bluuebunny/crossref_metadata_2025 huggingface dataset:
Overall survival (OS) in patients (pts) with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP): A real-world retrospective study.
Authors: Hennenfent Kristin L. , Girvan Allicia C. , Chaudhry Aafia , Abada Paolo , Sheffield Kristin , Herren Catherine K , Raju Aditya , Farrelly Eileen , Bowman Lee , Landsman-Blumberg Pamela
Published: September 2018

e15658

Background: HCC is associated with a worse prognosis in pts with high baseline AFP levels. The relationship between elevated baseline AFP and survival benefit with systemic HCC treatments in the real world setting is poorly characterized. Methods: A retrospective analysis of clinical outcomes among newly diagnosed advanced HCC pts treated in US community-based oncology practice settings was conducted. Pts treated with sorafenib or best-supportive care (BSC) between 10/1/2007 and 12/31/2013 were identified in the International Oncology Network electronic medical record (EMR) database and were followed until date of death, date of last visit, or 06/30/2014 (end of study). Baseline demographics, clinical characteristics, and AFP (≤ or > 400 ng/mL), plus date of death were extracted from the EMR and physician progress notes. Treatment differences in OS were evaluated and stratified by AFP, AST/ALT, and bilirubin using unadjusted Cox proportional hazards regression models. Results: A total of 370 advanced HCC pts receiving sorafenib (217) or BSC (153) were identified. The mean age was 65.6 years and 77.0% were male. Cirrhosis (38.4%), hepatitis C (36.8%), and alcoholic liver disease (22.4%) were common hepatic-related comorbidities. 45.1% of pts had elevated AFP ( > 400 ng/mL) at baseline. The sorafenib cohort had significantly longer median OS time than the BSC cohort (29.6 vs 19.7 weeks, p= 0.048). OS for sorafenib vs BSC cohorts with AFP≤400 ng/mL and AFP > 400 ng/mL were 45.1 vs 25.3 weeks ( p= 0.128) and 25.3 vs 13.1 weeks ( p =0.197), respectively. Cox models revealed a consistent effect of sorafenib vs. BSC, regardless of AFP level (AFP ≤400ng/mL: HR = 0.79 (95% CI 0.55-1.13), p= 0.200; AFP > 400 ng/mL: HR = 0.80 (95% CI 0.53-1.52), p= 0.297). Conclusions: This study supports the poor prognosis for advanced HCC pts with baseline AFP levels > 400 ng/mL compared to baseline AFP ≤400 ng/mL. Limitations with retrospective, real-world studies require caution in interpretation, but this analysis suggests an OS benefit with sorafenib treatment compared to BSC. There remains an unmet need for effective therapies for advanced HCC associated with elevated AFP levels.
Mutational profiling of resected intrahepatic cholangiocarcinoma.
Authors: Pak Linda Ma , Goldman Debra , Gonen Mithat , Allen Peter J. , Balachandran Vinod P. , D'Angelica Michael Ian , DeMatteo Ronald P. , Kingham T. Peter , Simpson Amber , Hechtman Jaclyn Frances , Vakiani Efsevia , Sigel Carlie S. , Lowery Maeve Aine , Jarnagin William R.
Published: September 2018

e15675

Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive neoplasm with increasing incidence and mortality. Resection is the only potential curative treatment and is associated with 5-year survival up to 44%. The objective of this study was to characterize the mutational landscape of patients with ICC undergoing resection and to identify potential prognostic genetic markers that may be unique to these patients. Methods: Sixty-six resected ICC tumor specimens were assessed for genetic alterations using next-generation sequencing of 410 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). We identified the gene alterations occurring with greatest frequency and grouped mutations by known cancer pathways and families, such as RAS-MAPK pathway, mTOR pathway, Notch signaling pathway, chromatin-remodeling gene family, and DNA repair gene family. Overall survival (OS) was calculated from time of resection until death and disease-free survival (DFS) was calculated from resection until recurrence or death. Kaplan Meier 5-year estimates and the log-rank test were used to evaluate the associations with OS and DFS, adjusted for multiple comparisons with false discovery rate (FDR) correction. Results: The median age of all patients was 65 years (range 29-87 years). Majority of tumors were T1 (24/66, 36%) or T2 (35/66, 53%), and of moderate differentiation (46/66, 70%). Lymphovascular invasion, perineural invasion, and periductal infiltration were present in 34 (52%), 20 (30%), and 8 (12%) patients, respectively. The median number of genetic alterations per tumor was 3 (range 0-26). The most common genetic alterations were PBRM1 (16/66, 24%), IDH1 (15/66, 23%), ARID1A (14/66, 21%) and TP53 (8/66, 12%). FGFR2 fusion mutations (5/66, 8%) were relatively rare. The median OS for all patients was 53.4 months (95%CI: 43.0-79.3 months) and median DFS was 17.4 months (95%CI: 10.4-32.6 months). None of the gene alterations or pathways were associated with OS (p = 0.29-0.84) or DFS (p = 0.23-0.65). Conclusions: In this cohort of resected ICC patients, genetic alterations or alterations within gene families, by themselves, did not stratify risk of disease recurrence or death.
High number of PD-1 positive tumoral lymphocytes as a potent biomarker for adopting cytokine-induced killer cells in hepatocellular carcinoma.
Authors: Chang Boyang , Wu Peihong
Published: September 2018

e15680

Background: Adjuvant cytokine-induced killer cell (CIK) treatment has shown potential in reducing recurrence rate and prolong survival of patients with hepatocellular carcinoma (HCC). We aim to evaluate the PD-1/PD-L1 expression in tumor cells and tumor infiltrative lymphocytes in HCC patients and their correlation with survival benefit from cytokine-induced killer cell therapy. Methods: Between 2004 and 2011, 290 HCC patients received curative section were retrospectively enrolled by one-to-one propensity score matching, including 145 cases received adjuvant CIK cell transfusion after surgery (Surgery-CIK group), and 145 cases underwent surgery only (Surgery only group). Immunohistochemistry (IHC) was used to measure the PD-1 and PD-L1 expression in formalin fixed paraffin embedded tissue of all subjects; IHC of CD4, CD8 and Foxp3 were also conducted in the surgery-CIK group to explore their correlation with PD1/PD-L1 expression and survival of HCC patients. Results: The surgery-CIK group had significantly improved overall survival (OS; HR 0.55, 95% CI 0.33-0.92) and disease-free survival (DFS; HR 0.59, 95% CI 0.42-0.83) as compared to the surgery-only group. In the surgery-CIK group, univariate analysis showed both high PD-L1 expression and a high number of PD-1+ TILs were significantly associated with improved OS, while only the high number of PD-1+ TILs was associated with improved DFS. Multivariate analyses showed a high number of PD-1+ TILs was the only independent factor predicting favorable OS (HR 0.19, 95% CI 0.08-0.45) and DFS (HR 0.40, 95% CI 0.24-0.66) in the surgery-CIK group. By contrast, in the surgery-only group, no significant associations between PD-1/PD-L1 expression and survival of patients were identified. Conclusions: A high number of PD-1+ TILs can serve as a potent biomarker to adopt CIK cell therapy in HCC patients after curative resection.
Prognostic factors influencing survival in small bowel neuroendocrine tumors with liver metastasis.
Authors: Manguso Nicholas , Harit Attiya , Nissen Nicholas N. , Mirocha James , Hendifar Andrew Eugene , Amersi Farin F.
Published: September 2018

e15688

Background: Management of liver metastasis in patients with small bowel neuroendocrine tumors (SBNET) remains unclear. Complete surgical resection improves long term survival however factors that influence overall prognosis are not clear. Methods: Database review identified 301 patients diagnosed with SBNET from 1990 to 2013. Only patients with known liver metastasis who underwent resection of the primary tumor were included. Outcomes among patients who underwent complete surgical resection, incomplete debulking of liver metastasis, and resection of the primary tumor alone were compared. The Kaplan-Meier method was used for survival estimates and Cox regression was used to identify predictors of death. Results: 111 patients met study criteria. Median age was 59 years (range 16-80); 49% were male. The terminal ileum (47/111, 42%) was the most common primary tumor location. The median number of liver lesions was 8.5 (range 1-31) and median lesions resected was 1 (range 0-31). In addition to resection of the primary tumor, 36 patients (32%) had no liver resection (NR), 41 (36.9%) had complete resection of liver disease (R0) and 34 (30%) had incomplete resection of liver metastasis (R1). 58 patients (36%) had one or more wedge resections, 12 (10.8%) underwent segmentectomy and 5 (4.5%) had a lobectomy. 33 (29.7%) patients underwent post-operative chemoembolization, 25 (22.5%) had radioembolization and 23 (20.7%) had radiofrequency ablation. The R1 group differed from the R0 group in median size of primary tumor (2.5 cm R1 vs 1.6 cm R0, p = 0.05) and median number of positive lymph nodes (5.0 R1 vs 3.0 R0, p = 0.05). The 5-year OS was 80.9%, 81.1% and 100% for NR, R1 and R0 groups respectively (p = 0.01). 10-year OS did not differ between groups (72.8% NR vs 81.1% R1vs 82.5% NR, p = 0.31). Cox regression showed post-operative administration of chemotherapy (HR = 3.68, p < 0.01) and higher tumor grade (HR = 18.4, p = 0.02) increased risk of death. Conclusions: In patients with SBNET with liver metastasis, higher tumor grade and post-operative chemotherapy increased risk of death. However, resection of the primary tumor along with liver metastasis improves the 5-year OS with complete cytoreduction providing the most benefit.
Surgery in combination with peptide receptor radionuclide therapy is effective in metastatic neuroendocrine tumors and is definable by blood gene transcript analysis.
Authors: Frilling Andreja , Kaemmerer Daniel , Kidd Mark S. , Clift Ashley K , Stebbing Justin , Baum Richard P. , Castellano Leandro , Wasan Harpreet Singh , Modlin Irvin Mark
Published: September 2018

e15697

Background: Neuroendocrine tumours (NET) of the pancreas (PNET) or small bowel (SBNET) frequently present with metastases at initial diagnosis, undermining the efficacy of surgical treatment. Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues, 90Y-DOTATOC and 177Lu-DOTATATE, has been shown to achieve prolonged progression-free survival (PFS) in a substantial number of non-surgical patients with advanced NET. Our aim was to prospectively determine the efficacy of a combination of radical loco-regional surgery and PRRT in patients with metastasised NET. Methods: A set of inclusion criteria was defined (e.g. G1/G2 NET, initial tumour diagnosis, treatment naïve patient, stage IV NET, positivity on 68Ga DOTA- PET/CT, eligibility for surgery and PRRT). Patients underwent PRRT within 3 months following surgery. Follow-up included biochemistry and imaging. In a sub-cohort, blood-based neuroendocrine gene transcript analysis of 51 genes (NETest) was used to define the effectiveness of treatment. Outcome measures included 5-year overall survival (OS) and PFS from initial diagnosis. Results: Twenty-five patients (5 PNET, 20 SBNET) met eligibility criteria and were included. There were 13 men (52%) and mean age was 57.1 years. All patients with SB NET underwent right hemicolectomy, terminal ileal resection and mesenteric lympadenectomy. In all PNET patients only limited pancreatic resection was required. The median number of PRRT cycles was 4 (range 2-6). Post-treatment mortality was 0%. Surgical morbidity was 12% (all Clavien-Dindo grade 1). Transient grade 1 toxicity occurred post-PRRT in 40%. NETest scores were increased in 8 patients (100%) pre-operatively and decreased in all following treatment. NETest decreases correlated with diminished tumour volume (R2=0.37, p=0.02). Median follow-up was 48 months (range 12-72months). Five-year OS was 90% and 5-year PFS was 84.3%. Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NET. The NETest accurately measures the effectiveness of treatment.
Broad safety impact of high-dose ascorbic acid and induction chemotherapy for high-risk pancreatic cancer.
Authors: Bruckner Howard , Hirschfeld Azriel , Gurell Daniel , Lee King
Published: September 2018

e15711

Background: High dose ascorbic acid inhibits many tumors in vitro. It may reduce chemotherapy's adverse hematologic events and improve quality of life. Moderate dose gemcitabine, fluorouracil, leucovorin, irinotecan, oxaliplatin (GFLIP) is an effective regimen for patients with many cancers (Anticancer Research 17). High dose ascorbic acid may reverse half the preexisting and largely eliminate the predicted cumulative toxicity of GFLIP (ASCO 15). Methods: High dose ascorbic acid AA 75-100 grams IV was given 1-2 times per week with GFLIP every 2 weeks until progression with serial wkly and Q2wk blood tests and 3 month imaging. Eligibility: Unresectable, III, recurrent and metastatic, mod and high grade typical pancreatic ca; ECOG 0-2; +/- prior chemo; adults of any age with consent. Results: A prescheduled 2 yr analysis found 26 patients; 16 ≥ 65, (9 ≥ 70 years of age). 25 stage IV; Nine had failed at least one prior standard chemo (35%), 3 were PS 2, 9 had severe weight loss. Safety: Five had uncomplicated 3 (19%) and none had 4 neutropenia or neutropenic infection, one (4%) had a 3 anemia and thrombocytopenia without bleeding. Prophylactic growth factors were not used and limited to 1-2 as needed low doses used infrequently. There was no limiting diarrhea, enteritis, stomatitis, weight loss or coagulopathy due to GFLIP. GFLIP is on track to reproduce/retain prior response and survival benefit (ASCO 08). Conclusions: Ascorbic Acid-GFLIP can be exceptionally safe and well tolerated. It may avoid standard 20-40% rates of severe toxicities. It can be, otherwise unavailable, safe reduced cost, treatment for many elderly and prior resistant tumor patients. Given the broad multi-disease role of the GFLIP drugs, and available personalized medicine tests (Cancer Letters), further development is very attractive and feasible. Potential outcome can spare all, and especially high risk pancreatic ca patients, 20k severe toxicities every year toxicities as much as $100 million cost and make some ineligibility criteria unnecessary. Development of safe AA regimens may benefit quality of life and improve survival for many with a broad spectrum of cancers that otherwise go untreated. Clinical trial information: NCT01905150.
Overall survival (OS) achieved with gemcitabine (G) or gemcitabine-abraxane (GA) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) who received first line modified FOLFIRINOX (m-FFX) palliative chemotherapy.
Authors: Aung Kyaw Lwin , Creighton Sean , Fraser Adriana , Dodd Anna , Moura Shari , Albaba Hamzeh , O'Kane Grainne M. , Hedley David W. , Dhani Neesha C. , Knox Jennifer J.
Published: September 2018

e15715

Background: The standard second line treatment in advanced PDAC pts after m-FFX first line palliative chemotherapy is not clearly defined. G is the standard 2nd line treatment in Canada and GA can only be prescribed for pts with a private fund or private drug plan that covers the cost of Abraxane. More data is needed to establish OS achieved with 2ndline G or GA. Methods: The OS of PDAC pts treated with G or GA after m-FFX palliative chemotherapy given between 01-Dec-2011 and 30-Nov-2015 at the Princess Margaret Cancer Centre (PM), Toronto, Canada were retrospectively reviewed. OS was calculated from date of commencement of 2ndline treatment until death or date of last oncology follow up. Results: Over the 4-year study period, 132 pts were treated with 1st line palliative m-FFX at PM. Of them, at disease progression, 78 (59%) pts received a 2ndline therapy (50 G, 17 GA, 9 clinical trials, and 2 other). The results including demographics, treatment details and survival outcomes of patients treated with G and GA are summarized in the Table 1. Conclusions: Our results do not support single agent G after m-FFX 1st line palliative chemotherapy as median duration of treatment was too short and OS observed with G in this setting is very much limited. The median duration of treatment on GA and OS achieved with GA seem superior but sample size was too small to make a conclusion. [Table: see text]
Effect of KRAS and P-STAT3 inhibition by SBT-100 on gemcitabine and pancreatic cancer growth in vivo.
Authors: Singh Sunanda , Murillo Genoveva , Singh Avani , Singh Samara , Parihar Meenakshi S , Singh Anjali H , Mehta Rajendra , Parihar Ashutosh S
Published: September 2018

e15727

Background: Over 90% of pancreatic cancers have KRAS mutations and hyper-expression of P-STAT3 oncoproteins, which if specifically targeted may help treatment of pancreatic cancers. Singh Biotechnology’s proprietary technology engineered SBT-100, a single domain antibody that is bispecific for KRAS & STAT3, which can cross the cell membranes and bind to these intracellular oncoproteins. Combining this targeted therapy with an established chemotherapy, such as gemcitabine, may improve patient’s response to treatment. Methods: Human pancreatic cancer cells (PANC-1 and BX-PC3) were used. Biacore assay demonstrates SBT-100 binding to KRAS, KRAS (G12D), and STAT3. Immunoprecipitation (IP) and western blot analysis confirmed binding to STAT3 by SBT-100. Pancreatic cancer cells were treated at varying doses of SBT-100 ranging from 0µg/ml to 200µg/ml ± gemcitabine, and after 72 hours growth inhibition was determined by a MTT assay. PANC-1 tumors were grown in athymic nude mice, divided into four groups and staged to a range of 100-150mm3 before treatment. Groups were: vehicle only, SBT-100, gemcitabine, and SBT-100 & gemcitabine. Animals received treatments for 14 days, then monitored for 7 days. Results: Biacore study shows SBT-100 binds KRAS with an affinity of 10-9M, KRAS (G12D) with 10-8M, and STAT3 with 10-8M. IP and western blot analysis demonstrates that SBT-100 binds P-STAT3. MTT assay demonstrates SBT-100 inhibits the growth of PANC-1 and BX-PC3 (p < 0.001). In PANC1 cells a combination of SBT-100 & gemcitabine demonstrates synergism in inhibiting growth of PANC-1, even at 1/8th the gemcitabine IC50 concentration. PANC-1 xenograft study demonstrates that combination therapy of SBT-100 & gemcitabine is superior to either SBT-100 or gemcitabine alone. Compared to the vehicle group, SBT-100 & gemcitabine is far superior (p < 0.001) and gives statistically significant suppression of pancreatic cancer growth in vivo. Conclusions: Targeted therapy for KRAS and P-STAT3 expressing tumors with SBT-100 & gemcitabine is synergistic for the treatment of pancreatic cancer. This study suggests that synergism maybe achieved with lower doses of gemcitabine, thereby reducing toxicity in patients.
Retrospective multicenter cohort of nab-paclitaxel plus gemcitabine (NG) after FOLFIRINOX failure in advanced pancreatic cancer (APC): Effectiveness, tolerability, and response markers.
Authors: Vendrell Ines , Ferreira Arlindo Rebelo , Pulido Catarina , Parmanande Anuraj , Ferreira Da Silva Filipa , Barreira João Vasco , Godinho João , Pinto João Moreira , Gago Joaquim , Couto Nuno , Castro Ana , Carvalho Carlos , Passos-Coelho José , Semedo Monica , Pinto Conceição , Costa Luis
Published: September 2018

e15743

Background: NG is a standard 1st line treatment for APC. Although recommended in 2nd line after FOLFIRINOX, there is little evidence of its efficacy, tolerability and of markers of efficacy. Methods: We performed a multicenter retrospective cohort study, including patients (pts) with APC from 5 centers in Portugal treated with 2nd line NG after 1st line FOLFIRINOX from 01/2013-12/2016. We collected demographic, clinicopathological characteristics and treatment data. We used descriptive statistics, Kaplan-Meier methods and Cox proportional hazards analysis. Results: 30 pts were included; median age was 64 years (range 45–78); the majority had stage IV (90%) disease, an ECOG Performance Status of 0 (76.7%) and had received a median of 8.5 cycles of FOLFIRINOX (range 1–18). A median of 6 cycles of NG were administered (range 1–13). Median progression free survival (PFS) and overall survival (OS) were 6.4 months (CI 95% 3.0-8.5) and 11.4 months (CI 95% 8.4–16.5), respectively, and did not differ by age < 65 or ≥65 (p = 0.87; p = 0.57 respectively). The most frequent toxicity was fatigue (66.6%, any grade). Grade 3-4 events occurred in 40% of pts – thrombocytopenia in 16.7%, neutropenia in 10.0%; anemia, sensorial neuropathy, fatigue and diarrhea each occurred in 3.3% of patients. No febrile neutropenia events or toxic deaths occurred. Median CA 19.9 at the beginning of NG was 1254U/mL (IQR: 207–6775); the median decrease of CA19.9 at 3 months was 45U/mL (IQR:-1373– +174). CA 19.9 variation at 3 months did not correlate with PFS (p = 0.53) or OS (p = 0.09) in multivariate analysis (adjusted for age and stage at diagnosis). Neutrophil to Lymphocyte ratio (NLR) was high ( > 3.0) in 37.5% of patients before 1st line treatment and in 27.6% at the beginning of NG. In multivariate analysis NLR before 1st or 2nd chemotherapy lines were not associated with PFS (p = 0.39; p = 0.14 respectively) or OS (p = 0.44; p = 0.12, respectively). Conclusions: In this cohort of pts with APC, NG was an effective and well tolerated 2nd line regimen after FOLFIRINOX failure, even in pts ≥65 years. Neither CA19.9 variation at 3 months nor NLR were markers of NG clinical benefit.
Use of phenotypic profiling to determine sensitivity of gemcitabine with nab-paclitaxel for front-line treatment of pancreatic cancer.
Authors: Ricigliano Mark , Cooper Brandon , Bartlett Andrew , Yu Kenneth H.
Published: September 2018

e15749

Background: Standard of care treatment for pancreatic adenocarcinoma (PDAC) consists of FOLFIRINOX (FFX) or gemcitabine with nab-paclitaxel (G/nab-P) in the front-line setting. The decision to use FFX or G/nab-P is a physician choice as there are no standardized assays to guide treatment selection. Here we report the results of a prospective clinical trial to evaluate a blood-based assay to select patients for G/nab-P in the front line setting. The assay was developed on the premise that if two patients have the same genomic profile, they will have the same response to chemotherapy. Methods: In a prospective study, 37 PDAC patients were pre-selected to receive G/nab-P at Memorial Sloan Kettering as a front-line treatment. Circulating tumor and infiltrating cells (CTICs) were isolated from peripheral blood samples using a cell invasion matrix. RNA was isolated and cDNA synthesized for qPCR gene expression. 83 drug transport genes were used as classifiers to create four treatment templates, one each for G/nab-P, GAX, FFX and FOLFOX. Nearest Template Prediction was used to match the genomic profile of the PDAC patient sample to one of the four a priori defined treatment templates. Results: Front-line PFS was correlated to treatment phenotype with G/nab-P (8.6 mos.), GAX (6.7mos.), FFX (5.6 mos.) and FOLFOX (5.0 mos.). Patients with a positive sensitivity (S+) to G/nab-P demonstrated a median PFS of 7.7 mos. vs. 4.7 mos. compared to those with a negative sensitivity (S-) to G/nab-P (p-value = 0.027). Contingency analysis demonstrated sensitivity (78%), specificity (64%), and likelihood ratio (2.139) with p-value = 0.048. Correlation between G/nab-P sensitivity and PFS was significant as measured by linear regression (R2= 0.90, p-value = 0.013). Conclusions: Phenotype profiling for selecting front-line treatment to G/nab-P is feasible in PDAC. Clinical trial information: NCT01474564.
A study of REOLYSIN in combination with pembrolizumab and chemotherapy in patients (pts) with relapsed metastatic adenocarcinoma of the pancreas (MAP).
Authors: Mahalingam Devalingam , Fountzilas Christos , Moseley Jennifer L. , Noronha Nicole , Cheetham Karol , Dzugalo Adrian , Nuovo Gerard , Gutierrez Andres , Arora Sukeshi Patel
Published: September 2018

e15753

Background: REOLYSIN is an immuno-oncology-reoviral agent that induces an inflamed tumor phenotype secondary to viral infection of cancer cells. In combination with chemotherapy, it achieves 1 & 2 year-survival rates of 46% & 24% in MAP pts, respectively. Tumor analysis from pts showed reovirus protein replication, T-cell infiltration and upregulation of PD-L1. Similarly, the combination of REOLYSIN with anti-PD-1 antibody documented survival benefit in a pre-clinical model. We hypothesized that REOLYSIN in combination with chemo and pembrolizumab in pts with MAP would be clinically efficacious. Methods: A phase 2 study (NCT02620423) enrolled MAP pts who progressed after first line treatment. Pts received REOLYSIN (4.5 x 10 10 TCID 50 IV, D1 & D2), plus pembrolizumab (2mg/kg IV, D8) plus either 1)5-FU (LV (200 mg/m2 /5-FU 200 mg /m2 IV bolus, 5-FU 1200mg/m2 continuous IV infusion D1) or 2) gemcitabine (1000 mg/m2 IV, D1), or 3) irinotecan (125 mg/m2 IV, D1) q3w, until disease progression/unacceptable toxicity. The primary endpoint was safety. Secondary objectives included tumor response & evaluation for reovirus replication/immune analysis. We report results of safety cohort analysis. Results: 11 pts were enrolled with REOLYSIN, pembrolizumab and gem (n = 6), 5-FU (n = 3), or iri (n = 2). Grade 1 or 2 TEAEs occurred in all pts: fever (64%), headache (55%), chills (46%), fatigue (46%), dehydration (27%), and nausea (27%). In one pt (gem arm), transient Gr 2 increased transaminases was reported on two occasions. Grade 3 or 4 TEAEs occurred in 8 pts (73%): abdominal pain, anemia, arthralgias, biliary obstruction, chills, DVT, diarrhea, fever, hyperglycemia, leukopenia, myalgias, nausea, neutropenia, pulmonary emboli, vomiting. Of the 5 efficacy evaluable pts, one had PR (6 m duration) and 2 SD (lasting 126 and 221 days). Seven died secondary to PD. On-treatment biopsy show reovirus infection in cancer cells and immune infiltrates. Conclusions: The combination therapy showed manageable safety profiles and antitumor activity in previously treated MAP pts. Further evaluation of anti-tumor activity of REOLYSIN and anti-PD-1 antibody ± chemotherapy combos is planned. Clinical trial information: NCT02620423.
Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine: A Pan-European study.
Authors: Javed Muhammad Ahsan , Beyer Georg , Le Nha Ngoc Hoa , Vinci Alessio , Wong Helen , Palmer Daniel H. , Morgan Robert , Lamarca Angela , Hubner Richard , Valle Juan W. , Alam Salma , Chowdhury Sumsur , Ma Yuk Ting , Archibugi Livia , Capurso Gabriele , Maisonneuve Patrick , Neesse Albrecht , Sund Malin , Schober Marvin , Krug Sebastian
Published: September 2018

e15774

Background: Gemcitabine (GEM) based chemotherapy has been the standard of care for patients with metastatic PDAC with marginal effects on overall survival (OS). In recent years, FOLFIRINOX and Nab-paclitaxel (NAB) + GEM regimens have shown significant survival benefits compared to gemcitabine in clinical trial settings. This study aims to investigate the efficacy of FOLFIRINOX and NAB + GEM versus GEM monotherapy and GEM doublet combinations in real-life settings across different European institutions. Methods: Patients from UK, Sweden, Germany, Italy and Hungary with metastatic PDAC receiving palliative chemotherapy between 2012 and 2015 were included in a retrospective multinational study. Kaplan-Meier method was used for survival analysis. Results: Of the 1089 included patients, 576 (52.9%) were male and 170 (15.6%) underwent primary resection before systemic recurrence. GEM monotherapy was the most commonly used regimen (40.0%; n = 436), followed by combination treatments such as GEM + oxaliplatin, GEM + cisplatin, GEM + capecitabine (24.2%; n = 263), FOLFIRINOX (17,5%; n = 191) and NAB + GEM (7.3%; n = 80). Overall, 6-months and 12-months mortality rate was 48.9% and 72.5%, respectively. The median OS in different groups was: FOLFIRINOX 9.0 months (95% CI 7.1-10.9), NAB + GEM 7.0 months (95% CI 5.8-8.2), other GEM doublet combinations 7.0 months (95% CI 6.0-8.0) and GEM monotherapy 5.0 months (95% CI 4.3-5.7). Compared to GEM monotherapy, intensified chemotherapy either with FOLFIRINOX (p = 0.0001), NAB + GEM (p = 0.02) or GEM doublets (p = 0.0001) was associated with significantly improved survival. Comparison of the different combination regimens was as follows: NAB + GEM vs. FOLFIRINOX (OS: 7.0 vs 9.0 months, p = 0.25), NAB + GEM vs. GEM doublets (OS: 7.0 vs. 7.0 months, p = 0.79) and FOLFIRINOX vs. GEM doublets (OS: 9.0 vs. 7.0 months, p = 0.29). Conclusions: The use of FOLFIRIOX and NAB in clinical routine is variable in Europe. GEM based regimens seem to be the preferred standard of care. Compared to GEM monotherapy, combination treatments improved survival. No significant differences amongst combination therapeutic regimens were identified within our cohort.
DNA sequencing of the small bowel adenocarcinomas to identify targetable ErbB2 mutations.
Authors: Adam Liana , Fowler Jerry , Wu Wenhui , Yu Yao , Wang Huamin , San Lucas Francis A , Huff Chad , Kopetz Scott , Scheet Paul , Overman Michael J.
Published: September 2018

e15800

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy of the digestive tract with limited knowledge about its genetic alterations. Methods: Eighteen tumor and normal matched samples were sequenced using the whole-exome-Illumina platform. Various agnostic analysis methods were used to identify relevant somatic mutations and the results were compared with the available TCGA datasets. To test potential targetable mutations we developed eight patient-derived xenografts (PDX) and three cell lines from freshly-collected primary or metastatic SBA tissues. Two kinase-activating ErbB2 mutations (V842I and Y803H) and one wild-type (wt) ErbB2 (n = 30) PDX models were used to measure the effect of Dacomitinib (Daco) on tumor growth. ErbB2-mutant tumor-derived cell lines were tested for Daco and Lapatinib (Lapa) response in-vitro. Reverse-phase-protein-arrays (RPPA) were used to identify molecular changes. Results: Several unexpected oncogenic mechanisms were suggested by the pattern of somatic mutations across the dataset, including mutations in the Notch and Hippo pathways. In addition, we found 6/18 APC truncating mutations exclusive to mutations in ZNRF3 or RNF43 genes, suggesting that non-APC wnt-activating mechanisms are important in SBA, while considered a minority in CRC. Importantly, 6/18 samples displayed ErbB2 mutations, of which 4 resided in the kinase domain, D769Y, V777L, Y803H and V842I. Nanomolar doses of both Lapa and Daco significantly inhibited ErbB2-mutants’ cell proliferation in-vitro. Target inhibition was confirmed by the RPPA results: EGFR-Y1068, ErbB2-Y1248 and PKCα-S657 dephosphorylation, PCNA reduction and PARP cleavage increase. In-vivo-administered Daco resulted in significant tumor reduction in ErbB2-V841I (39%, p = 0.03) and ErbB2-Y803H (59%, p = 0.03) tumors, and had no anti-tumor effect on wt-ErbB2 tumors. Conclusions: The generation of in-vitro and in-vivo model systems from rare cancers is possible and provides a valuable resource into understanding potentially relevant targetable mutations. Our findings suggest that SBA patients with ErbB2-activating mutations should be considered for clinical trials targeting this alteration.
An exploratory study to investigate the immunomodulatory activity of radiation therapy in combination with pembrolizumab in patients with renal cell cancer.
Authors: Lin Jianqing , Hoffman-Censits Jean H. , Kelly William Kevin , Tuluc Madalina , Shaw Colette , Philipose Sherin , Leiby Benjamin E. , Louie Jennifer , Harshyne Larry , Kean Rhonda , Bar-Ad Voichita , Den Robert Benjamin , Hurwitz Mark , Johnson Jennifer Maria , Hubert Christine , Deshmukh Sandeep , Dicker Adam , Hooper D. Craig , Lu Bo
Published: September 2018

e16058

Background: Preclinical data suggest there are synergistic effects of radiation therapy (RT) and check point inhibitors in anticancer immunity. The primary objective of this study was to explore the immunomodulatory activity of RT alone or in combination with Pembrolizumab (pembro) in solid tumors including renal cell cancer (RCC) patients (pts). Methods: RCC pts who progressed after at least one front-line therapy were eligible. Pts were treated with either RT (8Gy x 1 or 4Gy x 5) followed by (f/b)pembro or 1 dose pembro f/b RT f/b pembro. Pre- and post RT tumor biopsy was obtained to evaluate PD-L1 expression (assay by QualTeck). Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Treatment response was measured based on modified RECIST criteria. Results: Twelve RCC patients were enrolled including 2 with non-clear cell subtype. One pt was not evaluable since pt quickly deteriorated and was taken off study. As of January 13, 2017, 2 pts are still on active treatment. Two pts had partial response (18%) and were on study for at 54 and 63 weeks. One responder was treated with 8 Gy f/b pembro while 1 was treated with 1 dose pembro f/b RT f/b pembro. Five pts had stable disease of 18 to 45 weeks and 4 pts (36%, non-responders) had progression in 9 weeks. For adverse events, 1 pt developed grade 3 pneumonitis after 10 cycles of pembro (RT to adrenal mets). Grade 3 AEs include Fatigue, Nausea, Hyperglycemia, Lymphopenia, thrombocytopenia and AST elevation (post RT for liver mets). PDL1 expression and tumor infiltrating lymphocytes presence after RT showed various patterns. Preliminary flow cytometry showed persistent higher numbers of monocytes in non-responders comparing with responders. CD4+, CD8+ and NK cells and other markers are under analyzed and the results will be presented. Conclusions: The combination of RT (8Gy or 20Gy) with pembro is feasible and tolerated, and demonstrates clinical activity. The AE profile is similar to single agent pembro. Monocytes, T and NK cell kinetics are being examined. (ClinicalTrials.gov ID: NCT02318771) Clinical trial information: NCT02318771.
Thermo reversible hydrogel based delivery of mitomycin C for treatment of upper tract urothelial carcinoma (UTUC).
Authors: Lin Jeffery Shyh-Jye , Kleinmann Nir , Wirth Gregory J , Matin Surena F. , Mayer Gil , Nativ Ofer , Witjes Alfred , Shvero Asaf , Chamie Karim , Pantuck Allan J. , Smith Angela , Schoenberg Mark , Malchi Nadav , Hakim Gil , Agmon-Gerstein Yael , Jeshurun-Gutshtat Michal , Klein Ifat , Kopelen Helen , Lerner Seth P.
Published: September 2018

e16089

Background: There is a large unmet need for novel drug delivery systems and effective therapy for UTUC, especially for patients with CKD and anatomic solitary kidneys. A temperature sensitive water-soluble gel formulation of Mitomycin C (MMC) demonstrated increased drug delivery time (4 to 6 hrs) and safety in the pelvicalyceal system of swine and human bladders. We report the efficacy and safety of gel+MMC as primary treatment (tx) of UTUC on a compassionate use basis. Methods: Compassionate use approval was obtained on an individual patient basis from the respective regulatory authorities and IRBs. 22 patients were approved for tx to date from 14 institutions in 4 countries. Tx included 6 weekly instillations instilled via ureteral catheter or percutaneous nephrostomy. Gel volume ranged from 5-20cc and MMC concentration was 2-6 mg/cc. Adverse events were recorded throughout treatment. Ureteroscopy was performed 2-6 weeks following tx completion for response determination. Results: Median age of the cohort was 75 yrs, with 15 males. 18 patients (pts) had low-grade (LG) tumor, 2 high-grade (HG), and 2 indeterminate grade. 16 (73%) completed treatment - 9 pts had a complete response, CR (41%; 59% of those who completed tx), 5 pts had a partial response, PR (23%; 31%), and 2 pts had no response, NR (9.1%, 12.5%). 4 patients could not complete tx due to adverse events (pyelonephritis, acute renal failure, pancytopenia, and unstable cardiac condition), 1 patient was diagnosed with a non-urothelial cancer during treatment, and 1 patient died prior to the third instillation due to suspected pulmonary embolus, determined to be unrelated to treatment with MitoGel. A total of 77 adverse events were recorded with 6 events related to MitoGel and serious (requiring intervention), and 21 events related to treatment and not serious. CR (9) and PR (5) were observed in 14 of 15 evaluable patients completing treatment for LG tumors. Conclusions: This compassionate use program of a thermosensitive gel+MMC for chemoablation of UTUC demonstrates proof of concept for treatment of low-grade tumors. A single arm Phase III multi-center registration trial to treat patients with low-grade renal pelvis tumors has been activated.
Prognostic rule of programmed cell death protein 1 expression in resectable upper tract urothelial carcinoma.
Authors: Hayakawa Nozomi , Kikuchi Eiji , Mizuno Ryuichi , Oya Mototsugu
Published: September 2018

e16090

Background: Programmed cell death protein (PD-1) expressed on active T cells are related to immune tolerance. A close association between PD-1 expression and poor prognosis has been reported in several cancers, however, in upper tract urothelial carcinoma (UTUC) the rule of PD-1 expression on clinical outcome have not been investigated. Methods: The protein expression of PD-1 was evaluated by immunohistochemistry and the relationship with clinicopathological features was investigated in surgical specimens obtained from 155 patients who had been surgically treated for UTUC without previous history of bladder cancer. At a magnification of 400x, PD-1 protein expression was estimated and the positive cells was graded as weak and strong. The protein expression of PD-1 was evaluated in the most invasive part of the cancer with tumor periphery and inside separately. Results: The PD-1 expression was weak in 67 (43.2%) and strong in 88 (56.8%) in tumor periphery. On the other hands, the staining was weak in 117 (75.5%) and strong in 38(24.5%) in tumor insides. Regarding to pathological features, high grade (p = 0.026) and pT2≤ (p = 0.008) related to strong PD-1 expression in tumor inside, and high grade (p = 0.002), pT2≤ (p < 0.001) and positive LVI (p = 0.008) were associated with strong PD-1 expression in tumor periphery. The 5-year caner-specific survival (CSS) in patients with strong PD-1 staining in tumor periphery was 79.4%, which was significantly lower than those in their counterparts (86.0%, p = 0.044). The 5-year CSS in patients with strong PD-1 staining in tumor inside was 73.3%, which was significantly lower than those in their counterparts (85.1%, p < 0.021). Multivariate Cox regression analysis demonstrated that positive LVI (HR; 3.92, p < 0.001) and strong PD-1 expression in tumor inside (HR; 2.30, p < 0.036) were independent predictors for CSS. Conclusions: PD-1 expression, especially in tumor inside, may be a novel indicator for identifying a worse prognosis in UTUC patients with radical nephroureterectomy. Targeting therapy against PD-1 might be a promising therapeutic modality for UTUC, especially aggressive UTUC.
Evaluating the impact of bone-targeted agents in the era of novel androgen targeted therapy for metastatic castration-resistant prostate cancer.
Authors: Li Haoran , Kamel Dalia , Fernandes Ricardo , Bosse Dominick , Vo Dong , Souied Osama , Kumar Vikaash , Ong Michael
Published: September 2018

e16500

Background: Patients with metastatic castrate resistant prostate cancer (mCRPC) often develop bone metastases, resulting in a risk of symptomatic skeletal events (SSE). Bone-targeted agent (BTA) has been integrated into the overall treatment strategy, but its role in the era of novel androgen-targeted therapy (ATT) is still unclear. Methods: A retrospective analysis of real-world practice from 2010 to 2015 was conducted. Patients diagnosed with mCRPC and bone metastases who received systemic therapy (docetaxel/abiraterone/enzalutamide) with or without BTA (zoledronic acid/denosumab/alendronate) were included. Results: We obtained data from 299 patients with a median follow-up of 75.5 months. Compared with no BTA, concomitant BTA was associated with decreased incident of SSE (3.8% vs. 19.2%, p< 0.001), especially in the need for bone radiation (1.9% vs. 15.8%, p< 0.001). Compared to patients without SSE, patients with SSE were more likely to have previous fracture history (10.8% vs. 9.7%, p= 0.047), steroid use history (2.4% vs. 1.4%, p= 0.019), smoking history (53.0% vs. 38.9%, p= 0.009), diabetes (19.3% vs. 8.8%, p= 0.012) and reduced baseline mobility (9.6% vs. 4.2%, p= 0.002). Among those who received first-line novel ATT (n = 152), concurrent ATT+BTA significantly decreased the incident of SSE (2.8% vs. 27.3%, p= 0.004) and prolonged the time to SSE (24.3 vs. 3.2 mo, p< 0.001), when compared to ATT alone. But there was no difference in overall survival between two groups (134.2 vs. 138.9 mo, p= 0.99). In patients who responded to systemic treatment with PSA declining, the SSE rate (2.4% vs. 14.3%, p= 0.037) was lower and the time to SSE was longer (49.6 vs. 32.3 mo, p= 0.026) than those who did not respond. Smoking history (adjusted HR = 1.46, p= 0.013) and PSA response (adjusted HR = 0.19, p< 0.001) are independent risk factors for SSE. Conclusions: This real-world database suggests that concomitant BTA with novel ATT was associated with reducing SSEs. PSA decrease might be used as a predictive factor for those under BTA treatment. Further studies are warranted to validate the role of PSA response.
Metformin to treat prostate cancer (PCa) and prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Results of a randomized double-blind placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced PCa.
Authors: Mahalingam Devalingam , Salih Hanni , Fountzilas Christos , Michalek Joel , Sarantopoulos John , Datta Paromita , Romero Ofelia , Mulampurath Achutan Pillai Sureshkumar , Kuhn John G. , Pollak Michael N. , Thompson Ian Murchie
Published: September 2018

e16502

Background: ADT results in metabolic syndrome, characterized by hyperinsulinemia, insulin resistance and obesity. The hyperinsulinemia may result in ADT resistance; therefore preventing metabolic syndrome could have a therapeutic impact on PCa. In diabetes, metformin (MET) decreases glucose & insulin by inhibiting hepatic gluconeogenesis. There is preclinical evidence for additional antineoplastic activity due to mTOR inhibition secondary to AMPK activation. Methods: Men with biochemical relapse or advanced PCa due to receive ADT were randomized 1:1 in a double blind manner to MET (500mg TID) or placebo (P). Subjects required normal oral glucose tolerance test at baseline, with fasting serum insulin/glucose, PSA, MET, weight and waist circumference (WC) monitored at baseline, week 12 and 28. The primary endpoint of study was the metabolic consequences of MET vs P. Secondary endpoints were PSA response and PBMC analysis of downstream target of mTOR, phospho-S6 kinase. Results: 36 men were randomized to MET or P, mean age 68.4; biochemical failure (n = 15) & metastatic disease (n = 21). Mean weight, WC and insulin at baseline in MET cohort was 187 lbs, 41.14 cm and 10.03 mIU/L respectively, and 177.65 lbs, 40.52 cm and 8.02 mIU/L in P cohort. An increase in mean weight, WC and insulin levels was seen in both cohorts. At wk 12 and 28, no statistical difference in weight, WC and insulin was observe in either cohort. 4 men randomized to MET had undetectable serum drug levels despite drug-diary suggesting compliance; excluding them did not result in significant metabolic change. Assessing efficacy, 50% in MET and 53.3% in P cohort achieved undetectable PSA at wk 28; difference not statistically significant. PBMC analysis demonstrated variable down-regulation of phospho-S6 kinase in the metformin cohort. Conclusions: This study detected no impact of MET addition to ADT on the risk of metabolic syndrome and no additional anti-tumor effects. Control of hyperinsulinemia related to diabetes by MET does not necessarily imply MET has a similar action on hyperinsulinemia due to ADT. Clinical trial information: NCT02620423.
How do patterns of progression influence treatment selection after chemohormonal therapy in patients with metastatic hormone sensitive prostate cancer?
Authors: Aguado De La Rosa Carlos , Garcia Carbonero Iciar , De Velasco Guillermo , Alonso Teresa , Villalobos Maria L. , Garrido Maria , Gallegos Isabel , Martin Almudena , Pinto Alvaro , Maximiano Alonso Constanza , Rodriguez-Moreno Jf , Rodriguez Laura , Sereno Maria , Perezagua Carmen , Marrupe David , Riquelme Alejandro , Cassinello Javier , Grande Enrique , Puente Javier , Gajate Pablo
Published: September 2018

e16504

Background: In the CHAARTED and STAMPEDE clinical trials, Docetaxel combined with androgen-deprivation therapy (ADT) increased overall survival in mHSPC patients. Despite the increasing use of this strategy in clinical practice, there is a lack of information about the best treatment choice after progression. Methods: We retrospectively analyzed 96 patients with mHSPC treated with Docetaxel plus ADT in 18 Spanish centers (July 2014 to December 2016). The objectives of the study were to describe baseline and progression characteristics, as well as second-line treatment choice and its outcomes. Results: The median age was 66.7 years. 33.3% patients had visceral metastases at diagnosis and 81% had a Gleason Score 8-10. After a median follow-up of 12.2 months, 35.4% of patients developed castration-resistant prostate cancer (CRPC). The median time to CRPC was 15.4 months. 36.3% of patients had visceral progressive disease. 27 patients received subsequent treatment after progression: 9 (33.3%) were treated with chemotherapy (2 docetaxel, 6 cabazitaxel, 1 carboplatin-etoposide), and 18 (66.6%) received androgen receptor axis-targeted agents (12 enzalutamide, 6 abiraterone). Median progression-free survival was similar with hormonal therapies (4.3 months) than chemotherapy (3.5 months) as second line. Treatment choice was influenced by pattern of progression (visceral vs non visceral) and time to develop CRPC (≤ 12 vs > 12 months). Hormonal therapies were more frequent for non-visceral disease (75% vs 25%) or patients with longer time to develop CRPC (89% vs 11%). Chemotherapy was preferred in patients with visceral progressive disease (83.3% vs 16.7%). In patients with a time to CRPC less than 12 months both treatments were used equally (44.5 vs 55.5%). Conclusions: In our cohort, androgen receptor axis-targeted agents were used more frequently than chemotherapy after progression to chemo-hormonal therapy. Despite the low number of patients that received treatment at progression, our results suggest that the characteristics at the time of progression, such as pattern of progression and time to develop CRPC, could influence treatment choice.