bluuebunny/crossref_metadata_2025 huggingface dataset:
Onco-fertility care in a children's hospital: A quality improvement initiative.
Authors: Hayashi Masanori , Albert Catherine Michelle , Gubin Alexandra , Katz Ann , Kramer Cara , Loeb David Mark , Chen Allen Ray Sing
Published: February 2017

41

Background: Patients who will receive gonadotoxic cancer therapy should be counseled on fertility risks and be offered appropriate fertility preservation methods. Previous studies have shown low adherence to these quality measures. At Johns Hopkins Pediatric Oncology, a baseline survey revealed that only 70% of patients or their parents recalled receiving fertility counseling at initial diagnosis, and 50% of eligible patients were referred for fertility preservation procedures. Methods: A multidisciplinary group comprising Pediatric Oncology physicians, nurses, and social workers was formed to address barriers to appropriate oncofertility care. The team identified staff education, a practice standard, and familiarity with fertility preservation resources as needs. Many active resources were available, such as a pediatric ovarian cryopreservation research protocol. Results: Comprehensive fertility counseling and preservation practices for boys and girls were established to provide guidance and resources to the treating primary oncology team. Girls are risk stratified according to the planned therapy for their disease, and offered ovarian or oocyte cryopreservation if therapy carries an intermediate to high risk of fertility loss. Non-invasive sperm banking is recommended for all post-pubertal males who will receive therapy with any degree of gonadotoxicity. An oncofertility team provides 24/7 consultation for the primary oncology team and patients and proactively identifies newly diagnosed patients who need counseling. The comprehensive protocol has been published on the online center-wide policy repository, and the consult service has been frequently utilized. A cross-sectional questionnaire study will be performed annually to monitor compliance to protocol and quality of care. Conclusions: A proactive team approach can overcome barriers to quality oncofertility practice.
Identifying knowledge-translation opportunities in the treatment of locally advanced breast cancer.
Authors: Rajmohan Yanchini , Leonard Robyn , Hogeveen Sophie , Ebrahim Jalal , Han Dolly , Wong Audrey , Boileau Jean-Francois , Gandhi Sonal , Lee Justin , Dinniwell Robert Edward , Brackstone Muriel , Simmons Christine E.
Published: February 2017

47

Background: Guidelines are usually developed using systematic literature reviews. Expert opinion plays a key role but can be difficult to incorporate. The objective of this study was to develop a national consensus of expert opinion on the management of Locally Advanced Breast Cancer (LABC) and subsequently identify gaps in knowledge translation in current practice. Methods: 361 Canadian oncologists were subdivided into LABC experts (n = 83) and non-experts (n = 278). Experts were surveyed with a modified Delphi protocol to establish consensus. A systematic literature review was performed and compared to expert opinion. Non-experts were then surveyed with a 29-item questionnaire to determine current practice patterns. Z test was used to assess discordance. Results: Response rate for the expert survey was 61% (51/83). Consensus was achieved in all key aspects of care and was concordant to published literature in areas of: clinical assessment with caliper at each cycle, option of lumpectomy if good clinical response, radiotherapy to loco-regional lymph nodes, and no further adjuvant chemotherapy outside of clinical trial if residual disease found at time of surgery. Response rate for the non-expert survey was 50% (140/278). Areas of discordance are highlighted below. Conclusions: A national practice consensus guideline reflective of current evidence and expert opinion has been developed on the management of LABC. Differences in expert opinion and current practice have been identified as targets for knowledge translation interventions (KTIs) that may improve quality of care and resource utilization. Further exploration of KTIs to address identified gaps is warranted. [Table: see text]
Timeliness of care in patients with non-small cell lung cancer (NSCLC) at the Louis Stokes Veteran Affairs Medical Center (LSVAMC).
Authors: Manochakian Rami , Mervar Stephanie , Fox Deborah , Liu Yang , Bokar Joseph A. , Arfons Lisa
Published: February 2017

50

Background: Timeliness of care in patients with newly diagnosed lung cancer is a controversial topic. Although some studies have concluded that timeliness does not improve clinical outcomes, many experts agree that timeliness is an important aspect of quality care as it leads to shorter duration of emotional distress during the diagnostic process and treatment initiation. Methods: At the LSVAMC, we have established a 60-day time interval from first abnormal radiology to treatment initiation as our institutional standard of care. We have initiated several interventions to improve timeliness of care through our new lung cancer program launched in July 2012. These interventions, which were implemented over a 1 year period, include: 1) Weekly interdisciplinary lung nodule rounds. 2) A cancer care tracking system. 3) A lung cancer-specific case manager who collaborates with all disciplines to expedite workup and treatment initiation. We have retrospectively reviewed all NSCLC cases since the launch of the new lung cancer program (group 1) and compared the timeliness to a sample of patients before the interventions (group 2). Results: 58 patients (group 1) and 107 patients ( group 2) with NSCLC were diagnosed and treated at the LSVAMC from January to July 2011 and July 2012 to May 2013 respectively. Median time from first abnormal radiology to first treatment was 104 days (range 13-375, mean 113.4) in group 1 and 81 days (range 1-261, mean 84.9) in group 2. Median time from diagnostic radiology to tissue diagnosis was 39 days (range 2-226, mean 66) in group 1 and 29 days (range 2-206, mean 42.6) in group 2. Median time from tissue diagnosis to first treatment was 23 days (range 0-177, mean 38) in group 1 and 28 days (range 0-254, mean 36.5) in group 2. Conclusions: Timeliness of care in NSCLC patients at our center has improved. We still have not reached our target. Continued progress is expected as we transition to a multidisciplinary multi specialty care lung cancer program.
Survey of the University of Florida hematology/oncology fellows on perceived skills of independent management of oncologic pain, chemotherapy-related nausea and vomiting, and end-of-life discussions.
Authors: Ricks Jennifer Lynn , Chang Myron , An Qi , Dang Nam H.
Published: February 2017

7

Background: Prior literature in oncology suggests that oncologists receive less training during fellowship in the areas of pain management, chemotherapy-related nausea/vomiting (CRNV), and end-of-life (EOL) discussions than is desired for later practice. As such, confidence in management could be improved by focused interventions. This survey sought to determine whether fellows in the department of Hematology/Oncology at the University of Florida (UF) felt they would benefit from additional education in these areas. Methods: An anonymous voluntary survey was administered by an impartial third party to assess the fourteen fellows’ comfort levels. Questions numbered 1-7 focused on oncologic pain, numbers 8-17 on CRNV, and numbers 18-28 on EOL care. Answers were converted to a numeric scale in the range of 1-4, with 4 points as the highest endorsement of confidence and 1 point as the lowest comfort level. 95% confidence intervals were used to analyze results of each question. Results: 79% (95% CI:57%-100%) of fellows felt additional training in pain management and CRNV would be beneficial. Half of fellows surveyed (50%, 95% CI:24%-76%) considered need for additional training in EOL discussions worthwhile. The scores were not significantly different when stratified by year of training (p value = 0.10, 0.48, 0.20). Conclusions: We conclude that the majority of UF Hematology/Oncology fellows feel that additional training in oncologic pain and CRNV is desired. This is significant as it parallels national trends. Limitations of the study include relatively small sample size, thus the absence of any statistically significant differences in responses by year of training may have been a result of the sample size. Several methods exist to satisfy this perceived need, including targeted lectures or standardized online teaching modules from the American Society of Clinical Oncology. A future prospective study using these modules is underway to further validate our findings. [Table: see text]
Using RFID technology to drive quality improvement.
Authors: de Mendonca Ben , Cheung Matthew C. , Singh Simron , Charbonneau Flay , Wield Kirsty , Soudsa Philomena de
Published: February 2017

70

Background: The Odette Cancer Centre (OCC) is the sixth largest cancer institution in North America and manages over 24,000 chemotherapy patient visits/year. We initiated an automated system whereby patients can “actively” self-check-in using Radio Frequency Identification (RFID) cards to the chemotherapy unit as part of a quality improvement initiative. Methods: Four self check-in kiosks were implemented into the OCC and all patients received a unique identifiable RFID card. Patients “self-arrived” to the OCC upon entry as well as before the nursing assessment. The technology created an electronic data infrastructure to capture patient experience data for ambulatory chemotherapy. In addition, visual management boards have been implemented that display the patients’ unique identifiers and communicates their process status. This tool also acts as a call-in system wherein the screen flashes and prompts the patient to proceed to the service area. Data was extracted electronically from various information systems, consolidated in excel linking information by the patients hospital file number. Results were analyzed. Results: The mean number of patients treated per day is 85 with a range of 65 to 105 (n=853). Median wait time from arrival to chair placement was 1:52 minutes ranging 0:02 to 6:12. There were 43% of patients that had medication ready within 30 minutes of their appointment time. There was an observed reduction in interruptions to the assessment nurses related to patient status updates (data to be presented). Patient satisfaction was high despite the modest improvement in efficiency. Conclusions: A comprehensive business analysis is being performed on the operations of the OCC with the implementation of this technology. The visual management boards enhance communication to patients while increasing privacy and patient confidentiality. The boards allow for patient mobility in the waiting room and eases anxiety associated with being “lost in the queue”. Next steps for the OCC are to create a data cube linked with other systems to further enrich the data. This technology enabled data analysis, evaluated the impact of change, set baseline targets for performance and built continuous quality improvement.
Impact of a novel decision counseling program on treatment knowledge, decisional conflict, and choice in men with early-stage, low-risk prostate cancer.
Authors: Hoffman-Censits Jean H. , Petrich Anett , Quinn Anna , Leader Amy , Gomella Leonard G. , Dicker Adam , Den Robert Benjamin , Hurwitz Mark , Kelly William Kevin , Lallas Costas D. , Burns Katherine , Trabulsi Edouard John , Myers Ronald
Published: February 2017

9

Background: Active surveillance (AS - serial follow-up PSA, exam, and biopsy) is an option for men with early stage, low risk prostate cancer (LRPca). While data show comparable survival for AS vs active treatment (AT - surgery or radiation), currently most men with LRPca undergo AT. A pilot Decision Counseling Program (DCP) to assist men in making an informed, shared LRPca treatment decision was implemented. Methods: Men with LRPca seen at the Jefferson Genitourinary Multidisciplinary Cancer Center (JGUMDCC) were consented. A nurse educator (NE) reviewed risks/benefits of AS and AT; had the participant identify factors influencing treatment decision making and specify decision factor weights; entered data into an online DCP; and generated a report of participant treatment preference and decision factors. The report was used by the participant and clinicians in shared treatment decision making. A follow-up survey was administered 30 days after the visit, with treatment status assessed. Change in treatment-related knowledge and decisional conflict were measured using baseline and 30-day survey data. Results: Baseline decision counseling preference of 16 participants: 4 - AS, 8 equal for AS and AT, 4 - AT. At 30 days, 12 participants initiated AS, 4 chose AT; participant mean treatment knowledge scores (8-point scale) increased (+1.13 points); decisional conflict subscale scores (strongly disagree = 1, strongly agree = 5) decreased (uncertain: -1.15, uninformed: -1.36, unclear: -1.12; and unsupported: -1.15). Conclusions: Decision counseling and shared decision making helped participants become better informed about treatment choices and reduced uncertainty in treatment decision making. The combined intervention resulted in most participants choosing AS. Ongoing study recruitment, data collection, and analyses are planned.
A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer (AGC) in Asian population: Tytan study.
Authors: Bang Yung-Jue
Published: February 2017

11

Background: The use of trastuzumab has been established as the standard first-line treatment of HER2 positive (+) AGC. However, the role of anti-HER2 agents in the second-line treatment of HER2+ AGC has not been clearly established yet. TyTAN is the first randomized study to compare the efficacy and safety of adding lapatinib (L) to paclitaxel (P) vs P alone in the second-line treatment of HER2+ AGC. Methods: Eligibility required patients (pts) with AGC, amplification of HER2 by fluorescence in situ hybridization (FISH), and one prior regimen containing fluoropyrimidines and/or cisplatin. Pts were randomized 1:1 to L (1500mg QD) and P (80mg/m2, Day 1, 8, 15 q4w) or P alone. The treatments were given until disease progression or unacceptable toxicity. Stratification variables were prior trastuzumab treatment and gastrectomy status. Primary endpoint was overall survival (OS). Results: From March 2008 to June 2011, 1923 pts were screened and 430 pts were HER2+ AGC. 261 out of 430 pts were enrolled. All pts were from Asian countries: Japan (100), China (95), Korea (46), and Taiwan (20). Median OS was 11.0 months for L+P and 8.9 months for P alone in the intent-to-treat (ITT) population (HR 0.84; p=0.2088). In a pre-planned subgroup analysis, median OS in HER2 immunohistochemistry (IHC) 3+ subgroup was 14.0 months for L+P and 7.6 months for P alone (HR 0.59; p=0.0176). The endpoints in efficacy and AEs of special interest for L+P are summarized below (Table). Conclusions: Although OS was prolonged in L+P arm by 2 months, the difference was not statistically significant. HER2 IHC 3+ subgroup demonstrated statistically significant prolongation of OS by adding L. Clinical trial information: NCT00486954. [Table: see text]
C-reactive protein as an independent prognostic factor for metastatic gastric cancer.
Authors: Kitagawa Mika , Shimura Takaya , Yamada Tomonori , Itoh Keisuke , Hasegawa Chihiro , Kawai Takashi
Published: February 2017

110

Background: S-1 plus cisplatin has been recognized as the standard chemotherapy for metastatic gastric cancer (MGC). Inflammation is considered to be a critical component of tumor progression. C-reactive protein (CRP) has been associated with the development of many cancers, but the significance of CRP remains unclear for MGC. The present study assessed the relationship between serum levels CRP and antitumor effects in MGC. Methods: Among 109 MGC patients who received S-1 plus cisplatin as first-line chemotherapy from January 2006 to December 2011 in 3 Japanese institutions, we retrospectively identified 70 patients who fulfilled eligibility criteria of this study. Patients were categorized into 2 groups depending on serum CRP level before chemotherapy: 43 patients with CRP <1.0 mg/dl (CRP <1.0 group) and 27 patients with CRP ≥1.0 mg/dl (CRP ≥1.0 group). Results: Median overall survival was significantly shorter in the CRP ≥1.0 group than in the CRP <1.0 group [267 days (95% CI, 208 to 326) versus 416 days (95% CI, 325 to 507); p = 0.0007]. Moreover, progression-free survival (PFS) was significantly shorter in the CRP ≥1.0 group than in the CRP <1.0 group (median PFS 126 days [95% CI, 63 to 189) versus 188 days (95% CI, 159 to 217); p = 0.0050]. Meanwhile, response rate was determined in 58 patients with target lesions. No significant differences were noted between the CRP <1.0 group and the CRP ≥1.0 group (10/33, 30.3% versus 7/25, 28.0%; p = 0.663). In a multivariate analysis, serum CRP level before chemotherapy was an only independent prognostic factor for MGC (hazard ratio 3.09 (95% CI, 1.46 to 6.54); p = 0.003). Conclusions: Serum CRP level before chemotherapy might be an independent and potential prognostic factor for MGC. Stringent follow-up during chemotherapy is expected for patients with MGC and a high CRP level.
Preventive effect of rikkunshito, traditional Japanese medicine, for chemotherapy-induced nausea and vomiting.
Authors: Kajiura Shinya , Hosokawa Ayumu , Nanjyo Sohachi , Yoshita Hiroki , Suzuki Nobuhiro , Yamawaki Hidemoto , Ueda Yuko , Ueda Akira , Mihara Hiroshi , Hasumoto Yuushi , Ando Takayuki , Fujinami Haruka , Nishikawa Jun , Ogawa Kohei , Sugiyama Toshiro
Published: February 2017

131

Background: Supportive therapies are being developed for chemotherapy-induced nausea and vomiting (CINV). Rikkunshito is a Kanpo medicine, which is a part of traditionally practiced Japanese-based ancient Chinese medicine. It has been reported to be effective against cisplatin-induced anorexia in rats. In the present study, we evaluated the preventive effect of Rikkunshito for CINV in patients receiving high-dose cisplatin. Methods: We selected subjects who received chemotherapy including cisplatin (≥60mg/m2) for gastric or esophageal cancer between April 2010 and August 2012 at our institution. We targeted 20 cases treated without a reduction in the anti-cancer medication in the second course and added 7.5g/day of Rikkunshito, orally administered for seven days, to their second course treatment regimen. All cases were treated with 5-HT3 receptor antagonist and steroid, and palonosetron for the prevention of CINV in their first and second courses. We evaluated the complete response (CR, defined as no emesis and no rescue medication) rate and other toxicity, according to CTCAE v4.0, of the first and second courses. Results: The median age of the patients was 63 years (range, 49–77 years). The chemotherapy regimens were cisplatin + 5-FU in 15 cases with esophageal cancer, cisplatin + S-1 in five cases with gastric cancer. Anorexia in the first course was grade 0/1/2 = 5/11/4, but had been mitigated in the second course to grade 0/1/2 = 12/6/2 (P = 0.042). CR rate was 75.0% in the first course (95% CI, 56.0%–94.0%) and by the second course had improved to 95.0% (95% CI, 85.4%–100%). And about the other major toxicity, there was no significant difference between first and second courses. Conclusions: These results suggest that Rikkunshito has the potential to improve CINV in patients receiving high-dose cisplatin.
TH17 cells and early pancreatic tumorigenesis.
Authors: McAllister Florencia , Bailey Jennifer M , Alsina Janivette , Nirschl Christopher , Roeser Jeffrey , Blake Danielle , Lankapali Rachana , Sears Cynthia , Jaffee Elizabeth M. , Kolls Jay , Drake Charles G. , Pardoll Drew M. , Leach Steven D.
Published: February 2017

144

Background: Chronic pancreatitis increases the risk of developing pancreatic ductal adenocarcinoma (PDAC), one of the deadliest human cancers. Activating Kras mutations have been detected in 30% of early pancreatic intraepithelial neoplasias (PanINs), increasing to 100% in PDAC. We hypothesized that inflammatory cells recruited to the pancreas in response to chronic injury can interact with epithelial cells harboring activated KrasG12D and affect the progression of PanIN lesions. Methods: We used the the transgenic Mist1:CreERT2; LSL-KrasG12D (KCiMist1) adult mice in which the LSL KrasG12Dallele is activated specifically in the acinar compartment. This model leads to the formation of PanINs with a classic "ductal" phenotype and the progression of lesions is accelerated by the induction of chronic pancreatitis with recurrent cerulein injections. Results: We have found that TH17 cells, a subtype of CD4+ T-helper cells known to play an active role in inflammation, are recruited to the pancreas during chronic pancreatitis and further increased upon KrasG12Dactivation. The differentiation of CD4+T cells into TH17 requires IL-6 and TGF-B, factors that are increased in the pancreatic tumor microenvironment. Stat3, a key transcription factor that determines the differentiation of TH17 lineage, is activated in the pancreatic dysplastic epithelium and in the stroma. We have discovered that PanINs from KCiMist1 mice overexpress the IL-17 Receptor (IL-17RA) by immunofluorescence and furthermore we confirmed this finding on human PanIN tissue arrays. Intrapancreatic injections of adenovirus encoding IL-17A, the main cytokine produced by TH17 cells, into KCiMist1 mice led to an increase in the progression of PanIN lesions by 6 weeks when compared with mice injected with control adenovirus. Finally, we transplanted IL-17-/- bone marrow into KCiMist1 mice and showed a significant decrease in metaplasia and PanINs formation when compared with mice transplanted with WT bone marrow. Conclusions: We found that TH17 cells, recruited to the pancreas in the presence of chronic pancreatitis, can accelerate the progression of early pancreatic tumorigenesis, setting the basis for future translational studies targeting TH17 cells.
Association of dilated main pancreatic duct with biological high proliferative activity in intraductal papillary mucious neoplasm.
Authors: Eto Tsugio , Hayashi Hiromitsu , Kuroki Hideyuki , Nakagawa Shigeki , Hashimoto Daisuke , Ikuta Yoshiaki , Chikamoto Akira , Beppu Toru , Baba Hideo
Published: February 2017

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Background: Intraductal papillary mucious neoplasms (IPMNs) are characterized by multifocal and malignant potential represented by an adenoma (IPMA)-carcinoma (IPMC) sequence. Biologically, accelerated cell proliferative activity play an important role in the malignant step to IPMN (IPMC). Here, we investigated the biological significance of clinically available malignant predictive markers (such as diameter of main pancreatic duct, cystic size, and a mural nodule) in cell proliferative activity. Methods: From 2002 to 2011, surgically resected pancreatic specimens of IPMN were obtained from 49 patients (IPMA in 27(55.1%) and IPMC in 22(44.9%) patients, respectively). Median age was 73 years old (range 46-86 year). Men and women were in 31 and 18 patients, respectively. Cell proliferative activity was evaluated by MIB-1 index using Ki67 immunostaininig. Results: The MIB-1 index (20.1%±13.2) in IPMC was significantly higher than that in IPMA (9.0%±6.8)(p=0.004). In the comparison between the groups with high MIB-1 index (>15%) and low index (<15%), the diameter of main pancreatic duct in the high MIB-1 index group was and significantly larger than that in the low MIB-1 index group (p<0.05), 9mm (1-27mm) and 4.5mm(2-15mm), respectively. On the other hand, the cystic size and a mural nodule did not show any significant differences between of them. Regarding with the type of IPMNs (main- or branch-duct type), 60.9% of main duct type belongs to the high MIB-1 index group, whereas 19.2% of branch-type was in high MIB-1 index group. Conclusions: An increased diameter of pancreatic main duct showed the positive correlation with the high cell proliferative activity in IPMNs. Mucin production-induced dilatation of main pancreatic may predict the biologically high tumor proliferative activity.
Targeting Hedgehog in pancreatic cancer: An innovative approach but not for all tumors.
Authors: Andrikou Kalliopi , Faloppi Luca , Loretelli Cristian , Mandolesi Alessandra , Bianconi Maristella , Scartozzi Mario , Berardi Rossana , Bearzi Italo , Cascinu Stefano
Published: February 2017

205

Background: Exocrine pancreatic cancer is the fifth cause of cancer-related death in Europe and has a very poor prognosis for all disease stages. To date no medical treatment has significantly increased patients' survival. One of the reasons for pancreatic cancer's chemoresistance is the complex tumor architecture: cancer cells are surrounded by a dense desmoplastic stroma that blocks drugs delivery. Moreover, pancreatic cancer is characterized by a marked heterogeneity of cells, including cancer stem cells (CSCs) that act as tumor-initiating cells and hierarchically control the differentiated cancer cells. Recent studies in multiple pancreatic cancer model systems have implicated the Hedgehog signaling pathway in these tumor-stromal interactions. The Hedgehog signaling pathway, a crucial regulator of proliferation and differentiation during embryonic development, has been reported to be aberrant and SMO overexpression seems to be a mechanism of activation of this pathway in human pancreatic cancer fibroblasts. Several studies are ongoing to evaluate the potential role of Hedgehog inhibitors, we investigated the contribution of Hedgehog to pancreatic progression and aggressiveness, evaluating the associated of stemness and desmoplastic reaction. Methods: In 110 histological samples of pancreatic ductal adenocarcinoma were performed molecular biology assessment of SPARC, CD133, CD44, CD24, OCT3/4, SHH, IHH, DHH, SMO, PTCH1, PTCH2. Results: Our analysis showed a strictly correlation between overexpression of SMO and high levels of SPARC (p=0.0005) and stemness markers CD133 (p=0.04) and OCT3/4 (p=0.0023) Conclusions: Our data demonstrate a critical and conserved role of Hedgehog signaling in the regulation of stem cell lineages and in the determination of a pronounced desmoplastic reaction determining chemoresistance and disease progression. We can speculate that patients with an aggressive profile defined by SMO overexpression would be the best candidates for treatment with Hedgehog inhibitors. This evidence suggests that this pathway may hold promise for new therapeutic approaches.
FG-3019, a human monoclonal antibody to CTGF, with gemcitabine/erlotinib in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.
Authors: Picozzi Vincent J. , Pipas J. Marc , Koong Albert , Giaccia Amato , Bahary Nathan , Krishnamurthi Smitha S. , Lopez Charles D. , O'Dwyer Peter J. , Modelska Katharina , Poolman Vanessa , Chou James , Zhong Ming , Porter Seth , Neff Tom , Valone Frank
Published: February 2017

213

Background: Connective tissue growth factor (CTGF) is overexpressed in PDAC and facilitates local desmoplasia, tumor survival and metastasis. FG-3019 is a CTGF-specific monoclonal antibody that decreases tumor growth and metastases and prolongs survival in orthotopic and KPC mouse models. This study evaluates safety and efficacy of FG-3019 with gemcitabine/erlotinib in patients with PDAC. Methods: In a nongoing open-label, dose-escalation study, FG-3019 was used in combination with gemcitabine and erlotinib in patients with previously untreated, measurable, locally advanced or metastatic PDAC. Cohorts 1−6 received FG-3019 Q2W at 3, 10, 15, 25, 35 or 45 mg/kg. Cohort 7 received 35 mg/kg on Day 1 and then 17.5 mg/kg QW. Cohort 8 received 45 mg/kg on Day 1 and then 22.5 mg/kg QW. Results: 75 patients were enrolled at 7 centers. Baseline data: Stage III= 15, Stage IV=60; ECOG=0 (n=32), ECOG=1 (N=43). No SAEs or DLTs related to FG-3019 occurred at any dose. In per protocol population (n=68) median PFS and OS were 4.3 and 9.4 months respectively. Baseline plasma CTGF levels correlated inversely with PFS and OS (p=0.0029) (ITT population). Median FG-3019 Cmax and Cmin increased linearly with dose. Because of considerable overlap between subjects across cohorts, outcomes are correlated with drug exposure. OS, but not PFS, correlated with exposure after the first FG-3019 dose (Day 1 Cmax, p=0.009; Day 15 Cmin, p=0.005; ITT population). 47% of evaluable subjects had >50% decrease in CA19.9.The magnitude of reduction correlated with Day 1 Cmax (p=0.04) and inversely with baseline plasma CTGF (p=0.01). As FG-3019 accumulated over time, minimum FG-3019 exposure (Cmin) of 150 ug/mL on Day 43 appeared to be a threshold. Median OS was 7.7 and >8.6 months for subjects < (n=15) or ≥ (n=43) 150 ug/mL respectively on Day 43 (p=0.0034). Day 43 Cmin < 150, none alive at 12 months: Day 43 Cmin >150, 8 alive at 12 months, 17 alive 6.7-12 months. Conclusions: FG-3019 combined with gemcitabine/erlotonib is well tolerated. Interim results in this open-label study suggest OS improves with increasing exposure to FG-3019. Clinical trial information: NCT01181245.
Identification of unique somatic mutations with functional relevance through genetic characterization of gallbladder cancer (GB ca).
Authors: Javle Milind M. , Rashid Asif , Kar Siddhartha P , Schalper Kurt , Wang Nicholas , Peto Myron , Vauthey Jean-Nicolas , Aloia Thomas A. , De Aretxabala Xavier , Mills Gordon B. , Spellman Paul , Roa Ivan
Published: February 2017

214

Background: GB Ca is the leading cause of cancer mortality in Chilean women and its incidence is high in Southeast Asia. Molecular characterization of this disease is limited to small retrospective studies of prognostic biomarkers. Methods: 54 surgically resected GB Ca cases were selected. DNA was extracted from microdissected tumors; genetic mutations analyzed using two platforms a) Sequenom MassARRAY, a mass spectrometry-based approach for 90 targetable mutations including PIK3CA, KRAS, EGFR, FGFR, CTNNB1, MET, ALK and AKT and b) Exome sequencing using the Illumina HiSeq2000 sequencer for novel genetic variants in the coding regions. Sample preparation followed the standard Agilent SureSelect XT protocol with the 71Mb +UTR capture library. A stepwise filtering approach was used to identify variants by screening for nonsynonymous substitutions, comparison of exomes to matched control and dbSNP database to exclude common variants. Variants not predicted to affect protein function were excluded. KM survival curves and log rank test were used to correlate genotyping results with survival. Results: 46 cases were selected for Sequenom MassARRAY and whole exome sequencing performed on 8 cases and control non-tumor tissue. Sequenom identified mutations in KRAS (3 cases), IDH1 (4), ALK1 (1), MET (1), NRAS (3) and PIK3CA genes (2). Overall survival was poorer in KRAS [24 vs. 75 weeks, p=0.008] and IDH1 [27 vs. 80 weeks, p=0.0008] mutation carriers. Exome sequencing after filtering revealed genetic variants in 6 cases with an overall low mutation rate. There were no overlapping mutations and we identified 45 functional mutations in STK11, CDKN2A, IKZF3, GRM6, TP53 and CTNNB1 genes, known to be prognostic in other cancers. ABCB1 transporter, TP53 and STK11mutations were predicted to have high functional impact. Ingenuity pathway analysis identified p53, WNT/ ß-catenin, GBM and thyroid cancer signaling and cell cycle regulation to be the top hits. Conclusions: This first high-throughput genomic screening of GB Ca using different platforms identifies known and unique variants in cancer genes. Sequencing of additional cases and efforts to develop a GB Ca-specific somatic mutation panel are ongoing.
Extended neoadjuvant chemotherapy (CT) in borderline resectable pancreas cancer (BRPC): Is preoperative chemoradiation (CRT) essential?
Authors: Picozzi Vincent J. , Rocha Flavio G. , Rose J. Bart , Traverso L. William , Alseidi Adnan , Lin Bruce S. , Biehl Thomas A. , Ryan John A. , Moonka Ravi , Helton Scott
Published: February 2017

236

Background: The optimum approach to maximize R0 resection rate in BRPC is unknown. We evaluated an approach in BRPC using extended duration neoadjuvant CT, typically without neoadjuvant CRT to assess R0 resection rate on an "intent to treat"basis. Methods: Patients (pts) were identified from a prospectively-maintained database from 2008-2012. Pts required (1) BRPC per radiographic staging using NCCN/AHPBA criteria, (2) no prior PC therapy (rx) PC, (3) negative staging laparoscopy prior to rx, and (4) all cancer rx at VMMC prior to decision on "downstaging" surgery (S). Pts were initially treated with gemcitabine/docetaxel CT until (a) disease progression, or (b) 24 weeks (wks), before assessment for local rx. Pts with systemic progression and/or inability to complete 24 wks of CT were excluded from local rx; pts with localized cancer at 24 wks judged unlikely to achieve R0 resection were offered 5FU-based CRT then reassessed; all other pts were offered S. Results: Of 70 identified pts, 12/70 (17%) are on initial CT; 58 are fully evaluable. 51/58 pts (88%) completed 24 wks of CT. Response rates to CT were (a) serologic 42/58 (72%) > 50% decline in baseline CA19.9 (median 85%), and (b) radiographic of 47 pts evaluable by RECIST, PR/SD/PD were 60%/32%/8% respectively. 14/58 pts (24%) did not receive local rx (7 intercurrent illness, 7 disease progression). 44/58 pts (76%) were offered local rx- 12/58 (21%) CRT and 32/58 (55%) S. 2 pts receiving CRT later underwent S. CRT. 29 pts (50% total evaluable pts, 85% pts undergoing S) achieved R0 resection;10/29 pts (35%) via en bloc venous resections. 5 pts were inoperable (3 local - subsequently given CRT, 2 systemic). At median f/u of 16 mo, 21/29 (72%) R0 resection pts remain disease free (range 7+-47+mo) along with 4/12 pts (33%) receiving CRT w/o R0 resection (range 12+ -30 mo). 25/58 (43%) fully evaluable pts remain progression free on an "intent to treat" basis. Median OS for all pts is 27 mo (95% CI 15-39 mo); 25/29 R0 resected pts remain alive ( median OS> 20 mo). Conclusions: (1) extended neaoadjuvant CT is a feasible approach in BRPC. (2) Gemcitabine/docetaxel has significant activity in localized PC. (3) Neoadjuvant CRT may not be essential to R0 resection in BRPC.
A novel simplified approach to incorporating lymph node ratio into gastric cancer staging.
Authors: Fisher Sarah B. , Squires Malcolm Hart , Patel Sameer H. , Kooby David A. , Cardona Kenneth , Russell Maria C. , Staley Charles A. , Maithel Shishir K.
Published: February 2017

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Background: Previous investigators have reported on the value of lymph node ratio (LNR, defined as the number of positive nodes divided by the total number of nodes assessed) in gastric adenocarcinoma (GAC) staging. Given the complexity of previously proposed staging systems, it has not gained widespread acceptance. The aim of our study was to offer a novel simplified approach to incorporating LNR into gastric cancer staging. Methods: 131 patients who underwent curative intent resection with lymphadenectomy for GAC between 1/00-6/11 were identified. Clinicopathologic factors were assessed. Primary outcome was overall survival (OS). Results: Median age was 64 yrs, 51% were male. Median tumor size was 3.5 cm, 67% were poorly differentiated, 20% had perineural invasion, 31% had lymphovascular invasion, and 6% had a positive margin. Locoregional nodal metastases were present in 59% (n=77, N0: 41%, N1: 18%, N2: 22%, N3a: 14%, N3b: 5%). Median number of lymph nodes (LN) assessed was 15.5. Mean FU was 27.3 mos, median OS was 29.3 mos. Median LNR was 0.4 (.04-1). Patients with LNR ≥0.4 had decreased OS as compared to patients with LNR <0.4 (15.1 vs 41.5 mos, p<0.0001); the survival of patients with LNR <0.4 was similar to that of node negative pts (48 mos, p=0.882). On Cox regression analysis, LNR ≥0.4 was more strongly associated with decreased OS (HR 3.09, 95%CI: 1.81-5.26; p<0.0001) compared to the AJCC 7th edition N stage (HR 1.36, 95%CI: 1.11-1.68; p=0.004). In the subset of patients who were inadequately staged and had <16 nodes examined, a LNR ≥0.4 was associated with reduced survival compared to a LNR <0.4 (17.3 vs 41.5 mos, p=.04). Conclusions: Compared to the current lymph node staging system, a lymph node ratio using 0.4 as the cutoff may more accurately predict survival outcomes. It seems to be particularly useful in patients who have inadequate nodal assessment. This simplified approach to lymph node ratio may be a more valuable staging tool than the current AJCC nodal staging system for gastric cancer and needs to be validated.
Effect of geographic variability for pancreatectomy rates on outcomes in patients with stage I and II pancreatic adenocarcinoma.
Authors: McDowell Bradley D. , Howe James R. , Chrischilles Elizabeth A. , Mezhir James J.
Published: February 2017

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Background: Low usage of pancreatectomy for stage I/II pancreatic cancer in the US has been reported, yet it is not clear to what extent this reflects underutilization of resection versus appropriate selection of operative candidates. To address this, we examined the geographic variation in pancreatectomy. Methods: We queried the US Surveillance, Epidemiology, and End Results (SEER) data for stage I/II pancreatic head cancer diagnosed from 2004-2009. Factors included in multivariate analyses (MVA) were age, gender, race, stage, and geographic region and primary endpoints were rate of pancreatectomy and median survival. Results: 10,520 patients with stage I (n=2,068) and stage II (n=8,452) pancreatic head cancer were analyzed. Pancreatectomy was performed in 528 patients (25.5%) with stage I disease and in 4,295 patients (50.8%) with stage II disease (overall resection rate=45.9%). Rates of resection significantly varied across the 18 SEER regions after controlling for age, gender, race, and stage in MVA (p<0.0001). For the analysis, SEER regions were divided into groups of high/medium/low rates of resection (56.3%, 46.6%, and 41.1%, respectively). Median survival in the high resection regions was 12 months, which was significantly longer than in low and medium resection regions (both=10 months, p<0.0001). MVA confirmed that regions with high resection rates have improved survival while controlling for age, gender, and race (Table). Conclusions: Pancreatectomy rates vary highly across geographic regions, and areas with higher rates of resection are associated with better outcome. These data may reflect poor adherence to treatment guidelines, which possibly reflects a lack of confidence in the effectiveness of pancreatectomy or expertise in performing the procedure. Studies that control for patient selection factors are underway to further elucidate these important findings. [Table: see text]
Phase II study of alternate-day oral therapy with S-1 for unresectable advanced pancreatic cancer: An updated report.
Authors: Satoi Sohei , Miyazawa Motoki , Tani Masaji , Kawai Manabu , Hirono Seiko , Okada Ken-Ichi , Yanagimoto Hiroaki , Kwon A-Hon , Kanbe Takamasa , Mukouyama Tomoyuki , Tsunoda Hiroaki , Chijiiwa Kazuo , Ohuchida Jiro , Kato Jun , Ueda Kazuki , Yamaguchi Taketo , Egawa Shinichi , Hayashi Kazuhiko , Shirasaka Tetsuhiko , Yamaue Hiroki
Published: February 2017

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Background: Based on the results of GEST, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended regimen of 4 weeks of administration interrupted by 2 weeks of drug withdrawal frequently causes adverse effect. Grade3/4 toxicities (%) in S-1 were neutropenia 8.8, anorexia 11.4, diarrhea 5.5. On the other hand, we experienced in clinical practice that the alternate-day administration of S-1 reduced adverse effects and was tolerable for unresectable advanced pancreatic cancer patients unwilling to continue the standard daily administration. We therefore conducted a multi-center cooperative prospective study to compare daily with alternate-day administration of S-1 for unresectable advanced pancreatic cancer. Methods: Patients with unresectable advanced pancreatic cancer (PS, 0 to 1; age, 20 to 80 years; no other therapy) were eligible for enrollment in this trial. S-1 was administered a dose of 40 to 60 mg twice daily, assigned according to body-surface area, on Monday, Wednesday, Friday, and Sunday (specified days). Each treatment cycle will be 42 days (6 weeks). The primary endpoint was overall survival (OS). Secondary endpoints were safety, response rate (RR), progression free survival (PFS), time to treatment failure (TTF). Results: A total of 50 patients were enrolled from Sep 2009 to Feb 2011. 48 patients were evaluable for response. Male/Female was 21/27, PS: 0/1 was 40/8. With a median follow-up time of 28.2 months, OS as primary endpoint was 8.4 months (95% CI, 5.4-10.8) with the 1 year survival rate 29.2%. PFS was 5.5 months, and TTF was 3.9 months. RR was 10.4% (95% CI: 3.5-19.1), and Disease Control rate was 79.2%. Grade 3/4 hematological and non-hematological toxicities were minor. All of those adverse reactions were tolerable and reversible. Conclusions: We will report the data from the final analysis at this meeting. The current data show mitigation of adverse effects with alternate-day administration of S-1, and it appears to be a more sustainable option for unresectable advanced pancreatic cancer. A randomized phase II trial comparing this regimen of S-1 with standard regimen of S-1 is ongoing. Clinical trial information: 000003453.
The outcome of patients with advanced hepatocellular carcinoma (HCC) in pre- and post-sorafenib eras using the SEER database.
Authors: Tan Jiahuai , Choi Minsig , Philip Philip Agop , Dyson Gregory , Shields Anthony Frank , Kim Richard D.
Published: February 2017

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Background: HCC is the third most common cause of cancer-related death globally. Prognosis for advanced HCC is dismal due to lack of effective treatment options for the majority of patients who present with advanced disease. Sorafenib was the first agent reported to improve overall survival in patients with good liver function enrolled in phase III clinical trials. However, survival impact of sorafenib on the general population with advanced HCC has not been studied to date. Methods: Sorafenib was approved for patients with advanced HCC and Child-Pugh A liver disease in 2007. We analyzed 2005-2006 and 2008-2009 clinical outcome data from the SEER to compare the impact of this targeted therapy in the population based setting. The Kaplan-Meier method was used to estimate the median survival and 95% confidence intervals (CI). The log-rank test was used to test the difference in survival curves. Cox regression analyses were utilized for the estimation of hazard ratios. Results: We identified 2297 and 2808 stage III and IV HCC cases diagnosed in [2005, 2006] and [2008, 2009], respectively. Seventy-seven percent of the patients were male and the median age was 61 years old for males and 66 for females. The median survival estimates (95% CIs) are 3 (3, 4) months and 4 (4, 4) months for patients diagnosed in [2005, 2006] and [2008, 2009], respectively. The hazard ratio (95% CI) for overall survival comparing [2008, 2009] to [2005, 2006] was 0.92 (0.87, 0.98, p-value = 0.01). We performed multivariable Cox regression modeling and African American patients have a hazard ratio of death [1.14 (1.06, 1.23)] as compared to European American patients. Younger females have a decreased hazard of dying relative to younger men, while older females have an increase hazard of dying relative to older men. Conclusions: The approval of sorafenib treatment produced very modest median survival gain in advanced HCC patients based on SEER population study. However, the small benefit in hazard ratio may have been impacted by small number of patients with advanced HCC who are being treated or are able to be treated with sorafenib in this era.
Phase I trial of sorafenib in high-risk hepatocellular carcinoma (HCC) patients after liver transplantation.
Authors: Siegel Abby B. , El-Khoueiry Anthony B. , Finn Richard S. , Blanke Charles Davic , Hidalgo Rosa , Brown Robert S.
Published: February 2017

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Background: LT offers long-term survival for HCC patients within the Milan criteria. For those outside, rates of recurrence are higher. There are no known treatments which decrease risk of recurrence post-transplant. We began a multicenter Phase I study of sorafenib in high-risk HCC patients after LT. Methods: Eligible subjects had pathologically proven HCC that was either (1) outside Milan (pre- or post-transplant), (2) poorly differentiated (Edmondson and Steiner grade 4), or (3) had vascular invasion at explant. We used a standard phase I dose-escalation design, beginning drug between 4 and 16 weeks after LT, with a planned duration of treatment of 6 months. Cohort dosages are as follows: (1) 200 mg q day (6 enrolled), (2) 200 mg BID (3 enrolled), (3) 200 mg/400 mg (3 enrolled), and (4) 400 mg BID. Correlative studies include circulating endothelial cells (CECs) and plasma biomarkers which are being collected prior to treatment, at 1 month, and at recurrence. Results: We have enrolled 12 patients, 11 are reported here. Mean age is 62; 64% had underlying HCV, 27% HBV, and 9% ETOH. 45% were outside Milan based on preoperative imaging. On explant, 36% had high grade pathology, and 18% had vascular invasion. Grade 3-4 toxicities seen in >10% include: cytopenias (27% neutropenia), LFT abnormalities (T. bili 18%), HTN (18%), and diarrhea (18%). We are currently enrolling at the 3rd dose level. We had 1 episode acute rejection at the 3rd dose level. CEC data are available for 8 patients, with a baseline range from 15-91, and 1 month range from 2-254. Mean follow up time is 18.0 months. 3 patients have recurred, one who was on drug for < 1 month. Conclusions: To our knowledge, this is the only ongoing multicenter Phase I trial of sorafenib in the post-transplant setting in the US. Post-transplant sorafenib for high-risk patients is feasible, and toxicity has been manageable for the most part. DLT has not yet been defined. Clinical trial information: NCT00997022.