bluuebunny/crossref_metadata_2025 huggingface dataset:
Midlevel provider utilization within a large community oncology network.
Authors: Mikan Sabrina Q. , Cody Melinda Madison , Lindsey Lori , Carter Patricia , Hoverman J. Russell , Patt Debra A.
Published: February 2017

282

Background: The Association of American Medical Colleges (AAMC) reports that 56% of Oncologists work with midlevel providers (MLPs). MLPs include physician assistants (PAs) and advanced practice nurses (APNs). Within our large network of community oncology practices,there are 241 MLPs (88 PAs and 153 APNs). The MLP role encompasses the continuum of care beginning with genetic risk assessment throughout treatment, health promotion teaching, survivorship management and advance care planning (ACP) services. Methods: We used an online survey to elicit self-reported proficiency in eight core health care delivery roles. A 52 item, 5-point Likert scale (novice, advanced beginner, competent, proficient, expert) survey was sent in March 2013 to all MLPs. Results: Of all MLPs (n=241) invited to participate, 103 (43.5%) responded anonymously. Over half of all MLPs reported feeling proficient in the areas of collaborating with multi-disciplinary teams to formulate a plan of care (50.4%), facilitating patient and family decision-making in treatments, symptom management and end-of-life care (53.3%), and providing information to patients and families to facilitate adherence to cancer treatments and supportive care (54.2%). Secondly, the MLPs were confident in their ability to provide proficient care in health assessment through physical exam (46.6%), disease progression signs and symptoms (44.7%), and incorporating resources that meet diverse needs of the patients into the planning and delivery of care (52.3%) areas. Finally, the areas where MLPs reported feeling less than proficient were in specialty areas such as survivorship (34.2%) and genetics (34.2%). Also noted, for 45.7% of respondents, ACP was performed only 1-20% of their time. Conclusions: Self-assessment is one form of measurement that allows the individual provider to identify their strengths and weaknesses. It is important so that educational resources can be created, tested, and shared amongst providers to continue to improve their confidence and care delivery. Ongoing work in developing strong tools for survivorship visits, advance care planning, and genetic counseling within our network, is recognized as an imperative part of advancing PA and APN skills and quality patient care.
Use of a video decision tool to improve informed decision making in hospitalized patients considering palliative radiation therapy.
Authors: Dharmarajan Kavita Vyas , McCormick Beryl , Walters Chasity , Monether Christopher , Levin Tomer , Milazzo CarolAnn , Rawlins-Duell Robin , Giannantoni-Ibelli Gina
Published: February 2017

29

Background: Substantial evidence exists to suggest improved patient outcomes when oncologic patients are involved in making treatment decisions. Tools have been shown to facilitate the decision-making process for patients, yet aids to support decision making in radiation therapy (RT) are scarce. Given RT is one of the more difficult modalities for patients to conceptualize, there is a pressing need to develop and test decision aids, particularly in patients with incurable cancers. Methods: In this study, a video decision tool was developed and tested with 42 inpatients referred for palliative RT. Participants completed questionairres measuring their knowledge regarding palliative RT, treatment preferences and readiness, and decisional uncertainty before and after viewing the video. An additional 5-item tool was administered to participants after watching the video to assess their impression of the tool. Results: The mean percent of patients answering knowledge-assessing questions correctly increased 46.5% after viewing the video. Thirty-three percent (n=13) of patients rated their willingness to start palliative RT as 2 or greater (1= very ready; 10= not ready at all). Of these, 84.6% (n=11) showed improved scores in regard to their willingness to consent to palliative RT. Mean patient willingness scores improved 44% after watching the video. Decisional uncertainty scores changed minimally. Conclusions: Overall, participants' knowledge of palliative RT increased after viewing the video decision aid. With improved knowledge, there was a trend in increased willingness to begin RT. The next phase of this study will be a randomized trial to assess for differences in decisional uncertainty, knowledge of palliative RT, and treatment preferences for palliation. Clinical trial information: NCT01667965.
Operational efficiencies in the infusion center: Improving nursing efficiencies and patient wait times while decreasing costs.
Authors: Garth Alyssa , Schreiner Susan , Jourdan Dawn
Published: February 2017

56

Background: Decreased nursing efficiency and patient assignments has increased patient wait times and has significant implications on overall patient flow in the infusion center and labor dollars. Historically, staff nurses signed up for their patients, and took an average of 2 patients at one time. This created disparity in patient/staffing ratios, high number of labor dollars per worked infusion and an overall atmosphere of inequity among the nurses. Methods: Patient flow and labor cost were examined. Analysis of the nursing staffing matrix led to the creation of a patient placement nurse, taken from the daily staff allocation, assigning patients based on current patient assignment and acuity of patients. Nurses were identified to learn the patient placement nurse role based on critical thinking and organizational skills. With the assistance of a patient locator system, the patient placement nurse is able to identify when a patient’s wait begins and which nurse is the best choice to be assigned. A system was implemented in which a staff nurse was assigned a patient every 30-40 minutes with a maximum patient assignment of 4 concurrently. A standard 1:3 nurse to patient ratio was established unless a patient’s acuity prohibited this ratio. Results: Nursing ratios stabilized at 1:3. Staff became more efficient and work was reorganized for less subjectivity in patient assignments, producing more equitable workloads. This resulted in an increase in patients seen within 15 minutes improving from 69.8% to 85.3%. In addition, it allowed for the elimination of one nurse per day shift, resulting in a cost savings of approximately a 1.0 FTE/week or average annual salary of $62,129. Conclusions: Development of a standardized patient placement process can increase infusion center efficiencies and stabilize nursing workload, as well as decrease patient wait time and reduce the cost per infusion. This supports a delivery of patient-centered care while utilizing staff efficiently and appropriately and decreasing cost.
Examination of differences in quality of life and use of support services in urban versus rural breast cancer patients.
Authors: Roberts Sarah , Ahmed Shahid
Published: February 2017

98

Background: Many patients travel great distances, both for testing and for medical care. Previous studies have indicated that there can be significantly poorer quality of life in urban cancer patients. The purpose of this study was to determine any differences in support service use and quality of life in rural versus urban patients in Saskatchewan. Methods: This study is a survey based qualitative and quantitative analysis of women with breast cancer receiving treatment at the Saskatoon Cancer Center (SCC) in Saskatchewan, Canada. Surveys included demographic information, support service utilization and suggestions, as well as the WHO-QOL-bref quality of life assessment. Surveys were collected from 51 women with an age range of 43 to 87 years with a median age of 63. Participants travelled a mean distance of 99.2km to treatment center (range 1.9 – 307.6 km, SD 101 km) with 49% women travelling greater than 100 km (rural group) and 51% travelling less than 100 km (urban group). Results: Only 50% of urban participants and 56% of rural participants reported using support services at the SCC though this was found to be statistically non-significant by Fisher Exact Testing (p= 0.781). The support services reported to be most useful were nursing phone assessments, medication information, pharmacist support and mailing of medications. Further support services that participants would like to have available include: online support groups and blogs, local support groups, physician visits to rural communities and patient liaisons to help navigate the system. Overall, urban participants rated their quality of life on average at 3.96 with rural participants reporting 3.84 on a five-point scale, though non-significant by t-test (p=0.617). The WHO-QOL-bref study examines quality of life in 4 domains: physical health, psychological wellbeing, social and environment. Urban participants scored 68%, 72%, 76% and 77% in the 4 domains respectively while rural participants scored 61%, 73%, 79% and 78% in the 4 domains respectively. Conclusions: Our study did not find any significant difference between urban and rural patients in reported quality of life or support service use.
Incidence of brain metastases following trimodality therapy (TMT) in patients with esophageal and gastroesophageal (E-EGCJ) cancer.
Authors: Wadhwa Roopma , Taketa Takashi , Correa Arlene M. , Sudo Kazuki , Blum Mariela A. , Campagna Maria-Claudia , Komaki Ritsuko , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Liao Zhongxing X. , Rice David C. , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: February 2017

108

Background: Brain metastases in E-EGJ cancer patients following TMT are considered rare. We reviewed the cumulative incidence of brain metastases in a large cohort of patients who underwent TMT and had a long follow-up. Methods: Data were analyzedretrospectively for 579 E-EGJ cancer patients who underwent TMT between years 2000 and 2010. None had screening or surveillance brain imaging. Results: Median follow-up time was 57.4 months (95% confidence interval [CI]: 51.5-63.3 months). Common patient characteristics were as follows: median age: 59.5 years (range, 39-74 years), Caucasian ethnicity (90%), male gender (85%), pre-treatment clinical stage III (65%), and adenocarcinoma histology (90%). 197 (34%) of 579 patients developed distant metastases and of these 20 (3% of 579 and 10% of 197) patients developed brain metastases. 18 (90%) patients had brain metastases within the first 24 months (12 in the first 12 months and 6 in the following 12 months) of surgery. 18 (90%) of patients were symptomatic at diagnosis. 15 (75%) of 20 patients had a single metastasis, however, only 4 (25%) patients survived >20 months (overall survival times were [in months]: 20, 30, 92 and 137). The median overall survival time of all 20 patients was 10.8 months (95% CI: 4.7-16.9). Conclusions: 3% of patients with E-EGJ cancer developed brain metastases after TMT and 90% of these occurred within the first 24 months of surgery. A few patients survived ≥20 months. These data rule out the use of screening and surveillance brain imaging for TMT-eligible patients. Supported by UT M. D. Anderson Cancer Center Clinical Research and Generous Donors.
16-covariate propensity score matching between trimodality (TMT)-eligible esophagogastric cancer (EC) patients who had surgery and those who declined surgery after preoperative chemoradiation.
Authors: Taketa Takashi , Xiao Lianchun , Suzuki Akihiro , Blum Mariela A. , Sudo Kazuki , Lee Jeffrey H. , Weston Brian , Bhutani Manoop S. , Lin Steven H. , Wadhwa Roopma , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: February 2017

111

Background: Localized EC patients should receive chemoradiation followed by surgery (TMT). Nevertheless, some patients decline surgery after preoperative chemoradiation. Reports on the outcome of such patients are scant. Methods: Between 2002 and 2011, we identified 622 TMT-eligible EC patients in our databases. Of 622 patients, 425 achieved clinical complete response (negative biopsy and PET in the physiologic range) after preoperative chemoradiation. Of 425, 244 patients underwent surgery but 61 patients declined surgery. We were able to matched 16 covariates between 36 patients who declined surgery and 36 patients who had TMT. Results: Baseline characteristics between the two groups were well-balanced (p=NS). Within this matched cohort, the median overall survival (OS) and relapse-free survival were 57.9 months (95% CI, 27.7-NA), and 18.5 (95% CI, 11.5-30.4) for the declined surgery group and those were 50.8 months (95% CI, 30.7-NA), and 26.5 months (95% CI, 15.5-NA) for the TMT group. OS and RFS for both groups were not different (p=0.28, and 0.45, respectively). However, 11 of 36 patients in the declined surgery group had salvage surgery (median OS was 66.1 months). Conclusions: These provocative results are in a small series but need to be interpreted with caution. Nevertheless, the results reinforce a possibility of esophageal preservation strategy that could encompass biomarkers and sophisticated imaging. Currently, however, trimodality remains the gold standard. Supported by UTMDACC and generous donors.
Effectiveness of percutaneous radiofrequency ablation for metachronous liver metastases of gastric cancer.
Authors: Hwang Jun-Eul , Kim Dae-Eun , Shim Hyun-Jeong , Bae Woo Kyun , Cho Sang-Hee , Chung Ik-Joo
Published: February 2017

136

Background: This study evaluated the efficacy of percutaneous radiofrequency ablation (RFA) for the treatment of metachronous liver metastases of gastric cancer. Methods: We enrolled a total of 44 patients who underwent RFA for the treatment of metachronous liver metastases after resection of a primary gastric adenocarcinoma from January 2002 to November 2011. The primary endpoint of this study was overall survival (OS) and recurrence-free survival (RFS) after RFA. Results: Systemic chemotherapy was combined with RFA in 40 patients.The OS and RFS after RFA for all patients were 14.7 (95% CI, 10.1-19.2) and 6.1 months (95%, CI 4.2-8.1). the OS and RFS of the patients with liver-only metastasis who underwent RFA and chemotherapy were 20.9 months (95% CI 18.4-23.4) and 9.8 months (95% CI 9.2-10.5), respectively. On multivariate analysis, the factors independently, negatively associated with RFS were bilobar intrahepatic distribution (HR 3.9, 95% CI 1.5-9.9, p=0.001), and extrahepatic metastatic lesions (HR 3.6, 95% CI 1.6-7.8, p=0.003). The factors independently, negatively associated with OS were extrahepatic metastatic lesions (HR 12.6, 95% CI 3.7-42.9, p=0.001), no chemotherapy (HR 43.3, 95% CI 7.4-251.3, p=0.001), and tumor number (≥ 2) (HR 2.6, 95% CI 1.2-5.9, p=0.015). Conclusions: The efficacy of RFA for metachronous liver metastases of gastric cancer is limited to patients with a single, unilobar metastasis without extrahepatic metastatic lesions. Combined systemic chemotherapy is very important for the prolongation of overall survival.
Clinical characteristics of recurrent esophageal cancer after definitive chemoradiotherapy for stage II//III (non T4) esophageal squamous cell cancer.
Authors: Nishikawa Akiko , Kato Ken , Honma Yoshitaka , Iwasa Satoru , Takashima Atsuo , Hamaguchi Tetsuya , Yamada Yasuhide , Shimada Yasuhiro
Published: February 2017

137

Background: Recurrence after definitive chemoradiotherapy (dCRT) for locally advanced esophageal cancer is associated with poor outcome. No standard treatment strategy exist for recurrence after complete response (CR) to dCRT. We examined patterns of recurrence and clinical outcomes in patients with disease recurrence after dCRT. Methods: We retrospectively investigated 197 patients who had achieved initial CR after dCRT for locally advanced esophageal cancer between January 2000 and December 2008. We analyzed data from the 69 patients who had developed disease recurrence after CR, excluding 11 who died of other causes. Time to event was calculated by the Kaplan-Meier method, and the Cox proportional hazard model was used in univariate and multivariate analyses. Results: Characteristics of the 69 patients were as follows: male: female = 61:8; median age = 65 years (range 47 to 82); clinical stage at diagnosis (UICC 6th edition) IIA/IIB/III = 15/22/32; and performance status at recurrence (0/1/2) = (35/32/2). Primary CRT consisted of 5-FU+cisplatin (n = 66), 5-FU+nedaplatin (n = 2), or S-1+cisplatin (n = 1). The pattern of recurrence was locoregional failure (n = 35), or any distant failure (n = 34). Median time to recurrence from the start of dCRT was 13.6 months, and median survival time after recurrence was 17.4 months. Median survival time according to pattern of failure was 27.5 months (locoregional failure), and 17.4 months (any distant failure). In the univariate analysis, locoregional failure (HR 0.51), time to recurrence >13 months (HR0.38), clinical stage II (HR0.48), and any treatment for recurrence (HR: 0.15) were associated with better prognosis after recurrence. In the multivariate analysis, only time to recurrence (>13 months) was associated with better prognosis with HR 0.31(95%CI:0.14-0.66) Conclusions: Our study suggested that patients with early recurrence have a poor prognosis. More intensive treatment is needed to improve survival.
A randomized single blind controlled trial of beads versus doxorubicin-eluting beads for arterial embolization of hepatocellular carcinoma (HCC).
Authors: Brown Karen T. , Gonen Mithat , Do Kinh Gian , Covey Anne M. , Getrajdman George I. , Zhao Binsheng , Sofocleous Constantinos T. , Johnson Kristian , Beattie Christopher , DeMatteo Ronald P. , Solomon Stephen Barnett , Schwartz Lawrence H. , Abou-Alfa Ghassan K.
Published: February 2017

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Background: HAE using particles is a method of treatment for HCC. The added role of doxorubicin has never been fully understood biologically. To date, no study has demonstrated any difference in outcome using HAE versus trans-arterial chemoembolization (TACE). Methods: Patients (pts) with unresectable Okuda stage I or II HCC with adequate liver function were randomized to BB or LC loaded with 150 mg of doxorubicin. Pts were evaluated by multiphasic CT 2-3 weeks post-treatment. Progression by RECIST and/or evidence of ≤5% necrosis was considered treatment failure. Otherwise pts were followed with CT every 3 months until progression or death. Pts with either recurrent tumor or new tumor outside the treated area could be re-treated. The primary objective was response rate (RR) by RECIST. With 50 pts in each arm response rates can be estimated to within +/- 14%. Secondary objectives included assessing safety and tolerability, time to progression (TTP), progression free survival (PFS), and overall survival (OS). Quantification of tumor necrosis (TN) using CT volumetric data was correlated with outcome. Analyses were intention-to-treat. Results: Between December of 2007 and March of 2012, 101 pts were randomized, 51 to BB and 50 to LC. Demographics in the two groups were comparable: median age was 67, 77% were male and 81% were Okuda I. Median number of embolizations was 2 in both arms. There was no difference in adverse events, the most common being post-embolization syndrome of pain, fever, nausea, or vomiting (84% in both groups). There was no difference in RR: BB 11% vs LC 9% (p=0.58). Median TTP was not reached. 12 month TTP was 49 versus 56% (p=0.84), median PFS was 7 versus 9 (p=0.6), and OS 14 versus 16 months (p=0.7) for BB and LC respectively. Change in TN/tumor volume post treatment did not predict OS in either group (p=0.28). Conclusions: No difference in response was noted between pts treated with BB versus LC. Given the comparable safety profile, TTP, PFS and OS, HAE should be considered a reasonable and cost-effective therapeutic option and may be preferable to LC. Clinical trial information: NCT00539643.
Prognostic features and outcomes in primary liver sarcoma.
Authors: Guye Mary L. , Streja Leanne , Chen Steven L. , Uyeno Lori A. , Kim Joseph , Singh Gagandeep
Published: February 2017

150

Background: Primary liver sarcoma (PLS) is a rare and aggressive hepatic malignancy. Due to the low incidence of PLS, prognostic factors have not been well characterized. The purpose of our study was to evaluate survival outcomes in primary hepatic sarcomas and determine which factors predict survival. Methods: The Surveillance Epidemiology and End Results registry was used to identify patients with PLS from 1988-2009. Patients were evaluated by standard clinical and pathological indices including: age, gender, race, tumor size, tumor grade, histology, and extent of disease. Treatment related factors included surgery and radiation. Overall survival was assessed by Kaplan-Meier method. Univariate and stepwise multivariate Cox proportional hazards analyses were performed to identify prognostic factors. Results: 541 patients with PLS were identified. The mean age was 52 and most patients were male (55%) and white (75%). The most common histology type was blood vessel tumors (50.1%) followed by soft tissue neoplasms (17.7%) and complex mixed-stromal neoplasms (14.6%). Only 33% of patients underwent surgery and most (93%) did not receive radiation. When assessing outcomes, we observed median overall survival (OS) and cancer specific survival (CSS) of 6 months for the entire cohort. When stratified by treatment type, those who received surgery + radiation had the best survival (MS=97mos, p<.001) compared to those who received either radiation alone (MS=5mos) or no treatment (MS=2mos). Stepwise multivariate analysis showed that age, male gender, tumor size, advanced stage, and no surgery were independent predictors of worse survival, all p-values < .005. Conclusions: Primary liver sarcoma is an aggressive hepatic malignancy with low median OS of 6 months. Patients treated with surgery + radiation had the best outcome with a median survival of 97 months. Independent predictors for decreased survival included age, gender, tumor size, advanced stage, and no surgery.
The liver function assessment: The indocyanine green retention in correlation with the cholescintigraphic measurement—Retrospective validation study in 107 patients with liver malignancies.
Authors: Tomasek Jiri , Kiss Igor , Prasek Jiri , Dusek Ladislav , Tucek Stepan , Valek Vlastimil , Vyzula Rostislav , Kala Zdenek , Zimova Iveta , Podhorec Jan , Halamkova Jana , Krakorova Dagmar Adamkova
Published: February 2017

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Background: The transarterial chemoembolization (TACE) and the radiofrequency ablation (RFA) are the keystones of interventional therapy of primary and secondary liver malignancies in oncology. A compromised liver function may be a relative contraindication to these therapies. Child-Pugh liver scoring system is widely used to exclude patients with low liver function. The indocyanine green (ICG) retention rate at 15 min. (ICGR15) is a frequently used liver function test in liver surgery, however it is not widely available. The quantification of dynamic cholescintigraphy and the calculation of hepatic extraction fraction (HEF) describes specifically a functional efficiency of the liver parenchyma. Methods: We retrospectively studied 107 patients with primary or secondary liver malignancies who underwent TACE or RFA between February 2005 and February 2012. ICG test and dynamic cholescintigraphy and Child-Pugh score were assessed before the procedure. The comparison of relative frequencies of categories was performed by binomial test (independent testing) or by McNemar’s test (paired design). The association in occurrence of different categories was tested by the help of Fisher’s exact test. Results: The comparison of categorized outcomes of ICGR15 and HEF examination revealed high degree of agreement between these techniques (p = 0.773). The statistically significant similarity in the outcome of both methods was also proved by the analysis of contingency tables. 81% of tested samples obtained the same scoring by both approaches. Clinically important discrepancies between these methods were rare and were not observed in the two extreme categories, i.e. normal and very low liver function. Conclusions: The ICGR15 correlates well with the HEF in liver function assessment. Thus either method can be used in patients who are to undergo liver directed therapies when the assessment by Child-Pugh score is not sufficient enough.
Usefulness of circulating tumor cell detection in pancreatic adenocarcinoma diagnosis.
Authors: Basile Paul , iwanicki-Caron Isabelle , Toure Emmanuel , Antonietti Michel , Lecleire Stephane , Di Fiore Aude , oden-Gangloff Alice , Blanchard France , Lemoine Francoise , Di Fiore Frédéric , Sabourin Jean-Christophe , Michel Pierre
Published: February 2017

157

Background: For pancreatic tumor, guidelines recommend pancreatic cytology examination by EUS-FNA as the first diagnostic procedure in unresectable patients. Detecting CTCs in blood could play the role of a “liquid biopsy”. The usefulness of CTC detection in the clinical management of these patients has not been established yet. Here, we aimed to prospectively evaluate the accuracy of a diagnostic method based on CTC detection. Methods: All patients referred from January 2011 to March 2012 for EUS-FNA procedure in a context of pancreatic solid tumor diagnosis were prospectively enrolled after their consent. Prior EUS-FNA procedure a sample of peripheral blood was collected. CTCs were analyzed using the ScreenCell method. Cells were considered as tumoral if they met these morphological criteria: nuclear diameter >14 µ, anisocytosis, anisocaryosis, nuclear membrane irregularities, large nucleolus, clots of tumoral cells with platelets and fibrin. All analysis was performed by a pathologist blinded to the EUS-FNA results. The diagnosis of pancreatic adenocarcinoma was defined either by pathological evidence based on FNA or surgical specimen, or by clinical outcome with metastatic evolution and CA19.9 serum level rather than 10 fold normal value. Results: A total of 40 patients were included. A pancreatic adenocarcinoma was confirmed in 27/40 patients (68.3%). In 21 of the 27 patients, pathological proof of adenocarcinoma was obtained by EUS-FNA. For the diagnosis of adenocarcinoma, sensitivity and specificity of EUS-FNA were 77.8% and 100% respectively. The diagnostic accuracy of FNA was 85%. CTC detection was positive in 15 patients. Sensitivity and specificity were 55.5% (CI95% [40.1%; 70.9%]) and 100% (CI95% [75%; 100%]) respectively. The diagnostic accuracy of CTC was 70%. Metastatic statuses, lymph node involvement, vascular invasion, size of tumor and CA19.9 serum level were not statistically associated with CTC detection. Conclusions: We suggest that CTC detection be applied as first-line procedure before EUS-FNA in the strategy of pancreatic tumor diagnosis. With the implementation of this blood test on a routine basis, approximately one half of these patients could avoid invasive EUS-FNA procedure.
Prediction of prognosis in patients treated with everolimus for extrapancreatic neuroendocrine tumors by a single nucleotide polymorphism in PHLPP2.
Authors: Bellister Seth Albert , Zhou Yunfei , Sceusi Eric , Ellis Lee M. , Yao James C.
Published: February 2017

163

Background: Rapamycin analogs (rapalogs) have improved outcomes in patients with neuroendocrine tumors (NETs). Few factors affecting response to rapalogs have been characterized. PHLPP2 is a phosphatase that inhibits PI3K-Akt-mTOR signaling. We hypothesized that an inactivating single nucleotide polymorphism (SNP) in PHLPP2 may affect outcomes in NETs treated with the rapalog everolimus. Methods: Blood was collected from 32 patients enrolled in a Phase 2 single arm trial of single agent everolimus in patients with NETs. DNA was extracted and RT-PCR products were sequenced to detect the L1016S SNP in PHLPP2. Outcomes analyses determined the role of the SNP in predicting progression-free survival (PFS), overall survival (OS), and response rates (RR) in patients with NETs treated with everolimus. Response rate (RR) assessed by RECIST criteria was evaluated as a binomial endpoint. A subset analysis was conducted to evaluate the NET site-specific role of the SNP. Results: Overall median PFS was 15.2 months (95% Confidence Interval (CI)=11.5 -18.7). The PHLPP2 SNP did not predict for a significant difference in PFS (Median PFS; wild type vs. SNP 16.8 (95% CI=14-20) vs. 11.3 (95% CI=4-19) mos., respectively, Hazard Ratio (HR)=1.2 (95% CI=0.5-3.1)), p=0.154). In a subset analysis, patients with extra-pancreatic NETs treated with everolimus with wild type PHLPP2 demonstrated increased PFS compared to patients with the SNP (Median PFS = 16.8 (95% CI=7-26) vs. 7.7 (95% CI=6-9) mos., HR=10.8 (95% CI=2-67), p=0.002). OS and RR were unaffected by the presence of the SNP in all analyses. Conclusions: In this preliminary study, the L1016S SNP in PHLPP2 may be prognostic for poorer PFS in patients with extrapancreatic NETs treated with everolimus. This study is hypothesis generating and requires validation in larger retrospective and randomized, placebo controlled studies in patients with NETs treated with everolimus.
Neuroendocrine tumors (NETs) of unknown primary: Is early surgical exploration and aggressive debulking justifiable?
Authors: Wang Yi-Zarn , Rau Jeffery , Diebold Anne E. , Opoku-Boateng Adwoa , Boudreaux J Philip , Woltering Eugene
Published: February 2017

166

Background: Neuroendocrine Tumors (NETs) are rare tumors that often present with vague symptoms. Identification and localization of the primary NET can be challenging and up to 10% of patients are classified as having an unknown primary. These patients have been thought to have a poor prognosis compared to those patients with a known primary. Treatments for patients with unknown primaries are directed towards symptom control and/or cytoreduction of metastatic disease. We hypothesized that early surgical exploration and discovery of a previously unknown primary will increase long-term survival. Methods: The charts for all 342 surgical patients, seen in our clinic between 1/2009-9/2012 were retrospectively reviewed to determine which patients had a pre-operative diagnosis of a “NET with unknown primary”. Twenty-six patients were identified. For these patients, the rate of successful surgical exploration in which a primary site was identified were recorded. Clinical outcomes for these “unknown primary” patients were compared to historical survival data for patients with unknown primaries that did not undergo a surgical exploration in search of a primary. Results: Twenty-six (26/354, 7%) NET patients with a pre-operative diagnosis of an unknown primary were explored and cytoreduced. The primary tumor site was identified in all 26 patients (100%). The primary sites identified for these patients were 23 ileal (88.4%) and 3 pancreatic (11.6%). All twenty-six patients were still alive as of 9/2012 therefore, a survival curve could not be generated. Conclusions: Unknown primary NETs are not associated with a poor prognosis should timely surgical exploration and debulking result in an identification of the primary and a maximum cytoreduction. Early surgical exploration with aggressive debulking is indicated for the treatment of these patients.
Outcomes following stereotactic body radiotherapy for patients with Child-Pugh B/C hepatocellular carcinoma.
Authors: Culleton Shaelyn , Jiang Haiyan , Kim Joon-Hyung J. , Brierley James D. , Brade Anthony M. , Ringash Jolie , Dawson Laura A.
Published: February 2017

167

Background: Assessment of outcomes in patients with hepatocellular carcinoma (HCC) and Child-Pugh B or C liver function treated with stereotactic body radiotherapy (SBRT). Methods: From 2004 – July 2012, 39 patients with HCC and Child-Pugh B/C liver function were treated with SBRT. Inclusion criteria included Child-Pugh B/C, treatment with SBRT, 5 to 15 fractions, and radical or palliative intent. Univariate analyses (UVA) were performed to assess relationships of patient demographics, liver function tests and treatment characteristics on overall survival (OS) and time to progression (TTP). Results: The majority of the 39 patients had Child-Pugh B7 liver function (69%), performance status ECOG 0-1 (82%), radiological evidence of tumor vascular thrombosis (62%) and hepatitis C as underlying liver disease (49%). 10 patients treated as bridge-to-transplant. The median dose was 3300 cGy in 6 fractions (range: 2000-4500 cGy in 5-15 fractions), individualized based on spared liver volume and underlying liver function. The median survival for all patients was 9.9 months (95% CI: 3.4-18.4). UVA demonstrated significantly reduced survival with Child-Pugh score > B7, baseline AFP > 1049 ng/mL (upper quartile) and gross tumor volume > 93 cm3. The median survival of patients treated with SBRT as a bridge-to-transplant versus the non-bridge-to–transplant patients was 30.7 months (95% CI: 0.6-not reached) versus 7.9 months (95% CI: 3.4-15.1; p=0.008). No HCC tumors treated with SBRT demonstrated local progression during the follow-up time. The median TTP for all patients was 18.8 months (95% CI: 6.2-not reached). Model for end stage liver disease (MELD) score > 12 was the only factor associated with reduced TTP on UVA. 31% of patients had a decline in Child-Pugh score by 2 or more points at 3 months. No acute treatment related toxicities of grade 3 or higher were reported. Conclusions: SBRT may be considered as a treatment option for HCC with impaired liver function. Survival is best in patients who are treated as a bridge-to-transplant, have smaller tumors, are Child-Pugh class B7, and have lower AFP levels. Randomized trials of radiation therapy in HCC patients with impaired liver function are warranted.
Unique histopathologic features of brain metastases from hepatocellular carcinoma.
Authors: Shao Yu Yun , Hsieh Min-Shu , Huang Chung-Yi , Lu Li-Chun , Hsu Chih-Hung , Cheng Ann-Lii
Published: February 2017

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Background: In the era of anti-angiogenic therapy as treatment for advanced hepatocellular carcinoma (HCC), the incidence and importance of brain metastases are increasing. We aimed to study their histopathologic features. Methods: We searched for all patients who were diagnosed to have HCC with brain metastasis from 1999 to 2010 at National Taiwan University Hospital, Taipei, Taiwan. Patients who had HCC with lung metastasis were also included for comparison. Patients with available tissues of both primary and metastatic tumors were enrolled in this study. Tumor slides from paired primary and metastatic HCCs were stained by H and E, and immunohistochemically stained for CK7, p53, Ki67, vimentin, Hes1, and c-Met. The expressions of CK7, p53, and vimentin were graded according to percentages of positive staining, but those of Hes1 and c-Met were recorded as an H score, which was defined as intensity (0, 1, 2, or 3) × percentages of positive staining. Results: A total of 14 patients had available tumor tissues of both primary and metastatic brain tumors. Another 21 patients had tumor tissues of both primary and metastatic lung tumors. The metastatic brain tumors, comparing to the metastatic lung tumors, had significantly more bizarre dilated vessels (86% vs. 14%, p < 0.001), hyaline globules (50% vs. 5%, p = 0.003), higher Hes1 H scores (mean, 245 vs. 131, p = 0.001), and lower c-Met H scores (mean, 15.4 vs. 38.1, p = 0.046). Tumor necrosis also tended to be more common among metastatic brain tumors (93% vs. 62%, p = 0.056). On the contrary, the above differences were not identified between the primary tumors which later developed brain metastasis and those which later developed lung metastasis. When disease progressed from primary liver to brain metastasis, mitosis counts (p = 0.034) and bizarre dilated vessels (p = 0.020) significantly increased, and necrosis (p = 0.059) tended to be more common. Conclusions: Metastatic brain tumors from HCC had unique histopathologic features compared to primary liver tumors or lung metastases. The increased Hes1 expression and decreased c-Met expression in HCC brain metastasis should be further explored. (This study was supported by the grant of NSC101-2314-B-002 -141, 100CAP1020-2 & NTUH.101-N1965.)
Suppression of human HCC cell growth in vitro by siRNA silencing of forkhead box M1 expression.
Authors: Park Keon Uk , Kim Ji Hong , Kim Hye-Jin , Lee Yun-Han
Published: February 2017

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Background: Development of targeted therapy for hepatocellular carcinoma (HCC) remains a major challenge. The transcription factor forkhead box M1 (FOXM1) is a member of the forkhead family, and it induces the expression of genes involved in the execution of mitosis. Liver regeneration studies that used the albumin promoter/enhancer cre recombinase (Alb-Cre) transgene to mediate hepatocyte-specific deletion of the mouse Foxm1 LoxP/LoxP targeted allele (Foxm1fl/fl) demonstrated that Foxm1 is required for hepatocyte DNA replication and mitosis. Methods: We explored the possibility of FoxM1 being a potential therapeutic target for HCC.To inactivate target gene expression, Huh7 and HepG2 cells were treated with the various doses of three different siRNAs (FoxM1-1, FoxM1-2 and FoxM1-3). The change of FoxM1 expression in mRNA level was then determined by quantitative real-time PCR. Cell growth was analyzed by MTT assay, and apoptosis was estimated by ELISA for the detection of denatured ssDNA only formed during apoptotic progression. Results: Among the three tested siRNA molecules, the FoxM1-1siRNA was the most effective in inhibiting HCC cell growth. Both Huh7 and HepG2 cells transfected with 15nM of FoxM1-1siRNA showed more than 60% growth inhibition by 4 days. Inhibition of cell growth was due to increased rate of apoptotic cell death which was about 2-fold higher than in untreated control cells. Upregulation of apoptosis directly correlated with down-regulation of FoxM1 mRNA level. Furthermore, siRNA-mediated silencing of FoxM1 expression in HCC cells retarded cell cycle progression. Conclusions: These results indicate that FoxM1 plays a pivotal role in HCC pathogenesis and maybe an attractive molecular target for systemic HCC therapy.
Role of biliary CEACAM6 as a biomarker for cholangiocarcinoma.
Authors: Rose John B. , Correa-Gallego Camilo , Nelson James , Alseidi Adnan , Helton Scott , Allen Peter J. , D'Angelica Michael , DeMatteo Ronald P. , Fong Yuman , Kingham T. Peter , Kowdley Kris , Jarnagin William R. , Rocha Flavio G.
Published: February 2017

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Background: Distinguishing bile duct carcinoma from other diagnoses is often difficult using endoscopic or percutaneous techniques. The cell surface protein CEACAM6 is over-expressed in many gastrointestinal cancers and may be selectively elevated in biliary adenocarcinoma. The aim of the present study is to determine if CEACAM6 can be detected in the bile of patients with biliary cancer and can serve as a diagnostic biomarker for cholangiocarcinoma. Methods: Bile duct and gallbladder bile from patients with benign biliary disease and cholangiocarcinoma (hilar, intrahepatic and distal) was collected at the time of index operation. The concentration of CEACAM6 was quantified by sandwich enzyme-linked immunosorbent assay (ELISA) and correlated to pathologic diagnosis. Diagnostic capability of CEACAM6 was evaluated by Wilcoxon rank-sum, logistic regression, and receiver operating characterisitic (ROC) curve analysis. Results: Bile from 73 patients was analyzed: 40 with benign disease and 33 with cholangiocarcinoma. Patients in the benign cohort were younger, predominantly female, and had lower mean biliary CEACAM6 levels than patients in the malignant cohort (102 ng/ml vs. 239 ng/ml; p=0.0006). Logistic regression analysis determined CEACAM6 to be a positive predictor of extrahepatic but not intrahepatic cholangiocarcinoma (p=0.0015). ROC curve with a CEACAM6 level >22.1 ng/ml was associated with 85% sensitivity, 73% specificity, and a likelihood ratio of 3.15 (AUC 0.82) for extrahepatic cholangiocarcinoma. Conclusions: CEACAM6 levels in bile can predict patients with extrahepatic cholangiocarcinoma with acceptable accuracy. Further investigation is warranted in a larger cohort of patients prior to clinical application.
Targeting occult metastatic disease: A hematogenously derived xenograft model of human pancreatic tumor growth in the murine liver.
Authors: Lindberg James M. , Adair Sara J , Newhook Timothy E. , Tilghman Robert , Parsons J Thomas , Bauer Todd W.
Published: February 2017

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Background: Most pancreatic cancer patients will die following surgery due to recurrent metastatic disease. Thus, better systemic therapies are needed to treat occult metastases to improve survival. We have developed a model of occult liver metastasis from pancreatic cancer in order to evaluate novel treatment strategies. Methods: Pancreatic cancer cells (MAD 09-366, 08-608, MPanc96) transduced with green fluorescent protein (GFP) and luciferase were injected into the spleens of athymic, nude mice to generate hepatic metastases. Ninety-six hours after injection, tumor-bearing mice were treated with MEK1/2 inhibitor (trametinib, 0.3mg/kg, daily), gemcitabine (100mg/kg, twice weekly), or vehicle control. Sequential bioluminescence imaging, flow cytometry, and histologic evaluation were used to assess hepatic tumor growth and behavior. Results: All injected cell lines generated hepatic metastases. Different cell lines exhibited different growth kinetics. MPanc96 injected mice demonstrated a 64% decrease in average luminescence from 6 to 72 hrs after injection followed by a 146-fold increase from 72hrs until sacrifice at 21 days. Extensive liver metastases were noted at necropsy. Flow cytometry analysis of digested mouse livers following MPanc96 injection revealed rapid clearance followed by sharp outgrowth of tumor cells that mirror the bioluminescent imaging data. MPanc96 injected mice treated with trametinib exhibited significant hepatic tumor growth inhibition relative to gemcitabine and control treated mice. At 21 days, trametinib treated mice demonstrated a 14.9-fold increase in average luminescence while on treatment compared to an 82.5-fold increased for gemcitabine treated mice (p = 0.028) and a 195.5-fold increase for control mice (p = 0.027). Conclusions: This in vivo model of pancreatic liver metastases has proven effective in assessing treatment effects on pancreatic metastatic growth. Trametinib appears to be a superior agent to gemcitabine at inhibiting metastatic pancreatic tumor growth and its effectiveness will be evaluated using this model with additional patient-derived tumor cell lines.
Circulating bone marrow-derived stem cells in patients with pancreatic cancer.
Authors: Starzynska Teresa , Dabkowski Krzysztof , Blogowski Wojciech , Zuba-Surma Ewa , Salata Daria , Budkowska Marta , Dolegowska Barbara , Marlicz Wojciech , Lubikowski Jerzy , Ratajczak Mariusz
Published: February 2017

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Background: Various experimental studies suggest that bone marrow-derived stem cells (BMSCs) may be involved in the development and progression of pancreatic cancer. However, these observations require further studies, and delineation of exact mechanisms responsible for mobilization of BMSCs from the bone marrow to peripheral blood. Methods: A total of 23 patients with newly diagnosed pancreatic cancer (17 with distal metastases) and 15 healthy individuals were recruited to this study. Using fluorescence-activated cell sorter circulating hematopoietic (HSPCs), mesenchymal (MSCs), endothelial (EPCs), and very small embryonic/epiblast-like stem cells (VSELs) were enumerated and sorted. Plasma levels of various growth/inhibitory factors (hepatocyte [HGF], vascular-endothelial [VEGF], leukemia [LIF]), stem cells’ chemoattractants (stromal-derived factor-1 [SDF-1], sphingosine-1-phosphate [S1P]), and complement molecules (anaphylatoxins [C3a, C5a] and complexes [C5b-9/MAC]) were measured. Results: Significantly higher numbers of circulating VSELs and MSCs were detected in pancreatic cancer patients (in both p<0.05), while the numbers of circulating HSPCs and EPCs were comparable between the analyzed groups. Among analyzed biochemical and immunomodulatory factors, levels of C5a, C5b-9/MAC, HGF and S1P, but not of SDF-1, LIF nor VEGF were associated with observed mobilization of BMSCs. Conclusions: In patients with pancreatic cancer selective mobilization of BMSCs from the bone marrow to peripheral blood is observed. This seems to be strongly associated with increased levels of immunomodulatory substances. Our study also highlights that it is S1P and HGF but not SDF-1 that seem to be associated with BMSCs mobilization from the bone marrow to peripheral blood in patients with pancreatic cancer. (MNiSW grant 402 423038).
Role of KRAS mutations in the carcinogenesis of mucinous tumors of appendiceal origin with pseudomyxoma peritonei (PMP).
Authors: De Braud Filippo G. , Pietrantonio Filippo , Perrone Federica , Deraco Marcello , Baratti Dario , Kusamura Shigeki , Milione Massimo , Tamborini Elena , Dotti Katia F , Di Bartolomeo Maria , Bertan Claudia , Fanetti Giuseppe
Published: February 2017

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Background: Codon 12 KRAS and BRAF mutations may have a role in the mucinous differentiation pathway in colorectal cancer (Bazan V et al, Ann Oncol 2002; Tran et al, Cancer 2011). Elucidating the molecular mechanisms driving this disease is a priority for PMP, with the goal of identifying new markers and therapeutic targets needed to improve disease management. Due to the fact that neoplastic cells may be deceptively bland and sparse histologically within an abundant mucinous background, the adoption of high-sensitivity gene sequencing techniques may be extremely helpful. Methods: Mucinous tumors from 10 PMP cases of appendiceal origin treated in a multidisciplinary team at the National Cancer Institute of Milan were histologically classified according to Bradley classification. Following microdissection and DNA extraction, mutational analysis of KRAS exon 2-4 and BRAF exon 15 were performed by means of PCR, while KRAS exon 2 status was further confirmed through a specific mutant enriched PCR, shown to be a more sensitive approach in colorectal cancer (Molinari et al, Clin Cancer Res 2011). Results: Histological classification was low-grade in 6 and high-grade in 4 tumors. Codon 12 KRAS mutations were detected in 5/10 cases (50%). In the remaining 5 cases: sequencing of exon 4 lead to identification of a first-described A146V mutation in 1 case; with mutant enriched technique, we identified 3 additional codon 12 mutated cases. Due to use of high sensibility techniques and gene sequencing outside hotspot regions, we were able to identify KRAS mutations in 9/10 (90%) specimens. No BRAF exon 15 mutation was detected. Conclusions: The prognostic role of KRAS mutation in PMP patients is under investigation on a larger data-set of National Cancer Institute of Milan and will be presented at the Meeting. However, these preliminary data suggest a major role of KRAS in the carcinogenesis of mucinous tumors of appendiceal origin with PMP.