistent controversy regarding their safety. This study aimed to identify potentially modifiable differences in adverse perioperative outcomes after composite versus (vs) isolated resection for CRC/LM. Methods: All patients (pts) with CRC/LM in the American College of Surgeons-National Surgical Quality Improvement Program Participant Use File who underwent elective colon, rectal, and/or liver resections from 2005 to 2013 were identified. Patient/procedure characteristics and perioperative outcomes were compared in pts who had isolated colon or rectal resection (CR or RR), isolated liver resection (LR), or composite colon/liver or rectal/liver resection (CLR or RLR) using chi square or Wilcoxon tests. Multiple logistic regression models were used to determine the independent effect of resection type on outcomes. Results: 13,523 pts underwent CR (3,601; 26.6%), RR (2,018; 14.9%), LR (7,002; 51.8%), CLR (513; 3.8%), or RLR (389; 2.9%). In colon cancer pts, the 30-day (30-d) rate of death/serious complication (DSC) was significantly higher after CLR (33.7%) than after CR (22.0%; adjusted odds ratio [aOR] 0.41, 95% confidence interval [95% CI], 0.33 to 0.52) or LR (13.9%; aOR 0.33; 95% CI, 0.27 to 0.41). Similarly, in rectal cancer pts, the 30-d rate of DSC was significantly higher after RLR (24.7%) than after RR (21.5%; aOR 0.66; 95% CI, 0.50 to 0.88) or LR (13.9%; aOR 0.47; 95% CI, 0.36 to 0.62). Differences in adverse outcomes following composite resections were not due to mortality, but to higher rates of pulmonary/infectious complications and returns to the operating room. Conclusions: Composite resections for CRC/LM are associated with higher rates of DSC, particularly in colon cancer pts. Aggressive targeted strategies to prevent pulmonary and infectious complications could significantly improve outcomes in pts undergoing composite resections for synchronous CRC/LM.
Impact of stereotactic body radiation therapy on patient-reported quality of life in patients with unresectable or recurrent pancreatic cancer.
Authors: Rosati Lauren M. , Cheng Zhi , Robertson Scott P. , Kummerlowe Megan N. , Hacker-Prietz Amy , Wolfgang Christopher Lee , Pawlik Timothy M. , Le Dung T , Zheng Lei , Laheru Dan , Herman Joseph M.
Published: February 2017

413

Background: The impact of fractionated stereotactic body radiation therapy (SBRT) on patient-reported quality of life (QOL) and physician-reported toxicity in patients with recurrent or locally advanced pancreatic cancer (PCA) was prospectively evaluated. Methods: Forty-two PCA patients were treated with 25-33 Gy using SBRT in 5 fractions on a single-institution study. Both patient- and physician-reported outcomes were evaluated prior to SBRT and 4-6 weeks post-SBRT. Eight outcomes were consistently evaluated among both groups—performance status, fatigue, pain, anorexia, nausea, vomiting, constipation, and diarrhea. Patient-reported QOL metrics were assessed using a 4-point Likert scale on the EORTC QLQ-C30 and QLQ-PAN26, while physician-reported toxicities were graded using the NCI CTCAE version 4.0. Comparisons between those with paired patient- and physician-reported outcomes collected prior to and 4-6 weeks after SBRT were made using the Wilcoxon signed-rank test. Results: Of the 42 patients currently enrolled onto the study, 29 had both patient- and physician-reported outcomes collected prior to and 4-6 weeks after SBRT. Fifty-five percent were female and 83% were Caucasian. The median age at diagnosis was 65.6 years (range, 40.8-86.6). There was no significant impairment of any of the 8 physician-reported toxicities, nor were significant changes observed in patient-reported overall health (p = 0.66) or QOL (p = 0.18) scores following SBRT. Patients felt less worried about their future health (mean change [mD] = -0.45, p = 0.02), and an improvement in feeling less attractive as a result of disease and treatment reached borderline significance (mD= 0.31, p = 0.09). However, patients felt limited in planning activities in advance (mD= 0.45, p = 0.02) and were more constipated (mD= 0.38, p = 0.01) 4-6 weeks post-SBRT. Conclusions: Although the numbers are small, patients with unresectable or locally recurrent PCA do not appear to suffer any detriment of overall health or QOL after receiving a five-day course of SBRT. Moreover, this regimen may lead to a more optimistic point of view on future health and/or level of physical attraction. Clinical trial information: NCT01781728.
Association of decreased peak SUV on PET after neoadjvuant therapy in patients with borderline resectable pancreatic carcinoma with pathologic response.
Authors: Glazer Evan Scott , Rashid Omar Maen , Hodul Pamela Joy , Pimiento Jose Mario , Malafa Mokenge Peter
Published: February 2017

423

Background: Despite the use of PET scan in metastatic staging, its utility as a biomarker for borderline resectable pancreatic carcinoma (BRPC) is unclear. The peak standardized uptake value (SUVpeak) is the average SUV around the most avid portion of the tumor. We hypothesized that tumor pathologic response (PR) to neoadjuvant therapy will correlate with SUVpeak changes after therapy. Methods: We reviewed our database of patients with BRPC who completed neoadjuvant chemotherapy (GTX) followed by radiation and had pre- and post- neoadjuvant PET scans. Changes in the SUVpeak were calculated by subtracting the post-neoadjuvant/pre-resection PET scan from the pre-neoadjuvant PET scan. PET responders were defined as those patients whose SUVpeak decreased by 4 units (the overall average decrease in SUVpeak) or more. Results: We identified 74 patients- 32 patients developed progressive disease and 42 patients underwent surgery. The average age was 66 ± 9 years; 61% of patients were male. On the final pathologic specimens, 5 patients had a complete PR to therapy while 23 patients had a moderate PR (1-49% viable tumor) and 14 patients had a minimal PR (≥ 50% viable tumor). PR is associated with a decrease in SUVpeak (p = 0.02; Table). The area under the receiver operator characteristic curve for changes in SUVpeakand complete PR was 0.83 ± 0.08. Of the PET responders who underwent surgery, 29% had a complete PR while none of the PET non-responders had a complete PR (p = 0.004). Of the unresected patients, PET responders had a longer overall survival compared to non-responders (18 ± 7 vs. 12 ± 7 months, p < 0.05). Nodal disease was not associated with PR (p > 0.3). Conclusions: PR was significantly associated with a decrease in SUVpeak post-neoadjuvant therapy in patients with BRPC. Even in patients with unresectable disease, SUVpeak provides useful prognostic data. We believe that pre- and post-neoadjuvant therapy PET scans may be used as a prognostic biomarker in patients with BRPC. [Table: see text]
Can the sequence of chemotherapy regimens influence outcome in patients with metastatic pancreatic adenocarcinoma (MPAC)?
Authors: Schmidt Shannon Leah , Durkal Vipal , Pattali Jayavalsan Shinoj , Ritch Paul S. , Thomas James P. , Erickson Beth , Christians Kathleen K. , Tsai Susan , Evans Douglas B. , George Ben
Published: February 2017

428

Background: FOLFIRINOX(FFX)/FOLFOX(FX) and Nab-paclitaxel plus Gemcitabine (NabG) represent standard first line (FL) treatment options for MPAC, but there is no prospective data to ascertain the ideal sequence of these regimens when used off protocol for patients with MPAC. We reviewed our single institution experience to evaluate whether the sequence of these regimens influenced clinical outcome. Methods: All MPAC patients treated with FFX/FX or NabG, in either sequence, from 1/1/11 to 12/31/14 at the Froedtert and Medical College of Wisconsin (MCW) Clinical Cancer Center were identified and their charts reviewed. This study was approved by the Froedtert & MCW Institutional Review Board. Results: Among 64 patients reviewed, the median age at diagnosis was 62. 64.1% were male and 95.3% were Caucasian. Median Ca19-9 and CEA at diagnosis were 855 and 10.4 respectively. 37/64 (57.8%) patients received SL therapy. Details of treatment and disease control rate (DCR) are summarized in the Table. Of patients who were refractory to FL FFX/FX, 4/7 (57.1%) demonstrated disease control (DCR) with SL NabG; numbers were too small for reverse analysis. Median overall survival (OS) of patients who received 2 lines of therapy was 12.1 months, while median OS of patients who received one line was 4.1 months. Median OS associated with sequential therapy is summarized in the Table. Conclusions: Both FFX/FX and NabG are active in the SL setting. Outcomes appear to be fairly similar regardless of sequence. The numerically superior median OS associated with FL NabG followed by SL FFX should be interpreted with caution in the context of small number of patients in this subset. A substantial minority of patients do not receive second line chemotherapy due to deteriorating clinical status and/or patient preference suggesting unfavorable tumor biology. [Table: see text]
EUS combined with CT in predicting SMV/PV resection in patients with borderline resectable pancreatic carcinoma.
Authors: Glazer Evan Scott , Rashid Omar Maen , Klapman Jason , Harris Cynthia L. , Hodul Pamela Joy , Pimiento Jose Mario , Malafa Mokenge Peter
Published: February 2017

432

Background: Guidelines recommend pancreatic protocol CT scan (CT) for staging vascular involvement in patients with pancreatic cancer (PC). While endoscopic ultrasound (EUS) has been demonstrated to be effective in venous staging of PC, its role when combined with CT is poorly defined. We evaluated the utility of EUS in addition to CT in staging PC. We hypothesized that EUS complements CT in identifying SMV/PV tumor involvement as measured by the requirement for vein resection. Methods: We reviewed our database of patients with borderline resectable PC who went to surgery with curative intent. Inclusion criteria were pre-operative staging with CT scan, EUS, PET scan, and CA 19-9 levels, as well as completion of neoadjuvant chemotherapy and radiation. Results: We identified 62 patients with 74% of tumors in the pancreatic head. 97% of resections were R0. The average age was 65 ± 9 years; 60% were male. Patients were classified as borderline resectable by EUS alone in 29%, CT alone in 23%, and both modalities in 48% of patients, respectively. 34 patients required vein resection; EUS identified 88% of these patients pre-operatively while CT identified 68%. EUS identified 11 patients who required vein resection that CT did not identify while CT identified 4 patients that EUS did not identify. EUS had higher sensitivity and specificity than CT in identifying patients requiring venous resection (Table). On multivariate logistic regression analysis, EUS was predictive of vein resection (P < 0.02) but CT scan findings, PET scan findings, tumor size, and CA19-9 values were not predictive (each P > 0.1). In margin negative resected patients, median survival was longer when both CT and EUS identified borderline status compared to only 1 modality (43 vs 23 months, P < 0.05). Conclusions: EUS complemented CT in identifying patients with borderline resectable PC requiring vein resection- 29% of patients were identified with EUS alone. This observation supports the use of EUS in addition to CT scan for the vascular staging of patients with PC. [Table: see text]
Tumor response in the CLARINET study of lanreotide depot vs. placebo in patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Authors: Phan Alexandria T. , Dasari Arvind , Liyanage Nilani , Cox David , Lowenthal Susan Pitman , Wolin Edward M.
Published: February 2017

434

Background: In the CLARINET study, significant improvement in progression-free survival (primary endpoint) was reported in patients (pts) treated with lanreotide depot (LAN), a long-acting somatostatin analog, for moderately- or well-differentiated, nonfunctioning, locally advanced or metastatic GEP-NETs. A favorable safety profile was also observed. This retrospective analysis presents tumor response from CLARINET. Methods: Pts were randomized to LAN 120 mg (n=101) or PBO (n=103) once every 28 days for 96 weeks. Tumor response was evaluated centrally using RECIST version 1.0. Pts’ tumors were measured by sum of the longest diameter (SLD) of target lesions (TLs). Change was calculated for each pt’s SLD from baseline to last available post-baseline assessment. Tumor response was classified as complete response (CR): disappearance of all TLs and non-target lesions (NTLs) and no new lesions; partial response (PR): ≥30% decrease in SDL and no progressive disease (PD); stable disease (SD): not meeting criteria for CR/PR or PD; PD: ≥20% increase in SLD from baseline or nadir, unequivocal progression of NTLs or appearance of new lesions. The remaining pts were not evaluable (NE) for response. Results: 101 pts treated with LAN and 103 pts treated with PBO were assessed for tumor response. Among pts receiving LAN, 64% (65/101) demonstrated SD compared to 43% (44/103) of pts receiving PBO (Table). An additional 2 pts in the LAN group achieved a PR. Similar trends were observed in pts with pancreas and midgut origin tumors. Conclusions: A clinical benefit (defined as CR+PR+SD) of 66% (67/101) was observed with single agent LAN vs 43% (44/103) with PBO in the CLARINET population, further supporting the clinical efficacy of LAN. Clinical trial information: NCT00353496. [Table: see text]
Retrospective phase II study of efficacy and safety of 177Lu-DOTATOC peptide receptor radiotherapy in patients with advanced neuroendocrine tumours.
Authors: Baum Richard P. , Kluge Andreas , Kulkarni Harshad , Sayeg Manal , Schorr-Neufing Ulrike , Niepsch Karin , Bitterlich Norman , van Echteld Cees J.A.
Published: February 2017

436

Background: Emerging evidence, that 177Lu-DOTATOC has a particularly favorable therapeutic index compared to other PRRT agents, prompted us to further evaluate efficacy and safety of 177Lu-DOTATOC. Methods: 56 patients with metastasized and progressive neuroendocrine tumors (NET) (50% gastroenteral, 26.8% pancreatic, 23.2% other primaries) were consecutively treated with 177Lu-DOTATOC and analyzed retrospectively. Patients received on average 2.1 (range 1 – 4) cycles of 177Lu-DOTATOC as 7.0 GBq (median) doses at 3-monthly intervals. Efficacy was analyzed based on RECIST and stratified for number of treatment cycles and primary tumor origin. Results: Median progression-free (PFS) and overall survival in the total population (A) were 17.4 and 34.2 months, respectively. Patients treated with > 1 cycle had a PFS of 32.0 months for all NET (B), 34.5 months for gastroenteropancreatic NET (GEP-NET) (C), and 11.9 months for other NET (D). Objective response (OR) rates [complete (CR) or partial (PR)], were 34%, 41%, 54%, and 0% for A, B, C, and D, while disease control [CR, PR and stable disease, SD] rates (DCR) were 66%, 94%, 100%, and 75%, resp. CR was found in 16%, 19% and 25% of A, B and C, resp. In 68% of responders initial response occurred within 4 months from the 1st cycle, whereas in 32% this took 4-8 months. In 47% of all OR it took > 8 months to achieve OR. No renal toxicity was found, although 20% of patients had mild renal insufficiency at baseline. No SAE and only a single case of self-limiting grade 3 myelotoxicity was observed. Conclusions: 177Lu-DOTATOC shows unparalleled potential to induce OR and long lasting DC in progressive NET, even when administered at moderate activity doses. In GEP-NET patients CR was 25%, which is the highest value ever reported. Efficacy was highest when the agent was administered in repetitive cycles. Overall DCR was 94%, compared to 80-85% reported for 177Lu-DOTATATE. This difference in DCR is mainly accounted for by an approx. 10-fold higher rate of CR with 177Lu-DOTATOC. This high efficacy together with the observed safety profile suggests a very high therapeutic index, reflecting a uniquely low systemic uptake of 177Lu-DOTATOC.
The impact of modified Glasgow Prognostic Scale as a predictor of survival advantage by FOLFIRINOX in metastatic pancreatic cancer.
Authors: Yamada Ikuhiro , Ozaka Masato , Kanata Ryo , Saito Kei , Sasaki Takashi , Matsuyama Masato , Takano Kouichi , Sasahira Naoki
Published: February 2017

440

Background: The superiority of FOLFIRINOX (FFX) therapy over gemcitabine (Gem) alone in patients with metastatic pancreatic cancer (mPC) has been demonstrated in ACCORD11. However, this combination regimen is associated with relevant toxicity and predictors for response to therapy are warranted. The aim of this study is to determine the prognostic factors associated with an indication for FFX therapy in patients with mPC. Methods: The current study included data from all consecutive patients who were diagnosed as mPC at our hospital between September 2007 and December 2014. Selection criteria were as follows: patients who 1) had histologically confirmed pancreatic adenocarcinoma, 2) were diagnosed as having metastatic disease, and 3) received first-line chemotherapy with Gem alone or FFX. We examined the prognostic markers, such as derived neutrophil–lymphocyte ratio, platelet–lymphocyte ratio, modified Glasgow prognostic scale (mGPS), ECOG Performance Status (PS), CA19-9 level and number of metastatic sites from the medical records and analyzed their survival data by chemotherapy regimen subgroups. Results: There were 187 patients who met the selection criteria. 159 (85%) received Gem alone, 28 (15%) received FFX. Univariate and multivariate regression analyses revealed that mGPS (1≦), number of metastatic sites (2≦) and high level of CA19-9 level (1000 U/ml≦) were significantly associated with worse prognosis in Gem group. PS (1≦) and mGPS (1≦) were significantly associated with worse prognosis in FFX group. Since mGPS was the only significant prognostic marker in both groups, we analyzed survival data stratified by regimen in both mGPS 0 or 1≦ cohort. In mGPS 0 cohort, the median survival time was 17.9 months in the FFX group as compared with 8.5 months in the Gem group (hazard ratio, 0.27; 95% CI, 0.11 to 0.55; P = 0.004). However there was no significant difference in mGPS 1≦ cohort (P = 0.4). Conclusions: This data suggests that mGPS 0 is associated with better survival time, and suggests it may also be predictive of benefit for FFX in Japanese patients with mPC. Incorporating mGPS into the clinical context may better inform prognosis and chemotherapy decisions in mPC patients.
Randomized, multicenter phase II trial of CAP7.1 in patients with advanced biliary tract cancers.
Authors: Pape Ulrich-Frank , Kasper Stefan , Sinn Marianne , Caca Karel , Kuhlmann Jan , Keilholz Ulrich , Vogel Arndt , Utku Nalan
Published: February 2017

441

Background: Non-resectable biliary tract cancers (BTC) have poor prognosis, but are chemosensitive. CAP7.1 is a new chemical entity that releases etoposide in the presence of carboxylesterases, leading to higher intra-tumor etoposide (E) with improved safety and efficacy. Methods: The primary objective of this trial is to determine the rate of disease control (DCR) (stable disease, SD; partial response, PR and complete response, CR) according to Recist 1.1. of CAP7.1 in patients (pts) with BTC. Secondary objectives are progression free survival (PFS), overall survival (OS) and safety. Pts with adenocarcinoma arising from bile ducts or gallbladder were randomized (1:1) to either CAP7.1 or best supportive care (BSC) group (institutional palliative treatment). Pts in CAP7.1 arm subjected to a 3-week cyle (cy) with CAP7.1 on days 1-5 in 3-week cy was given with either 200 or 150mg/m2. until progression. At progression BSC pts were allowed to cross over to CAP7.1. Safety was assessed with CTCAE v 3.0 and efficacy after 2 cy of treatment. 18 /50 pts (9 in each study arm) finalized 1st stage and analyzed for efficacy and safety. Results: DCR in the CAP7.1 arm was 56%, with 5/9 of pts with SD (including tumor shrinkages), while all pts in the BSC arm progressed. The median PFS time was 3.5 months (95% CI, 1.9 to 8.4 months) in the CAP7.1 arm. 5 pts crossed over to the CAP7.1 arm. 2/3 pts continued CAP7.1 treatment up to 5 and 8 cycles as SD, respectively, while one pts achieved PR. The median OS time from first treatment with CAP7.1 was 5.9 months (95% CI, 2.6 to 15.3 months) over all evaluable pts, including BSC after crossing to CAP7.1. Commonly observed drug related adverse events (AE) are hematoxicity/myeolosuppression, various events of infection, alopecia, fatigue, nausea and abdominal pain, which were in general well managed. G3-4 neutropenia occurred in 4/10 pt at a dose of 150 mg/m²/d and in 6/11 pts at 200 mg/ m2/d; uncomplicated g 3-4 thrombocytopenia occurred in 2/11 pt at 200 and in 1/10 at 150 mg/ m2/d. Non-hematological AE were mainly mild or moderate e.g. abdominal pain and alopecia as most frequent AEs. Conclusions: CAP7.1 showed promising activity in therapy refractory advanced BTC patients.
Can response to treatment predict outcome in patients with metastatic pancreatic adenocarcinoma (MPAC)?
Authors: Pattali Jayavalsan Shinoj , Schmidt Shannon Leah , Durkal Vipal , Ritch Paul S. , Thomas James P. , Erickson Beth , Christians Kathleen K. , Tsai Susan , Evans Douglas B. , George Ben
Published: February 2017

443

Background: Front-line (FL) chemotherapy regimens for MPAC include FOLFIRINOX (FFX)/FOLFOX (FX) and Nab-paclitaxel plus Gemcitabine (NabG). We examined our hypothesis that objective response (OR) to these regimens can influence clinical outcome when employed sequentially. Methods: All MPAC patients treated with FFX/FX or NabG from 1/1/2011 to 12/31/2014 at the Froedtert and Medical College of Wisconsin (MCW) Clinical Cancer Center were reviewed. This study was approved by the MCW Institutional Review Board. Results: 64 patients were evaluated and the baseline characteristics are summarized in the table below. OR to FL chemotherapy included partial response(PR) - 23/64 (35.9%), stable disease (SD) - 14/64 (21.9%) and disease control rate (DCR) of 57.8%; OR to second line (SL) therapy included PR - 7/37 (18.9%), SD - 14/37 (37.8%) and DCR of 56.7%. Only 57.8% patients received SL chemotherapy. Among patients who demonstrated PR to FL chemotherapy, 64% were refractory to SL chemotherapy, while 33% of patients who were refractory to FL chemotherapy demonstrated a PR to SL chemotherapy. 3/64 patients who demonstrated PR to both FL and SL chemotherapy had excellent outcomes with overall survival (OS) of 20.9 months, 37 months and not met (PFS of 11 months to FL chemo and ongoing response of > 4 months to SL chemo). Median OS of patients who demonstrated a PR/SD to FL and SL chemotherapy (15/64; 23.4 %) was 20.9 months. The patients who demonstrated progressive disease(PD) to both FL and SL chemotherapy (5/64; 7.8%) had a median OS of 3.8 months. Conclusions: Patients with MPAC who are refractory to FL chemotherapy may demonstrate a response to SL chemotherapy. Patients who are able to undergo sequential therapy with FFX/FX and NabG (in either sequence) and demonstrate either a PR or SD with both treatment regimens have an excellent clinical outcome. The minority of patients who demonstrate PR to both sequential regimens have a distinctly different outcome compared to patients who demonstrate PD to both regimens; tumors from these two subsets of patients need to be better characterized to improve our understanding of pancreatic cancer biology. [Table: see text]
Perioperative calculator to predict complications for patients with hepatocellular carcinoma resection.
Authors: Ostapoff Katherine , Attwood Kristopher , Kurenov Sergei , Kuvshinoff Boris W. , Hochwald Steven N. , Kukar Moshim , Nurkin Steven J.
Published: February 2017

446

Background: Hepatocellular carcinoma (HCC) is a common cancer worldwide, but few patients are optimal surgical candidates due to liver disease. Current prediction models (Childs-Pugh and MELD) poorly estimate serious morbidity risks for those patients considering resection. Methods: Using ACS-NSQIP database, patients with HCC were selected from 2006-2013. Patients included had a curative resection (partial hepatectomy or formal lobectomy) and were excluded if they had emergency surgery or disseminated cancer. Outcomes included 30 day morbidity and serious morbidity. Data was randomly divided into testing (n=1764) and validation (n=441) cohorts. Regression analyses of the testing cohorts were used to construct prediction models, then optimized using the validation cohort. Results: We identified 2,205 patients. Major morbidity or serious morbidity occurred in 34% (n=745) and 21% (n=456). Patient demographics are shown in Table 1. Factors significant for morbidity include age, surgical procedure, BMI, ASA class, hypertension, alkaline phosphatase (AP), bilirubin (Bili), BUN, AST, albumin and MELD score. Factors included in risk score for morbidity included MELD, ASA class, surgical procedure, platelet count, smoking and AP. The model predicts morbidity AUC 0.616 vs 0.597 for model and validation cohort respectively. Factors significant for serious morbidity included age, race, procedure, BMI, diabetes, ASA class, hypertension, AP, Bili, AST and albumin. Serious morbidity score included MELD, surgical procedure, platelet count, diabetes and AST. The model predicts serious morbidity AUC 0.566 vs 0.592 for model and validation cohort respectively. Conclusions: Our calculator predicts morbidity based on surgical procedure for patients undergoing HCC curative intent surgery. Risk prediction can assist in appropriately selecting patients for surgical vs medial therapy. [Table: see text]
Perioperative management of pancreatoduodenectomy patients: Are North American practices any different? A survey involving IHPBA/AHPBA members.
Authors: Anantha Sandeep , Macedo Fransisco Igor , Race Alice J , Singh Awinderpreet , Parikh Janak A , Mittal Vijay K , Jacobs Michael J
Published: February 2017

447

Background: Pancreatoduodenectomy is performed worldwide with significant variations in the perioperative management. The aim of this study is to evaluate the practice patterns across regions of the world. Methods: A pilot cross-sectional 25-item survey questionnaire was electronically distributed using Survey Monkey to IHPBA and AHPBA members between May and August 2015 regarding practice patterns and perioperative care of patients undergoing pancreatoduodenectomy. Results: A total of 285 responses were obtained. The majority of participants were from United States (34.7%), Europe (28.1%) and Asia (14.3%). North American (NA) surgeons are less likely to culture intraoperative bile (36.5% vs. 53.1%, p<0.02), routinely check postoperative drain amylase (80.5% vs. 91.3%, p<0.03) or irrigate the wound with Betadine solution (7.7% vs. 29.1%, p<0.001) as compared to European members. Overall, NA surgeons are more likely to use 1 drain (46.3% vs. 88.7% other regions (2 drains), p<0.001), limit the prophylactic antibiotic use within 24 hours of surgery (70.1% vs. 68.5%, p<0.001) and do not culture drain fluid routinely (91.5% vs. 67.1%, p<0.001). Conclusions: Our survey evaluated a wide range of practice patterns globally amongst surgeons performing pancreatoduodenectomy. North American surgeons do not routinely check for amylase rich fluid in the drains, utilize one drain routinely when compared to European surgeons. Further studies are warranted to evaluate if these variations translate into impacts upon surgical outcomes on patients undergoing Whipple operation.
Randomized, open-label trial of gemcitabine/nab-paclitaxel (G/NP) ±FG-3019 as neoadjuvant chemotherapy in locally advanced, unresectable pancreatic cancer (LAPC).
Authors: Picozzi Vincent J. , Rocha Flavio G. , Helton Scott , Mody Kabir , Asbun Horacio , Pishvaian Michael J. , Jackson Patrick G , Etheridge Tina , Carney Mairead , Neff Thomas B , Porter Seth , Crans Gerald , Valone Frank , Shi Wen
Published: February 2017

457

Background: Curative therapy for PDAC is currently achievable through resection only, but ≤ 15% of patients are candidates for surgery. FG-3019, a recombinant human mAb to connective tissue growth factor (CTGF), plus gemcitabine (G) significantly reduced tumor growth, increased apoptosis and improved survival vs G alone in the KPC mouse model. Higher FG-3019 exposure and lower baseline (BL) CTGF were independently and significantly associated with improved overall median and 1-year survival (OS) in a Ph2a trial with G and erlotinib in stage 3 or 4 PDAC. Neoadjuvant treatment of LAPC with FG-3019 combined with multidrug therapy may change the fibrotic character of LAPC and thus may make it amenable to surgical resection and potentially improve OS. Methods: Patients with unresectable LAPC (confirmed by laparoscopy) are randomized to G/NP ±FG-3019 for 6-cycle/24-week treatment. Safety, efficacy, PK and changes in CT, PET, & CA19.9 from BL through end of treatment (EOT) are assessed. Up to 4 endoscopic ultrasound (EUS) guided core biopsies are collected at BL. Protein microarrays of pre- and post-treatment biopsies are prepared from tumor and stromal cells isolated by laser capture microdissection. Surgical exploration is performed in subjects who achieved the protocol-defined criteria for possible resection. Results: To date, 11 subjects were enrolled with 5 randomized to +FG-3019 arm. There were no complications from laparoscopy or EUS core biopsies that were clinically significant or delayed dosing. Per investigator assessment, no FG-3019-related SAEs were reported, nor any identified toxicity suspected from combination of FG-3019 with chemotherapy. Overall, CA19.9 mean change from BL was −62.7% at Week 8 (n = 8), and target lesions were reduced by 20.6% (n = 6) at Week 16. Three out of 4 subjects had PET SUVmax reductions of ≥ 30% at EOT. Additional data from protein microarrays will be presented. Conclusions: Based on the limited data collected so far, this trial design is feasible and the G/NP +FG-3019 combination is well-tolerated and appears to be active. Summary results on surgical exploration of subjects will be provided later. Clinical trial information: NCT02210559.
The effects of HOXB7 in the promotion of migration, invasion and anti-apoptosis in gastric cancer.
Authors: Joo Moon Kyung , Park Jong-Jae , Yoo Hyo Soon , Lee Beom Jae , Chun Hoon Jai , Lee Sang Woo , Oh Sang Cheul , Bak Young-Tae
Published: February 2017

46

Background: HOX genes, a subset of the homeobox gene family, are known to be aberrantly expressed in various types of cancers. Among them, HOXB7 recently has been reported to be highly expressed in esophageal or colorectal cancers. We aimed in this study to demonstrate the critical roles of HOXB7 in development and progression of gastric cancer. Methods: We screened gene and protein expression of HOXB7 in various gastric cancer cell lines, and also compared gene expression level of HOXB7 among chronic gastritis, intestinal metaplasia and gastric cancer tissues. To figure out the oncogenic effects of HOXB7 in vitro, we performed annexin-V assay, wound closure assay and Matrigel invasion assay. We performed Western blot analysis to examine the impact of HOXB7 on AKT pathway. Results: Both mRNA and protein was substantially expressed in stomach cancer cell lines (SNU-638, SNU-719, MKN-28, MKN-45, AGS, KATO-III, NCI-N87), however, they were nearly abolished in normal gastric tissues. Gene expression was significantly higher in primary or metastatic stomach cancer, compared with chronic gastritis or intestinal metaplasia. Knockdown of HOXB7 by transfection with siRNA in AGS and SNU-638 cells significantly inhibited migration and invasion, and showed anti-apoptotic effect. Because a previous study demonstrated that enforced expression of HOXB7 could enhance PI3K/AKT pathway activity in colon cancer cells (Liao W.T. et al, Clin Cancer Res; 17(11) June 1, 2011), we investigated the modulation of AKT/PTEN pathway by HOXB7 and observed that knockdown of HOXB7 significantly downregulated phospho-AKT and upregulated PTEN in both cell lines. Furthermore, target gene products of AKT pathway including cyclin D1, survivin, Bcl-xL and MMP-9 were significantly downregulated by siHOXB7. Conclusions: Our findings suggest that HOXB7 might play a crucial role in migration, invasion and anti-apoptotic effect via modulating AKT/PTEN pathway.
The impact of the multiple types of treatments on OS and the decline of liver function in patients with advanced stage of HCC.
Authors: Prins Petra , Bhardwaj Prarthna , Fishbein Thomas , Johnson Lynt B. , Smith Coleman , Satoskar Rohits , Kim Alexander Y. , Jha Reena , Wang Hongkun , Sullivan David , Taher Salha , Zhang Tiger , Zhu J , Pishvaian Michael J. , Smaglo Brandon George , Salem Mohamed E. , Hartley Marion L. , Marshall John , He Aiwu Ruth
Published: February 2017

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Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related death worldwide. Most HCCs develop in severely damaged liver. Methods: The effect of multiple treatment options on liver function (LF) and disease outcome of patients (pts) with HCC (n = 185) were examined retrospectively. Pt tumor burden (using Barcelona clinic liver cancer [BCLC] classification) and LF (Child Pugh [CP]) were assessed at time of diagnosis and then after treatment. Using Kaplan Meier with log rank and T tests, BCLC and CP scores were correlated with overall survival (OS) following individual treatment regimens. Results: We show that better BCLC and LF scores at time of diagnosis predict a better outcome (median OS; p < 0.05). Pts received one or more of the following: no treatment, experimental treatment, TACE, Y90 radioembolization, radiofrequency ablation, resection, radiation, and sorafenib (SFB). Considering all treatment scenarios, LF improved in 9.5%, did not change in 33%, and worsened in 57% of pts. Sixty percent of untreated pts experienced LF decline, compared with 33, 54, 48 and 50% of pts receiving TACE, SFB, TACE/SFB, and Y90/SFB, respectively (no significant differences [NS]); 72% of pts receiving TACE/Y90/SFB (NS); and 85% of pts receiving other Y90/SFB combinations (p = 0.006). In general, pts who saw no change or an improvement in LF from baseline had longer median OS versus pts who had declining LF (p < 0.002). However, pts receiving TACE/Y90/SFB (n = 29) had similar OS to those receiving TACE/SFB (n = 35), despite the toxicity difference (72% [TACE/Y90/SFB] vs. 48% [TACE/SFB] of pts had declining LF). TACE/SFB or TACE/Y90/SFB led to longer median OS than any other treatment group (p = 0.017). Conclusions: The outcome of pts with HCC depends on disease stage and LF. Most pts experience LF decline during treatment. Despite LF decline in 48% of pts receiving a SFB/TACE, these pts experienced longer median OS than pts on any other treatment. Balancing survival benefit with liver toxicities is critical to the successful treatment of pts with advanced HCC. Agents with good antitumor activity and minimal liver toxicity are desperately needed for these pts.
Outcomes of perioperative systemic therapy (ST) in patients with R0 resection of metastatic colorectal cancer (mCRC).
Authors: Lee-Ying Richard M. , Renouf Daniel John , Lim Howard John , Speers Caroline , Cheung Winson Y.
Published: February 2017

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Background: Adjuvant fluoropyrimidine (FP) +/- oxaliplatin (OX) ST improves overall survival (OS) following curative resection of stage II or III CRC, while other regimens do not. Utility of pseudo-adjuvant ST in mCRC patients who achieved R0 resection of their metastases remains controversial. We aim to describe population-based outcomes based on choice of ST. Methods: Patients diagnosed with mCRC from 2003 to 2010 and referred to any 1 of 5 cancer centers in British Columbia, Canada were reviewed. We categorized patients who underwent a successful R0 resection of their metastases into 3 groups based on receipt of peri-operative ST: 1) FP alone; 2) OX-based; and 3) non-standard or no ST. We compared OS using multivariate Cox regression models that adjusted for potential confounders. Results: We identified and reviewed 1,641 patients with mCRC among whom 225 achieved R0 resection of their metastases. In this cohort, median age was 63 years (Interquartile range (IQR) 55-70), 118 (52%) were men, 196 (87%) reported ECOG 0/1, 149 (66%) had a colonic primary, and 103 (46%) presented with de novo metastatic disease. The site of metastatic resection was hepatic in 144 (64%), pulmonary in 34 (15%), locoregional in 11(5%), and other in 36 (16%). A total of 122 (54%) received standard ST. Regimens included 28 (12%) FP alone, 94 (42%) OX-based, 25 (11%) irinotecan and 38 (17%) including bevacizumab. The median duration of ST was 10 cycles (IQR 7-12), with 56% and 44% delivered pre- and post-operatively, respectively. In multivariate analyses, liver or lung involvement (HR 0.60, 95% CI 0.40-0.88, p=0.01) predicted for improved OS when compared to metastases affecting other organs or sites. Receipt of OX-based ST was the only regimen associated with better OS, while the rest were not (Table). Conclusions: Findings from this population-based cohort of mCRC suggest that use of a defined course of OX-based ST for pseudo-adjuvant intent around the time of R0 resection of liver or lung metastases is correlated with improved OS. [Table: see text]
Objective sleep duration (SD) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (MCC).
Authors: Spiegel David , Levi Francis , Bjarnason Georg A. , Ulusakarya Ayhan , Palesh Oxana , Innominato Pasquale F.
Published: February 2017

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Background: Sleep is often altered in patients with cancer, with clinical repercussions. Short sleep duration (SD) has been associated with increased risk of earlier death in the general population. The prognostic relevance of SD in cancer pts is unknown. We explored the effect of short ( < 7 hours) SD on the clinical outcomes of pts with MCC before chemotherapy. Methods: Participants were 236 pts with MCC: M/F ratio: 1.66; median age: 60.4 years; range: 21-78; WHO Performance Status (PS) = 0/1/2: 60/34/6%; synchronous metastases: 63%; 2 or more metastatic sites: 55%; prior chemotherapy for metastatic disease: 35%. Pts wore an actigraph for 72 hours before receiving the initial course of an oxaliplatin-based chemotherapy; objective night-time SD was estimated from actigraphy recordings using the Cole-Kripke algorithm. SD was considered short if < 7 hours, based on previous studies. Multivariate Cox proportional Hazard models were built to assess the prognostic value of short SD on OS and progression-free survival (PFS); Binary logistic regression was used to assess the predictive value of short SD for an objective response (OR) or grade 3-4 Toxicity (Tox). Results: Median night SD was 7.4 hours (range: 1.5-10.5). Short SD was observed in 105 (44.5%) pts. Median OS and 3-year survival rate were 14.6 months (mo) [95% C.I.: 11.8-17.4 mo] and 16% [9-23], respectively, in patients with short SD as compared to 16.4 mo [13.0-19.8] and 27% [20-36%] in those with longer SD (p = 0.04). There was no significant difference in PFS (p = 0.25), OR (p = 0.1) or Tox (p = 0.43) rates according to SD. The negative prognostic value of short SD on OS remained significant even after adjustment for age, sex, body mass index, PS, number of metastatic sites, prior chemotherapy and stage at diagnosis (multivariate hazard ratio: 1.45 [1.08-1.93]; p = 0.013). Conclusions: We observed that sleep duration of less than 7 hours before chemotherapy was associated with a significantly shorter survival, independently from other prognostic factors, in pts with MCC. Sufficiently long restorative sleep should be promoted in cancer pts. More research is needed to understand the relationship and mechanisms behind shorter sleep duration and prognosis.
RAS mutation prevalence among patients with metastatic colorectal cancer: A meta-analysis of real-world data.
Authors: Kafatos George , Lowe Kimberly , Jenkins-Anderson Sophie , Garawin Tamer , Traugottová Zuzana , Bilalis Antonios , Molnár Edit , Wieruszewska-Kowalczyk Karolina , Niepel Daniela , van Krieken J. Han ,   on behalf of the RAS Prevalence Research Project (RPRP) Group
Published: February 2017

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Background: Guidelines for prescribing anti-EGFR therapy for metastatic colorectal cancer (mCRC) require prior testing to confirm RAS (exons 2, 3, 4 of KRAS and NRAS) wild-type status in Europe and the USA. There is limited published evidence reporting the prevalence of RAS mutations in patients with mCRC in a real-world setting. The aim of this study was to use data from a range of real-world sources to obtain RAS mutation prevalence estimates for different geographic regions. Methods: Aggregated RAS mutation prevalence data were collected from 13 sources, including individual pathology centers (n = 7), mCRC registries (n = 3), and Amgen-sponsored studies (n = 3). Data sources included in this study originated in Europe (n = 10), the Middle East (n = 2), and South America (n = 1). A meta-analysis of all collected data was carried out to investigate the effect of heterogeneity amongst the data sources and obtain pooled RAS prevalence estimates for each, using a mixed regression model. Results: Aggregate data from 4322 patients with mCRC were included in the pooled meta-analysis. The overall RAS mutation prevalence across all data sources was estimated to be 43.5% (95% CI: 41.5–45.5%). RAS mutation prevalence varied between data sources, ranging from low estimates of 33.7% (95% CI: 28.4–39.3%) for a Middle Eastern pathology dataset, and 34.6% (95% CI: 27.7–42.1%) for a Middle Eastern mCRC registry, to the highest estimates of 53.6% (95% CI: 43.2–63.8%) and 54.1% (95% CI: 51.7–56.5%) in two European pathology centers, in the Czech Republic and Poland, respectively. Conclusions: This is one of the first studies to carry out a large pooled analysis of RAS mutation prevalence, based on real-world data. There was a high degree of heterogeneity between the sources included, possibly due to the types of data source, patient selection criteria, geographic location, or differences in laboratory testing methods. The estimated RAS mutation prevalence reported here is lower than that in a recent pooled analysis of past clinical trials, which reported an overall prevalence of 55.5% (95% CI: 53.9–57.9%) (Peeters M, et al. Eur J Cancer 2015;51:1704–13). Further investigations are required to explain the disparity in these findings.
Germline pharmacogenomics in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.
Authors: Khushman Moh'd M. , Hosein Peter Joel , Cameron Daniel , Clarkson David Roland , Butler Thomas Wayne , Vu Mary A. , Norden Carole Wiseman , Baliem Wilma , Jones Vanessa , Bhadkamkar Sanjyot , Nelson Cindy , Lee Frances , Singh Ajay , Taylor William R.
Published: February 2017

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Background: DPD deficiency is a pharmacogenetic syndrome associated with dose-limiting toxicity to fluoropyrimidines. Oncologists are expected to recognize and diagnose this syndrome, as toxicities could be fatal. Over 40 single nucleotide polymorphisms (SNPs) and deletions have been identified within the DPYD gene. IVS14+1G>A (DPYD*2A) is the most common (40-50%) and best studied of these SNPs. Yet, it showed a median sensitivity of 30% and is absent in Japanese, Korean and African Americans. Overall, the data on DPYD testing is insufficient to provide enough guidance to diagnose DPD deficiency. Herein we describe our experience with germline pharmacogenomics in patients with DPD deficiency. Methods: Between 2011 and 2015, 35 patients with gastrointestinal malignancies were tested for DPYD mutations; 17 were tested after developing toxicities to treatment and 18 were tested prior to treatment. IVS14+1G>A (DPYD*2A) was tested in all patients. DPYD c.85T>C (DPYD*9A), DPYD c.1679T>G (DPYD*13A), DPYD c.-1590T>C, and DPYD c.2846A>T were tested in 24 patients (69%) only. We explored the association between DPYD mutations and fluoropyrimidine-related toxicity using Fisher’s exact test. Results: Median age was 60 years, 43% were male, 80% were Caucasian and 20% were African American. Capecitabine-based regimens (71%) and 5-Fluorouracil-based regimens (29%). 14 out of 35 patients (40%) had DPYD mutations. Grade 3 toxicities were encountered in 64% of patients with DPYD mutation and 48% of patients with no DPYD mutation. In patients who received full dose fluoropyrimidines (57% of patients with DPYD mutation and 81% of patients with no DPYD mutation), DPYD mutations were associated with a significantly higher rate of grade 3 diarrhea (p=0.026). In patients with DPYD mutation, 2 (14%) had DPYD*A2 mutation and 12 (86%) had DPYD*9A mutation. Conclusions: In patients treated with fluoropyrimidines, the rate of grade 3 diarrhea was significantly higher in patients with mutated DPYD gene. Testing for DPYD*2A alone to diagnose DPD deficiency is suboptimal. Testing for other DPYD mutation variants including DPYD*9A provides a more comprehensive approach. These data should further be validated in prospective clinical trials.