bluuebunny/crossref_metadata_2025 huggingface dataset:
ADXS11-001 Lm-LLO Immunotherapy, Mitomycin, 5-fluorouracil (5-FU) and Intensity-modulated radiation therapy (IMRT) for Anal Cancer.
Authors: Safran Howard , Leonard Kara Lynne , DiPetrillo Thomas A. , Klipfel Adam , Schechter Steven , Oldenburg Nicholas , Vrees Matthew , Roth Leslie , Shah Nishit , Mantripragada Kalyan C. , Rosati Kayla , Rajdev Lakshmi
Published: September 2018

e15072

Background: Human papillomavirus (HPV) DNA is present in the majority of anal cancer. ADXS11-001 Lm-LLO immunotherapy is a live attenuated Listeria monocytogenes ( Lm) bioengineered to secrete a HPV-16-E7 fusion protein targeting HPV transformed cells. The Lmvector is phagocytosed by antigen presenting cells where it cross presents, stimulating MHC class 1 and 2 pathways resulting in specific T-cell immunity. The objective of this study was to determine the safety of ADXS11-001 with mitomycin, 5-FU and IMRT (chemoradiation therapy, CRT) and obtain preliminary data on progression free survival (PFS) in locally advanced anal cancer. Methods: Eligibility included patients (pts) with anal squamous cell cancer and stages T1N2-N3; T2( < 4 cm)N1-N3; T2(≥4cm)N0-N3, T3N0-3, T4N0-3; without evidence of metastases. Pts received standard 54 Gy IMRT with 2 cycles of mitomycin and 5-FU. ADXS11-001, 1x109colony forming units IV, was given x 1 dose before CRT then x 3 additional monthly doses after CRT. Results: The study enrolled the first pt in April 2013. Ten patients were treated (median age 62.5, range 37-71) including 5 with pelvic adenopathy. Two patients had grade 3 toxicities related to the vaccine including chills/rigors (n = 2), back pain (n = 1), hyponatremia (n = 1). All toxicities were within 24 hours of the vaccine and resolved successfully with standard care. There was no exacerbation of CRT toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment which was judged to be unlikely related to ADXS11-001and possibly related to CRT. Eight patients treated on the study had a complete response at six-month sigmoidoscopy. One additional patient who did not undergo six-month sigmoidoscopy had complete response on sigmoidoscopy performed at approximately one year. Eight of 9 patients (89%) are disease-free at a median follow-up of 34 months. Conclusions: ADXS11-001 can be safely administered with CRT for anal cancer. Promising PFS was observed in patients with locally advanced disease. Clinical trial information: NCT01671488.
HER2 overexpression and amplification in patients with colorectal cancer: a large-scale retrospective study in Chinese population.
Authors: Ni Shujuan , Peng Junjie , Huang Dan , Xu Midie , Wang Lei , Tan Cong , SUN Hui , Cai Sanjun , Sheng Weiqi
Published: September 2018

e15099

Background: Recent studies have shown that human epidermal growth factor receptor 2 (HER2) overexpression or amplification may be a potentially predictive factor for anti-HER2 response and anti-EGFR resistance in colorectal cancer (CRC). However, the prevalence of HER2 positivity in CRC patients and its correlation with clinicopathologic features are not clear. Methods: HER2 expression was tested by immunohistochemistry (IHC) in 4,913 consecutive patients with CRC treated with surgical resection of primary tumor during 2011-2014 in our institution. The formalin-fixed, paraffin-embedded samples of the primary tumors were used. Dual color silver-enhanced in situ hybridization (DISH) was performed in all IHC 3+/2+ cases and randomly selected IHC 1+/0 cases subsequently. The scoring criteria of HER2 status in gastric cancer was used. Results: HER2 positivity was found in 160 (3.3%) out of 4,913 cases of CRC. Among them, 68 cases were IHC 3+, while 92 cases were IHC 2+ and DISH+. 157 cases (3.2%) were HER2 amplified determined by DISH, including 66 (97.1%, 66/68) IHC 3+ and 92 (35.6%, 92/258) IHC 2+ cases. None of the 50 cases of IHC 1+/0 was HER2 amplified. HER2 positivity was correlated with perineural invasion, vascular invasion, lymph node metastases, and higher TNM stage. HER2 positivity was more common in younger patients ( < 60 year old). Only one HER2 positive case had mismatch repair protein (MMR) deficiency. HER2 positivity was found not related to tumor location. Conclusions: To our knowledge, this is the largest study of HER2 status in Asian patients with CRC. HER2 overexpression or amplification of tumor cells occurred in a small number of patients with CRC. HER2 positivity was related to unfavorable prognostic factors, more common in younger patients and rare in MMR deficiency cases. The further study of molecular heterogeneity of HER2 expression or amplification in patients with CRC was ongoing.
Effect of neoadjuvant chemoradiation on the tumor microenvironment in rectal cancer.
Authors: Jani Prashant Mukesh , Renz Paul , Brem Candice , Abel Stephen , Raj Moses S. , Monga Dulabh K. , McCormick James , Silverman Jan F , Kirichenko Alexander V. , Finley Gene Grant
Published: September 2018

e15115

Background: Chemoradiotherapy (CRT) followed by surgery is standard treatment for most rectal cancers. This creates an inflammatory reaction which recruits and enhances T-cell mediated killing. Tumors can evade destruction by expressing immune modulating proteins such as PD-L1. Inhibitors of PD-L1 can circumvent immune evasion potentially enhancing neoadjuvant treatment. We assessed CD8+ infiltrates and PD-L1 expression before and after neoadjuvant CRT. We correlated these changes with clinical and pathological endpoints. Methods: We obtained tissue from 22 patients treated with neoadjuvant CRT followed by primary surgery for rectal adenocarcinoma from 2005-2015. Patients received 5FU based chemotherapy with concurrent radiation (mean 51.2 Gy in 27 fractions). Pre- and post-CRT samples were stained with VENTANA PD-L1 (SP263) Rabbit Monoclonal Primary Antibody to quantitate PD-L1 expression. CD8 + lymphocytes were assessed over one high power field (40x objective) in the area of densest expression. Analysis of 8 patients was completed at the time of this submission. Results: 37.5% of cases had upregulated PD-L1 expression post-CRT. 62.5% maintained similar PD-L1 expression in the biopsy and resection specimen. All patients had a CD8+ infiltrate after CRT with 87.5% demonstrating an increase in CD8+ lymphocytes. Patients without increased PD-L1 expression had a trend toward improved pathologic response. Conclusions: A majority of patients had an increased inflammatory infiltrate post-CRT indicating immune activation within the tumor microenvironment. A subset of tumors had increased PD-L1 expression. This population might benefit from neoadjuvant PD-L1 inhibition, which could translate to better pathological response and clinical outcomes. We will present the results from 22 patients currently under study. [Table: see text]
Prognostic impact of MSI in stage II colon cancers: An additional translational study of the SACURA trial.
Authors: Ishikawa Toshiaki , Ishiguro Megumi , Nakatani Eiji , Uetake Hiroyuki , Ueno Hideki , Murotani Kenta , Matsui Shigeyuki , Tomita Naohiro , Shimada Yasuhiro , Takahashi Keiichi , Kotake Kenjiro , Watanabe Masahiko , Mochizuki Hidetaka , Teramukai Satoshi , Sugihara Kenichi ,   SACURA Study Group
Published: September 2018

e15155

Background: The SACURA trial is a phase III study to evaluate the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone for stage II colon cancer. Superiority of adjuvant treatment with UFT to surgery alone was not demonstrated (ASCO2016 abst#3617). In an additional translational study, we assessed microsatellite instability (MSI) status of cancer tissues and prospectively examined the association of MSI with prognosis in stage II colon cancer patients. Methods: Formalin-fixed, paraffin-embedded samples were prospectively collected from 1026 patients enrolled in the SACURA trial. MSI was evaluated using 5 markers; BAT25, BAT26, D2S123, D5S346, and D17S250. MSI-high (MSI-H) was defined as the presence of instability in more than 20% of the markers. Median follow-up time was 69.6 months. Results: MSI-H, MSI-low (MSI-L) and microsatellite-stable (MSS) was observed in 74 (7.2%), 24 (2.3%), and 928 (90.5%) samples, respectively. Patients with MSI-H was significantly frequent in female, right-sided colon cancers, > 5cm tumors, poor histological type, and elevated CEA. Relapse rate for MSI-H patients (4.1%) was significantly lower than that for MSI-L/MSS cancer (13.4%, p = 0.02). Relapse free survival (RFS) in MSI-H patients was significantly better than in MSI-L/MSS patients (hazard ratio: 0.40, 95%CI: 0.17-0.98, p = 0.045), as well as adjusted results by prognostic factors. The 5-year RFS rates in MSI-H and MSI-L/MSS patients were 92.9% and 84.1%, respectively. Although there was no statistical significance, the 5-year RFS rate in MSI-H patients was tended to be better than that in MSI-L/MSS patients in the surgery alone group (94.3% vs. 83.1%, p = 0.086) as well as in the UFT group (91.7% vs. 85.1%, p = 0.233). Conclusions: MSI was an independent prognostic factor in stage II colon cancers. By considering their favorable RFS, adjuvant chemotherapy for stage II colon cancer patients with MSI-H may be unnecessary. Clinical trial information: NCT00392899.
Regional and practice setting differences in the management of EGFR rash among mCRC patients treated with panitumumab: Results of a national survey in the United States.
Authors: Hool Kristina , Lowe Kimberly , Garawin Tamer , Bergstresser Rachel , Kafatos George , McNamara Michelle , Collins Seth , Bach Bruce A.
Published: September 2018

e15170

Background: Skin toxicity can be a limiting factor for the use of anti-EGFR therapies, such as panitumumab, and there are currently no standard practice guidelines for rash management in the United States (U.S.). This study aimed to evaluate if there were regional or practice setting differences in strategies used among oncologists to manage EGFR rash, including utilization of dermatologic and nursing support. Methods: 250 practicing oncologists who had treated at least three mCRC patients with panitumumab in the last year completed an online survey to report their opinions and perceptions regarding skin toxicity management strategies. Participants reported if they were affiliated with an academic/university or a community-based practice. Participants were stratified into years of practice post-fellowship ( < 10 and > 10 years) and geographic region of primary practice (West, Midwest, Northeast, Southern U.S.). Results: Oncologists surveyed did not consistently utilize dermatology support. 40% (n = 99) of practicing oncologists surveyed reported consulting a dermatologist “occasionally.” Less than 5% reported “always” consulting dermatology and 6% reported “never” utilizing dermatology support. Utilization of dermatology support varied significantly by region. In the Southern US more oncologists reported “never” consulting dermatology while in the Midwest more oncologists reported “always” utilizing dermatology support (p = 0.05). While dermatology was inconsistently utilized, oncologists frequently utilized nursing support to minimize and manage anti-EGFR skin toxicity. 73% (n = 182) of oncologists engaged nursing support to “monitor skin toxicity during treatment” and 70% (n = 175) of oncologists had nursing support to “educate on skin toxicity prior to starting treatment.” Conclusions: While nursing support is consistently utilized by oncologists in the management of EGFR rash in mCRC patients treated with panitumumab, use of dermatology support was inconsistent and varied significantly by region. This lack of consistency in toxicity management strategies highlights the need for increased physician education.
HIPEC in treatment of gastric cancer with high risk of carcinomatosis: Russians Regional Centre experience.
Authors: Privalov Alexey , Vazenin Andrey , Antonov Andrey
Published: September 2018

e15501

Background: Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is a treatment method in patients with gastric cancer having a high risk of development of peritoneal carcinomatosis which can improve treatment results. Methods: HIPEC in a "prophylactic" setting in gastric patients having a high risk of peritoneal carcinomatosis development has been applied in our centre since 2015. This method was used in cases of diffuse type poor-differentiated tumor histology , massive tumor invasion of the stomach serosa and relatively young age of the patient. A “closed” HIPEC technique, with 3 inflow and 3 outflow catheters, RAND HT performer and 7 liters of saline solution with 200 mg cisplatinum was performed. Up to this moment we have treated 8 patients with gastric surgery added by HIPEC. There were 4 men and 4 women. Median age was 48 years. In 2 cases distal subtotal gastric resection was performed, in other 6 cases - total gastrectomy with a D2 lymph nodes dissection. In 2 cases was also performed an edge resection of the pancreas. 2 procedures were performed in cases with ovarian metastases and local diaphragm canceromatosis, with complete cytoreduction. Median surgery time was 4 hours. Results: There was no mortality in early postoperative period, with 25% morbidity. In one case a severe postoperative pancreonecrosis occured which required several re-operations. In one case there has been an acute renal failure, after 3 dialyse sessions the renal function was recovered. Median post-operative hospital stay was 20 days. Two patients are alive without progression on 14 and 23 months respectively. One patient developed a local anastomotic recurrence, no other progression was found, and anastomosis extirpation was performed. Patients having ovarian metastases and local canceromatosis progressed in 6 months, in other cases progression was found in 6 to 12 months. Conclusions: The use of HIPEC doesn't result in elevation of complications or mortality rate. It shows a trend to improve the results of treatment gastric cancer. In cases of already existing canceromatosis the effectiveness of HIPEC is doubtful.
Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: A cost-effective analysis compared with conventional chemotherapy.
Authors: Wu Bin , Li Te , Xu Yuejuan , Zhao Gang
Published: September 2018

e15531

Background: Apatinib can improve survival in patients with metastatic gastric cancer (mGC) who do not respond to or who experience progression with second-line chemotherapy. Apatinib Patient Assistance Program (PAP) is implemented for Chinese patients. A cost-effective analysis is needed for apatinib with PAP. Methods: A Markov model was developed to simulate the clinical course of typical patients with chemotherapy-refractory mGC. We estimated 10-year quality-adjusted life-years (QALY), costs, and incremental cost-effectiveness ratios (ICER). The Clinical efficacy and safety were derived from the pivotal phase II and III trials of apatinib. Direct costs were estimated from the perspective of Chinese health care system. One-way and probabilistic sensitivity analyses were conducted. Scenario analysis for Patient Assistance Program (PAP) was checked. Results: Baseline analysis showed that the apatinib increased the cost and QALYs by $7,859 and 0.191, respectively, relative to conventional chemotherapy, resulting in an ICER of $40,997/QALY gained. The ICER was $21,132/QALY when 3+X PAP (paying for 3 months following free donation until disease progressed) was available. Probabilistic sensitivity analyses confirmed that apatinib with 3+X PAP achieved nearly two 2/3 likelihood of cost-effectiveness under the Chinese willingness-to-pay threshold of $ 22,200 per QALY gained. One-way sensitivity analyses found that the utility of progression-free survival was the most influential factor with respect to the robustness of the model. Budget impact analysis estimated that the annual increase in fiscal expenditures would be approximately 0.45 million dollars. Conclusions: Our analysis suggests that apatinib is likely to be cost-effective in patients with chemotherapy-refractory mGC when 3+X PAP is available.
Molecular profiling-selected treatment in metastatic gastric and oesophageal cancer: Real-life clinical experience.
Authors: Purim Ofer , Beny Alexander , Inbar Moshe J. , Brenner Baruch , Dudnik Elizabeth , Bokstein Felix , Temper Mark , Limon Dror , Sarid David , Semenisty Valeriya , Brenner Ronen Mordechay , Peretz Tamar , Idelevich Efraim , Pelles Sharon , Meirovitz Amichay , Russell Kenneth , Voss Andreas , Dvir Addie , Soussan-Gutman Lior , Hubert Ayala
Published: September 2018

e15537

Background: We evaluated real-life clinical experience with molecular profiling (MP)-guided therapy in metastatic gastric and oesophageal cancer in Israel Methods: This multicenter retrospective cohort study included patients with metastatic gastric or oesophageal cancer who were treated in the participating institutions and underwent MP (Caris Molecular Intelligence). Treatment was considered as having benefit if the ratio between the longest progression-free survival (PFS) post MP and the last PFS pre MP was ≥1.3. The null hypothesis was that ≤15% of patients gain such benefit. Results: The analysis included 46 patients (61% males; median age, 58 years; 57% with poorly-differentiated tumours). At least one actionable (i.e., predictive of response to a specific therapy) biomarker was identified per patient. Immunohistochemistry was performed on all samples and identified 1-8 (median: 3) biomarkers per patient (most commonly: low TS, high TOPO1, high TOP2A). Twenty-eight patients received therapy post MP (1-4 lines). In the 1st-line post MP, 5 patients (18%) achieved partial response and 5 (18%) stable disease; the median (range) PFS was 4.3 (0.4-38.5) months. Twenty-four patients were evaluable for PFS ratio analysis; in 7 (29.2%), the ratio was ≥1.3. In one-sided exact binomial test vs. the null hypothesis, P = 0.019; therefore, the null hypothesis was rejected. Conclusions: Our findings demonstrated that implementing MP is feasible and that MP could provide clinical benefit for a considerable proportion (~30%) of patients with metastatic gastric or oesophageal cancer.
Phase II XELOX + lapatinib treatment in HER2-amplified gastric cancer: Monitoring with serial cell-free DNA genomics.
Authors: Lee Jeeyun , Kim Seung Tae , Banks Kimberly , Lanman Richard B. , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Lee Hyuk , Kim Kyoung-Mee , Kang Won Ki
Published: September 2018

e15610

Background: It is important to identify biomarkers that predict which patients may benefit from the dual EGFR/HER2 inhibitor, lapatinib in HER2 amplified GC. Methods: We evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin (CapeOx) treatment in patients with previously untreated, HER2-overexpressing gastric cancer GC with limited metastases. A parallel biomarker study was conducted by IHC, and cfDNA NGS. Results: Thirty-two HER2-overexpressing AGC patients were enrolled between May 2013 – Nov 2015. Complete response (CR) was confirmed in 7 patients. Of 32 patients, we were able to obtain 10 primary-metastasis paired samples. Of 10 paired samples, 6 patients had concordant HER2 results and 4 patients had discordant HER2 positivity between primary and metastasis. Of discordant patients, patient #22 had gastric HER2 2+ but synchronous SCN LN HER2 0 and had progressive disease after one cycle. All of the patients with H index > 200 had tumor reductions. Beyond HER2 overexpression, other genomic alterations (e.g., CRKL amplification) associated with differences in lapatinib sensitivity and/or PFS. One patient with de novo resistance to lapatinib had HER2 and CRKL co-amplifications. We confirmed CRKL overexpression in both tumor tissues and established matched patient-derived cell (PDC) lines via IHC. CRKL knockdown reversed HER2-overexpressed PDC sensitivity to lapatinib. Lastly, serial cfDNA genomics from 11 enrolled patients change during lapatinib treatment demonstrates emergence of MET amplification and myc amplification at progression. Conclusions: This is the first report to show 1) CRKL amplification as a culprit molecule for lapatinib resistance; 2) cfDNA genomics demonstrating tumor evolution during lapatinib treatment which can potentially guide to subsequent treatment. Clinical trial information: 02015169.
Identification of patient population with longer survival when treated with S-1 plus cisplatin via predictive enrichment strategy analysis of the FLAGS phase III trial.
Authors: Ajani Jaffer A. , Takeuchi Madoka , Takeuchi Masahiro
Published: September 2018

e15612

Background: FLAGS, a randomized phase III trial, compared S-1, an oral fluoropyrimidine, plus cisplatin (SP) with 5-fluorouracil plus cisplatin (FP) in the first-line treatment for advanced gastric cancer (AGC). The purpose of this analysis was to discover a clinically significant covariate model using the Predictive Enrichment Strategy Analysis (PESA) to identify a patient population most likely to benefit from the treatment. Methods: PESA is a newly introduced concept proposed by the United States Food and Drug Administration and provides robust results. Consensus-based 15 clinical covariates were selected for enrichment analysis and a large cohort with no missing data (889 patients) was analyzed for model development. The models generated were cross-validated 200 times and ROC-AUC for the Cox PH model with the selected variables by the enrichment analysis were computed. Results: ECOGPerformance status (PS = 1) was the strongest covariate and most significant in identifying the enrichment group for SP. In the population with PS = 1, the OS in the SP group was significantly longer than the FP group (Hazard Ratio [HR] = 0.798, 95%CI = (0.66-0.96) p = 0.0166) Other covariates with high potential to be associated with benefit included: diffuse-type histology, presence of peritoneal metastases, and the lack of liver metastases. Various models using different combinations of the covariates were compared using ROC-AUC analysis and found that the model including all four covariates had the best ROC-AUC (0.566, 95%CI = (0.546-0.587)). Conclusions: PESA identified a cross-validated, robust model (PS, diffuse histology, peritoneal mets, and no liver mets). This patient population is associated with improved OS in Advanced Gastric Cancer patients who receive SP. An independent validation of this model will be carried out with data derived from the DIGEST trial. NCT00400179
Efficacy and safety of FOLFIRINOX in advanced cholangiocarcinoma.
Authors: Kim Byung Moon , Armenio Vincent Anthony
Published: September 2018

e15620

Background: Cholangiocarcinomas are invasive carcinomas of uncommon diagnosis and often diagnosed at an advanced and metastatic stage. To this date, there is limited clinical data to support a standard chemotherapy regimen. Single agent systemic chemotherapy such as 5FU or gemcitabine achieves ORR of about 25% while combination regimens including 5-FU, adriamycin, mitomycin or 5-FU and cisplatin has OS of less than a year. Methods: We conducted a single institution retrospective analysis of survival, response and toxicity in patients with advanced or metastatic hepatobiliary carcinoma who had been treated with fluoropyrimidine, irinotecan, and oxaliplatin combination therapy from October 2008 to May 2015. Primary endpoint was PFS measured as the date of first treatment until evidence of clinical progression and/or death. Secondary endpoint was toxicity based on National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE) for non hematologic and hematologic toxicity. Patients were age greater or equal to 18, histologically confirmed, locally advanced unresectable or metastatic adenocarcinoma of the biliary tract (intrahepatic or extrahepatic cholangiocarcinoma), treatment naive or one prior chemotherapy, ECOG performance status of 0-2. Results: Twenty-five patients were eligible for analysis. A total of six patients (24%) received FOLFIRINOX either as first line therapy or as a second line therapy after progression on gemcitabine based regimen. The median PFS was 5 months (151 days). The median OS was about 14.5 months (436 days). Frequency of hematologic toxicity was more common than non-hematologic toxicity. Thrombocytopenia (67%) and nausea (67%) were the most common adverse event. No treatment related death was recorded. All patients discontinued therapy due to disease progression. Conclusions: In this single institution retrospective outcome analysis, FOLFIRINOX was shown to have activity in maintaining disease control as either a first or second line therapy in advanced cholangiocarcinoma. Hematologic and non-hematologic side effects were frequent but manageable without significant treatment delay or discontinuation. There was no treatment related deaths.
Biopsy practices for the diagnosis of hepatocellular carcinoma (HCC).
Authors: Raybould Alison L , Chang YunKyung , Barritt Alfred S , Hayashi Paul H , Sanoff Hanna Kelly
Published: September 2018

e15646

Background: American Association for the Study of Liver Disease (AASLD) guidelines endorse radiographic diagnosis of HCC if key features are present on dynamic contrast-enhanced imaging (arterial hyperenhancement and venous washout) with biopsy for those without these features. As many HCC patients (pts) are diagnosed outside liver transplant centers, we sought to describe the methods of diagnosis of HCC and factors associated with biopsy in routine care in the US. Methods: HCC cases were identified from 2 data sources: SEER-Medicare (M) 2004-2011 and North Carolina Central Cancer Registry (NCCCR) linked to Medicare, Medicaid and private claims 2004-2013. Diagnostic confirmation was identified from registries as pathologic (path) or clinical. Key covariates included age, cancer stage, cause and severity of cirrhosis, and comorbid disease. Specialty consultation, prediagnosis imaging, AFP testing were determined from claims -3 to 0 months from diagnosis. Multivariable logistic regression was used to identify factors associated with path. Results: Path was obtained in a majority of HCC pts: 68% of 10,989 in SEER-M, 72% of 1,809 in NCCCR. In SEER-M, claims for contrasted abdominal CT were more common in those with path than those without (34 vs 30%) but not for MRI (14 vs 14%). Odds of path was higher in pts with contrasted CT (adjusted odds ratio [OR] 1.48, 95% confidence interval [CI] 1.30-1.69) or MRI (OR 1.53, CI 1.31-1.80) vs pts without imaging. In NCCCR, CT (51 vs 41%) and MRI (35 vs 34%) were performed more. Both were associated with increased odds of biopsy vs pts without imaging: contrasted CT scan (OR 1.74, CI 1.22-2.47) or MRI (OR 1.48, CI 1.02-2.13). In neither cohort did ultrasound increase odds of path over no imaging. Pts seen by an oncologist (OR SEER-M 1.66, CI 1.46-1.89) were more likely to have path than pts not seen by oncology. In SEER-M, pts seen at abdominal transplant centers were less likely to have path (OR 0.87, CI 0.77-0.98). Conclusions: Most pts diagnosed with HCC had path confirmation of cancer despite internationally accepted guidelines supporting radiographic diagnosis. The use of biopsy was greater among those with cross-sectional imaging, suggesting this high biopsy rate cannot solely be explained by nondiagnostic imaging.
Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict efficacy of axitinib for treatment of advanced hepatocellular carcinoma (HCC).
Authors: Huang Po-Hsiang , Chen Bang-Bin , Lin Zhong-Zhe , Shen Ying-Chun , Chao Yee , Shao Yu Yun , Cheng Ann-Lii , Hsu Chiun
Published: September 2018

e15656

Background: Axitinib, a potent inhibitor of vascular endothelial growth factor receptor, has moderate antitumor efficacy for advanced HCC. Vascular response (VR) measured by DCE-MRI has been demonstrated to correlate with efficacy of systemic therapy for advanced HCC. Methods: Patients enrolled into a phase 2 trial of axitinib as second-line therapy for advanced HCC (NCT01273662) with liver tumors evaluable by DCE-MRI were included. Patients must have documented progression on or intolerance to sorafenib and Child-Pugh class A liver function. The primary endpoint was disease stabilization, defined as complete or partial response per RECIST1.1 or stable disease lasting for 8 weeks without progression of tumor-related symptoms. The quantitative parameter Ktrans and semi-quantitative parameter peak, measured by DCE-MRI at baseline and after 2 weeks of axitinib treatment, were used to evaluate VR, defined by a greater than 40% decrease of Ktrans or peak. Results: From April 2011 to March 2016, 40 patients were enrolled at National Taiwan University Hospital and 5 at Taipei Veterans General Hospital, all had documented progression after sorafenib treatment. Disease stabilization rate was 62.2% (95% CI 48.0-76.4). Median progression-free survival (PFS) and overall survival (OS) were 2.2 months (95% CI 0.3-4.1) and 10.1 months (95% CI 3.6-16.5) respectively. 33 patients were evaluable for VR. VR evaluated by peak was significantly associated with better PFS (5.5 vs. 1.8 months, HR 0.41, 95% CI 0.16-1.02, p = 0.04) and OS (13.0 vs. 5.8 months, HR 0.28, 95% CI 0.09-0.85, p = 0.02). Treatment-related adverse events were compatible with previous reports of axitinib. Conclusions: VR measured by DCE-MRI may help identify HCC patients most likely to benefit from axitinib treatment. Clinical trial information: NCT01273662. [Table: see text]
Final phase Ib data for the oral c-Met inhibitor tepotinib in patients with previously treated advanced hepatocellular carcinoma.
Authors: Faivre Sandrine J. , Blanc Jean-Frédéric , Merle Philippe , Fasolo Angelica , Iacobellis Angelo , Decaens Thomas , Villa Erica , Trojan Jorg , Grando Véronique , Ellers-Lenz Barbara , Zhao Charles , Raymond Eric
Published: September 2018

e15676

Background: The prognosis for patients (pts) with advanced hepatocellular carcinoma (HCC) after failure of sorafenib is poor, with few systemic therapy options. c-Met is a receptor tyrosine kinase implicated in the progression of HCC. Tepotinib, a highly selective c-Met inhibitor, has shown activity first-line in patients with c-Met+ HCC. We report final results of a phase Ib study of tepotinib in pts with advanced HCC after failure of first-line sorafenib. Methods: Eligible pts were ≥18 years with advanced HCC, Child-Pugh Class A, ECOG PS 0-1, and progression after ≥4 weeks of sorafenib. Tepotinib doses of 300 and 500 mg/day on a 21-day cycle were explored to establish the recommended phase II dose (RP2D) of tepotinib. Secondary objectives included antitumor activity by RECIST v1.1, biochemical response, and safety. Results: Seventeen pts were enrolled: 4 pts received tepotinib 300 mg/day and 13 pts 500 mg/day, confirmed as the RP2D. Fourteen pts experienced treatment-related adverse events (TRAEs), the most frequent being peripheral edema (n = 5, 2 grade 3), lipase increase (2, 1 grade 3), acute kidney injury (2, 1 grade 3), renal impairment (2, 1 grade 3), fatigue (2), nausea (2), asthenia (2). One pt with peripheral edema permanently discontinued treatment. No grade ≥4 TRAEs and no dose-limiting toxicities (DLTs) were reported. The best overall response was partial response (PR) in 2 pts and stable disease (SD) in 4 pts. The duration of the PRs was 57 and 91 weeks. In the first of these pts, tumor size decreased by 55% and serum alfa-fetoprotein (AFP) levels had decreased from 15,923 μg/L at baseline to < 3,000 μg/L by day 15 of cycle 2 and remained at this level until progression. In the second pt, tumor size decreased by > 60% from baseline. No consistent change in AFP was seen in pts with SD. Median overall survival was 7.2 months (range 0.7–22.9 months). Conclusions: The RP2D of tepotinib as second-line therapy for pts with advanced HCC who progress after sorafenib treatment is 500 mg/day. Tepotinib was well tolerated at this dose and showed signs of activity. The ongoing phase II part of this trial is investigating the efficacy and safety of tepotinib 500 mg/day in pts with c-Met+ HCC. Clinical trial information: NCT02115373.
A multicenter phase II study of donafenib in patients with advanced hepatocellular carcinoma.
Authors: Bi Feng , Qiu Meng , Chai Xiaoli , Niu Junqi , Ding Yanhua , Bai Yuxian , Wu Lihua , Shentu Jianzhong , Hao Ping , Chen Jinfei , Li Qiu
Published: September 2018

e15682

Background: In an early dose-escalation study, Donafenib, a new oral multikinase inhibitor, showed antitumor activity and favorable tolerability in treatment of different type solid tumors including HCC at both 0.2g bid and 0.3g bid dose levels. This prospective study aimed to evaluate the safety and efficacy of Donafenib in the patients with advanced HCC. Methods: In this phase 2 study, patients with unresectable HCC, who had Child-Pugh class A liver function and received no prior systemic therapy were enrolled across 10 sites in China. All patients received oral Donafenib 0.2g bid or 0.3g bid for several 4-week cycles, based on 1:1 randomization ratio. The radiology assessment was done every 8 weeks. The primary end points were safety and tolerability; secondary endpoints were time to progression assessed by an independent radiology committ, ORR , DCR, and PK. Results: Between June 17, 2014, and May 4, 2015, total 106 patients were enrolled and included in the safety analyses. Of them, 52 received donafenib 0.2g bid and 54 received 0.3g bid. The most common adverse events that led to dose discontinuation or reductions were hand-foot skin reaction in 10 (9.4%) patients (2 vs 8), liver dysfunction in 4 (3.8%) patients (1 vs 3), and leukopenia in 2 (1.9%) patients (1 vs 1). Other reported AEs caused dose reductions were hypertension, thrombocytopenia, throat ache, and cough. The median duration maintained for the initial dose was 90 and 72 days, respectively. The full analysis set for TTP includes104 patients (51and 53, respectively) and the per-protocol analysis set for ORR and DCR includes 84 patients (40 and 44, respectively). Median TTP was 111 days in 0.2g group compared with 110 days in 0.3g group (HR 0.99, 95% CI [0.62, 1.60]). At the Week 16, there were no complete responses in both groups, but partial response was confirmed in 4 (4.8%) patients (2 vs 2); and stable disease was in 35 (41.7%) patients (17 vs 18). Conclusions: Donafenib 0.2g bid and 0.3g bid were well tolerated. Significant adverse events were reported more frequently in 0.3g group. Both regimens showed similar treatment responses for patients with HCC, while 0.2g bid seems to be an appropriate first line therapeutic option for the treatment of HCC. Clinical trial information: NCT02229071.
Prognostic factor for third-line chemotherapy in patients with advanced gastric cancer.
Authors: Choi Jonggwon
Published: September 2018

e15702

Background: To evaluate prognostic factors for patients with advanced gastric cancer treated by Third-line chemotherapy, and to identify the characteristics of long-term survivors. Methods: Eighty seven advanced gastric adenocarcinoma patients, who received third-line chemotherapy, were enrolled in this retrospective study from January 2010 until December 2014. Univariate and multivariate analyses were created using log-rank tests and Cox’s proportional hazard model, respectively. Results: In univariate and multivariate analyses, poor prognostic factor were investigated and four independent factors were found to be associated with poor overall survival: time-to progression under first-line chemotherapy≤6 months (HR, 1.64; 95% CI, 1.18–2.25; P ≤ 0.01), CA 19-9 level > 50 ng/ml (HR, 1.78; 95% CI, 1.32–2.67; P ≤0.007), the presence of ascites (HR, 1.67; 95% CI 1.295– 2.37, P ≤0.001), the presence of greater than or equal to three metastatic sites of disease (HR, 1.45; 95% CI 1.19– 2.19, P ≤0.004). 87 patients were classified as low-risk group( no risk factor), intermediate-risk group (one to two risk factors), high- risk group (three to four risk factor), and median survival times for each groups were 14.3 months, 12.1 months, and 7.4 months, respectively (P ≤0.01). Conclusions: This model will help in selecting the patients with advanced gastric cancer who could benefit from proceeding with third-line chemotherapy.
Ex-vivo tumor resection and auto-transplantation: A single-institutional long-term experience.
Authors: Kato Tomoaki , Liou Peter , Schwartz Gary K. , Emond Jean
Published: September 2018

e15705

Background: Conventionally unresectable tumors involving mesenteric vasculature or critical areas of the liver may be amenable for resection using novel techniques developed from organ transplantation. The concept of ex-vivo resection allows tumor removal and vascular reconstruction in cold perfusion while ensuring visceral preservation, followed by autotransplantation of the remaining organs. Methods: A retrospective chart review of 34 patients at a single-center who underwent ex-vivo tumor resection and auto-transplantation between the years of 2008 and 2016. Results: Indications for ex-vivo resection were tumors involving the hepatic vasculature (hepatic tumors involving vasculature n = 13, pancreatic tumors involving hepatic vasculature n = 7), mesenteric vasculature (n = 9), or both (n = 4) and renal vasculature (n = 1). Tumors included cholangiocarcinoma (n = 6), liposarcoma (n = 6), leiomyosarcoma (n = 4), pancreatic adenocarcinoma (n = 3), and others. 27 out of 34 patients underwent attempted treatments including surgery or chemoradiation prior to ex-vivo resection, with a mean of 2.5 treatments. Types of procedures included: hepatic autotransplantion (n = 11). Whipple procedure with hepatic autotransplantion (n = 8), intestinal autotransplantion (n = 9), and multivisceral autotransplantion (n = 4). The median age was 48 (range 5 to 71). Thirty-day and ninety-day mortality were 8.8% and 11.8%, respectively. Three patients died within 30 days with hepatic artery anastomotic rupture (n = 1) and sepsis (n = 2). Thirty-one patients (91.2%) were discharged alive from the hospital at a median of 20 days. One-year and three-year overall survival rates were estimated at 64.7% and 42.4%, respectively. At the time of submission, 14 patients are alive and 13 are disease free with a median follow-up of 5.8 years. Conclusions: Ex-vivo tumor resection is a highly complex procedure associated with significant morbidity and mortality. Nevertheless, for carefully selected patients with conventionally unresectable tumors, ex-vivo surgery may be a viable option offering reasonable long-term outcomes.
Retrospective review of FOLFIRINOX in local advanced pancreatic cancer: Single institution experience.
Authors: Manne Ashish , Reddy Sushanth , Heslin Martin , Jacob Rojymon , Vickers Selwyn M. , Contreras Carlo M. , Kasi Anup , Christein John , Li Peng , Posey James , Paluri Ravi Kumar
Published: September 2018

e15714

Background: Although combination of fluorouracil, irinotecan, Leucovorin and oxaliplatin [FOLFIRINOX] significantly increases survival in metastatic pancreatic cancer (MPC) compared to gemcitabine based on ACCORD trial, the efficacy and toxicities may be different in non-metastatic setting. We reviewed our institution’s experience with FOLFIRINOX in locally advanced pancreatic cancer (LAPC). Methods: We performed a retrospective review of clinical outcomes in patients diagnosed with LAPC and receiving between June 2010 and July 2015, with at least one year of follow up from diagnosis, at University of Alabama at Birmingham. Results: Total of 41 patients with ECOG performance scale of 0 or 1, who underwent neoadjuvant chemotherapy with FOLFIRINOX were assessed for clinical and pathological characteristics. Median age was 61 years (range 38-81) with 23 (56.1%) males, 28 (68.3%) Caucasians and 16 (39.0%) underwent surgery (whipple operation) post-neoadjuvant. Median OS (time of diagnosis to last follow up/death) is 83.5 months for whole cohort, survival rates are 94.9% at 1 year, 58.4% at 2 year, and 33.3% at 5 year.Median OS for those who underwent surgical resection following the chemotherapy is 38.6 months; 100% at one year, 85.1% at 2 year, 55.3% at 5 year; while median OS for those who did not undergo surgery is 21.8 months; 91.7% at one year, 41.5% at 2 year, 20.7% at 5 years. Among those who underwent surgery, the median recurrence free survival (time from surgery to relapse/progression) is 19.9 months with liver being common recurrence site (81%). There was no post-operative mortality in 30 days. Grade 3-4 toxicity occurred in 46% ( vomiting (12%), fatigue (28%) and neutropenia (54%), febrile neutropenia (9%)). There is a significant difference between surgery and non-surgery groups (p = 0.012) for improved OS by log-rank test. Conclusions: Neoadjuvant FOLFIRINOX treatment associated with high response rates leading to surgical resection in our cohort. Patients who underwent neoadjuvant chemotherapy followed by resection for LAPC have statistically significant improved OS compared to those who did not.
Brain metastases (BM) in pancreatic ductal adenocarcinoma (PDAC): Clinical and molecular characteristics.
Authors: Jordan Emmet , Kaley Thomas Joseph , Capanu Marinela , Estrella Hayley , Leach Steven D , Basturk Olca , Klimstra David S. , Allen Peter J. , Berger Michael F. , Yu Kenneth H. , Lowery Maeve Aine , O'Reilly Eileen Mary
Published: September 2018

e15728

Background: BM from PDAC represents a rare clinical entity (<0.6%) of PDAC cases for which the clinical and molecular features are not well described. We reviewed detailed clinical characteristics and molecular profiling performed in a cohort of PDAC pts with BM evaluated at MSKCC. Methods: Patients (pts) with BM from PDAC diagnosed from 01/1990-08/2016 were identified from a prospectively maintained database, following IRB approval. Clinicopathological data including time to BM development, overall survival (OS) from PDAC diagnosis (dx) and OS from BM dx was recorded. Molecular profiling was performed by MSK-IMPACT testing (>340 key cancer genes) or via Seqeunom testing (8 gene panel). Results: We identified n= 24 pts with BM from PDAC. Twenty-three/24 pts had imaging for symptoms. Mean no. of systemic regimens was 3 (range 0-7). Three/24 (13%) had BM at initial dx. Median time from PDAC dx to BM development was 17 months (mths) (range 0-79). Median survival from BM was 50 days (range 7-975). BM treatment included; surgery; n=4, RT; n=13 or supportive care; n=7. Two pts had survival of 21 & 31 months post BM, both had resection. Median OS from PDAC dx was 18 mths (0-82). 10 pts had consent/pathology for molecular testing (MSK-IMPACT n=7, Sequenom n=3). Results are available for 6 pts, 3 by IMPACT. 6/6 pts had KRAS mutations (MUT); G12D (4), G12V (1), Q61K (1). 0/6 pts had ERBB2 AMP or MUT. One tumor arising from an IPMN had concurrent GNAS and KRAS MUT. By MSK-IMPACT; 2/3 pts had MYC AMP, 2/3 TP53 MUT, 1/3 ARID1A loss, 1/3 CDKN2A loss. 5/24 pts had germline testing, 3 had BRCA MUT; BRCA1 (2), BRCA2 (1). Conclusions: The presence of BM portends a poor prognosis. In general pts who develop BM are younger at initial PDAC dx and may have a better OS from dx [median OS 18 mths (all pts); OS de novo stage IV pts; 17 mths]. Somatic profiling identified KRAS MUT in all resulted pts with alterations in TP53 and MYC also detected. Although speculative, germline BRCA MUT occurred in 13% (60% of pts tested). See table. [Table: see text]
Hypoxia induced HIF1a-mediated O-GalNAc glycosylation of cytosolic O-GlcNAcylated proteins to regulate signaling pathways in pancreatic cancer.
Authors: Wolters-Eisfeld Gerrit , Mercanoglu Baris , Strohmaier Alina , Guengoer Cenap , Izbicki Jakob R. , Bockhorn Maximilian
Published: September 2018

e15739

Background: Hypoxia induced reprogramming of cell energy metabolism and changes in glycosylation are hallmarks of cancer promoting the induction of an invasive and treatment-resistant phenotype, triggering metastases at an early stage of tumor development. We examined the impact of hypoxia on O-GalNAc glycosylation in human HEK293, PDAC cell lines and clinical specimens. Methods: We profiled the expression of 88 glycosylation related genes by qPCR in HEK293 cells subjected to hypoxia either induced by 1% O2 or 200 mm CoCl2 identifying key O-GalNAc glycosyltransferases downregulated. Functional assays and glycoprotein analysis displayed a pronounced rate of O-GalNAc modified cytosolic proteins derived from hypoxia treated cells and PDAC specimens. Glycosidase assays could validate specificity of detection method used. Aberrant glycotype could be induced by HIF pathway activator ML 228 and inhibited using Echinomycin. PTK and STK analysis of cell lysates displayed correlation between phosphorylation and O-glycosylation in hypoxic samples. Results: Mechanistically we could show, that hypoxia induced decreased levels of C1GALT1C1 results in reduced T-Synthase activity with subsequent expression of truncated O-glycans (Tn antigen). Differential O-GalNAc glycosylation is inducible using HIF pathway activator ML228 under normoxia and the effect is reversed using 5 µM Echinomycin under hypoxia underscoring the role of HIF1a regulated transcription. Interestingly, the pattern of Tn antigen modified proteins derived from hypoxic samples differs significantly from engineered COSMC deficient cells, displaying O-GalNAc moieties in addition to O-GlcNAc in cytosolic protein fractions. Conclusions: Our findings point to a novel crosstalk of O-GalNAc and O-GlcNAcylation under hypoxia extending the knowledge base of differential O-GalNAc glycosylation in pancreatic cancer.
Phase II study of regorafenib (Reg) in patients with previously treated advanced pancreatic cancer (APC).
Authors: Salmon John Stuart , Hwang Jimmy J. , Robinson Myra M. , Symanowski James Thomas , Dillon Lloye M , Das Roy Lopamudra , Beldner Matthew A. , Preston Kelry , Buige Sharon , Nazemzadeh Reza , Mukherjee Pinku , Farhangfar Farhang , Kim Edward S.
Published: September 2018

e15751

Background: APC that has progressed after treatment with gemcitabine has a dismal prognosis and novel treatment approaches are needed. Reg is a potent oral inhibitor of VEGFR 1-3, PDGFR, TIE-2, FGFR-1, KIT, and the RAF kinases, and has activity in pancreatic xenograft models. We tested the activity of Reg in patients (pts) with refractory APC. Methods: This single arm, single center phase II study evaluated Reg (120mg/d, for 21 days, followed by 7-day break, with escalation to 160mg after the 1st cycle if tolerated) in pts with metastatic pancreatic cancer whose disease had progressed after at least one prior line of therapy and treatment with gemcitabine. Pts underwent radiographic evaluation every 2 cycles. The primary endpoint was 16-wk PFS. Kaplan Meier techniques were used to estimate PFS and OS. Serum tumor MUC1 antigen (tMUC1) concentrations were measured at baseline, end of cycle 1, and off-treatment using the TAB 004 antibody (Agkura Personal Score blood test, OncoTAb, Inc). Relative change of tMUC1 from baseline to end of cycle 1 was compared between those with and without 16-wk disease control. Results: 20 pts were enrolled into the study. Median age = 65 (47-79), and 80% (16/20) had 2 or more prior lines of therapy for advanced disease. Landmark 16 wk PFS = 10% (2/20), crossing a predefined futility boundary to demonstrate 20% improvement over historical controls with BSC. ORR was 5% (1/20), and DCR at 8 wks was 20% (4/20). Median PFS was 6.1 wks (95% CI: 2.9 – 7.1), and median OS was 9.4 wks (95% CI: 8.1 – 17.0). 10% of pts (2/20) had protocol defined Reg dose escalation to 160mg, and 30% (6/20) had dose reduction to 80mg. The most frequent grade 3-4 adverse events included hyponatremia (35%), fatigue (20%), and hypoalbuminemia (20%). Baseline tMUC1 varied substantially, mean 69.6ug/mL, median 51.3ug/mL (10.8 – 310.5). Serum tMUC1 decreased by a mean of 20.8% in the pts with disease control at 16 wks (n = 2), but increased by 65% (mean) in pts with disease progression or death within 16 wks (n = 13, p = 0.048). Conclusions: Reg has minimal activity as a single agent in pts with heavily treated APC. Serum tMUC1 levels measured by TAB 004 antibody may be a novel tumor marker in this disease. Different treatment approaches are needed. Clinical trial information: NCT02080260.