bluuebunny/crossref_metadata_2025 huggingface dataset:
Portal vein infiltration in patients with hepatocellular carcinoma: The relevance of correct classification.
Authors: Weinmann Arndt , Steinle Verena , Koch Sandra , Pinto dos Santos Daniel , Marquardt Jens Uwe , Sprinzl Martin , Lang Hauke , Düber Christoph , Galle Peter R. , Woerns Marcus A. , Kloeckner Roman
Published: September 2018

e15651

Background: Portal vein invasion (PVI) is has a significant impact on the prognosis of patients with hepatocellular carcinoma (HCC). Patients with PVI are classified as stage C in the BCLC score and systemic therapy is recommended. Patients with minor PVI are frequently misclassified due to radiological challenges in determining malignant PVI or non-adherence to guidelines. The concept of resection or TACE in limited PVI is sometimes followed with the assumption of a negligible influence on survival. Aim of this study is the reevaluation of PVI and the analysis of the impact of a misclassification. Methods: 763 patients with HCC of a total of 1413 were extracted from the clinical registry of our tertiary center as an ongoing effort to reevaluate the extent of PVI in all patients treated between 1/1/2000 and 12/31/2015. PVI was diagnosed by re-evaluating all available CT or MRI scans by an experienced liver imaging radiologist. PVI was documented using the Liver Cancer Study Group of Japan classification ranging from Vp0-Vp4: Vp0 = no PVI; Vp1 = segmental; Vp2 = right anterior or posterior PV; Vp3 = right or left PV; Vp4 = main trunk. The influence on survival was calculated for each BCLC stage. Results: 259 patients (pat) were classified with PVI. Median age at diagnosis was 65.3 years, 213 patients (82.2%) were male. Etiology of liver disease was alcohol (43.6%), viral hepatitis (29.8%), NASH (5.8%), and others (10.4%). No liver disease was present in 18 pat (6.9%). No liver cirrhosis (LCI) was present in 32 pat (12.4%). LCI was classified as Child Pugh stage A/B/C in 65 (25.1%)/109 (42.1%) and 52 (20.1%) of patients. BCLC classification prior to reevaluation in pat with new PVI was A/B/C/D in 9/13/164/71 of cases. Comparing the overall survival (OS) of pat initially classified as BCLC A with or without PVI was 21.3 months vs. 106.4 months (p = 0.001), in BCLC B the OS was 11.0 months vs. 37.7 months (p = 0.001). Conclusions: Even minor PVI leads to dismal prognosis. Meticulous evaluation of cross sectional imaging is crucial for the clinical management of patients with HCC. Once PVI has been diagnosed, such patients have to be classified as advanced stage. The guidelines should be followed closely, irrespective of the extent of PVI.
Survival in patients with hepatocellular carcinoma (HCC): A report of 1444 patients treated within a multidisciplinary program.
Authors: Maluccio Mary A. , Zang Yong , Pi Wenhu , Tann Mark , Kubal Chandrashekhar , Lacerda Marco A , O'Neil Bert H. , Agarwal David M , Kong Feng-Ming (Spring)
Published: September 2018

e15652

Background: The evolution of treatment for HCC has seen novel therapies emerge as front line treatment alternatives. The aim of this study was to report survival in HCC patients treated within the context of a robust multidisciplinary program and to identify patient and tumor specific factors that direct patient centered treatment decisions and optimize outcome. Methods: This is retrospective analysis of medical records identified through the cancer registry at our institution from 2000 to 2016. Variables analyzed for survival significance included patient factors (age, gender, race, tobacco history, alcohol history, and marital status) and tumor factors (tumor size, histology grade, AFP level, SEER stage, clinical and pathologic stage). Survival was estimated from the time of diagnosis to the last contact. Results: A total of 1444 consecutive patients with confirmed HCC were eligible for this analysis. Median follow-up was 45 months. Median survival was 18 months (95% CI: 11-25 months). The overall 1-, 3-, and 5-year survival rates were 63, 40, and 35%, respectively. Significant prognostic parameters were SEER stage (HR = 2.3, p = 2x10-16 local as the reference), pathologic stage (HR = 1.2, p = 3×10-9), tobacco history (HR = 1.2, p = 0.03), , and clinical stage (HR = 1.1, p = 4x10-5). Of a total of 380 patients resected, median and 3-year survival were 75 months and 63% (95% CI: 58-69%). The only significant prognostic parameter associated with survival in resection patients was SEER stage (HR = 1.7, p = 0.002). The 5 year survival for all patients versus those resected were 44% (95% CI: 40-48) /59% (95% CI: 53-65), 21% (95% CI: 17-27) /36% (95% CI: 24-54), and 11% (95% CI: 5-20) /25% (95% CI: 6-100) for localized, regional, and distant disease, respectively. Conclusions: Survival has improved for patients with HCC due to an increased number of available options and better methods to identify tumor and patients specific variables that individualize care. The significance of SEER stage suggests that early detection remains critical for survival.
Molecular landscape of fibrolamellar carcinoma (FLC): Beyond the DNAJB1-PRKACA chimera.
Authors: El Dika Imane Hassan , Capanu Marinela , Berger Michael F. , Arcila Maria E. , Benayed Ryma , Harding James J. , Rusek Matthew , Valentino Emily , O'Reilly Eileen Mary , Saltz Leonard , Abou-Alfa Ghassan K.
Published: September 2018

e15668

Background: FLC is a rare cancer arising in non-cirrhotic liver of young adults. A functional chimeric transcript resulting from the in-frame fusion of DNAJB1 with PRKACA genes on chromosome 19 is thought to be universal and unique in FLC. This chimera has possible role in pathogenesis, yet with no determined prognostic or therapeutic value. Methods: Archival FFPE samples from FLC patients who prospectively consented to an IRB-approved protocol from 2014 onward were analyzed using the MSK-IMPACT platform, a hybridization capture based next generation sequencing assay for targeted deep sequencing of all exons and selected introns of > 400 key cancer genes. Tumor and matched normal libraries were sequenced on an Illumina HiSeq 2500. Sequencing output was processed using a custom analysis pipeline. Archer targeted RNAseq was performed in select cases. Demographic, treatment, and outcome data was prospectively collected. Fisher’s exact tests were performed to look for associations between clinical characteristics and genetic alterations. Results: 18 patients were identified. Median age at diagnosis was 18 years and 61% were women. 17 (94%) underwent upfront surgery, and median number of therapies was 5. The DNAJB1-PRKACA fusion transcript was detected in 100% of cases. 7 samples were negative via MSK-IMPACT, (2 false-negatives, and 5 due to an older panel not including the fusion transcript) and were confirmed positive on Archer targeted RNAseq. The second most common genetic mutation was TERT, detected in 4 patients, whereas CIC, NOTCH1, ERBB3, EPHAS, MCL1, PNRC1, NCOR, INPP4B, ARID1A, CHECK1, NKX3-1, TET1, RAD52, DIS3, SF3B1, MDM2, MED12, MPL, KRAS, PAK7, BCOR, HGF, ROS1, MYCL1, CTNNB1, and YAP1 were detected in 1 patient each. 3-year overall survival (OS) was 98%, median OS was not reached. Conclusions: This limited cohort of patients with FLC exhibited universally the DNABJ1-PRKACA chimera, and demonstrated a favorable outcome compared to a 3-year OS approaching 70% previously reported by the Fibrolamellar Consortium. The fusion transcript did not imply a prognostic value considering its expression among all patients with FLC. Other drivers or the lack of may be responsible for the improved outcome in this small cohort
Prospective evaluation of the factors predicting the prognosis of advanced hepatocellular carcinoma (HCC) patients treated with sorafenib.
Authors: Adachi Takuya , Nouso Kazuhiro , Miyahara Koji , Dohi Chihiro , Wada Nozomu , Takeuchi Yasuto , Kuwaki Kenji , Onishi Hideki , Ikeda Fusao , Nakamura Shinichiro , Shiraha Hidenori , Takaguchi Koichi , Uematsu Shuji , Iwadou Shouta , Takuma Yoshitaka , Hagihara Hiroaki , Takabatake Hiroyuki , Takaki Akinobu , Okada Hiroyuki ,   Okayama Liver Cancer Group
Published: September 2018

e15674

Background: Several factors including pro-angiogenic cytokines have been reported as predictive markers for the treatment effect of sorafenib in patients with HCC; however, many of them were determined based on the results of retrospective studies. Methods: In this prospective cohort study (UMIN000009771), we recruited advanced HCC patients who were treated with sorafenib, and periodically measured serum levels of eight pro-angiogenic cytokines, which were risk factors for the prognosis reported by us and others. The effect of the cytokine expressions before and at 2 (4) weeks after starting sorafenib and at PD, on progression free survival (PFS), overall survival (OS), and post progression survival (PPS) were evaluated. The effect of early appearance of adverse events within 30 days, which were reported as other risk factors, was also evaluated. Results: Eighty patients were enrolled. Median PFS and OS were 3.1 and 11.7 months, respectively. There was no statistically significant variable that could predict PFS, which included patients’ characteristics, cytokines before the therapy, and early onset of adverse events. However, PFS of the patients who showed the decrease of platelet-derived growth factor after 2 weeks (HR2.78, 95%CI 1.35-6.21, P=0.005) or vascular endothelial growth factor after 4 weeks (HR3.31, 95%CI 1.59-6.83, P=0.001) compared to the values before sorafenib treatment was short. OS was short in patients with poor performance status, large tumor size (>30mm), large tumor number (>5), high des-gamma-carboxyprothrombin (DCP, >100mAU/mL), high hepatocyte growth factor, and high angiopoietin-2 (Ang-2) before therapy, in addition to no hand foot syndrome within 30 days. Multivariate analysis with these factors revealed that high Ang-2 (HR2.25, 95%CI 1.08-4.86, p=0.029) and high DCP (HR3.55, 95%CI 1.25-12.7, p=0.014) were the independent risk factors for OS. High Ang-2 at PD could also be a marker of short PPS. Conclusions: The prediction of PFS, OS and PPS is possible by measuring serum pro-angiogenic cytokines at appropriate timing. Ang-2 is a key cytokine for predicting the prognosis of HCC patients treated with sorafenib.
Efficacy and safety of localized concurrent chemoradiation therapy and sorafenib sequential therapy in advanced hepatocellular carcinoma: A prospective phase II trial.
Authors: Kim Beom Kyung , Kim Do Young , Choi Hye Jin , Beom Seung-Hoon , Lee Hye Won , Kim Seung Up , Park Jun Yong , Ahn Sang Hoon , Seong Jinsil , Han Kwang-Hyub
Published: September 2018

e15678

Background: Patients with advanced hepatocellular carcinoma (HCC) have a particularly poor prognosis of the median overall survival of less than 12 months. Even though sorafenib has been approved for treating advanced stage HCC, the unsatisfactory objective response rate still remain unresolved. In the current study, we aimed to evaluate the efficacy and safety of localized concurrent chemoradiotherapy (CCRT) followed by sequential sorafenib treatment for advanced hepatocellular carcinoma. Methods: This study is an ongoing, phase II trial. Patients with advanced HCC not amenable for curative treatments were eligible. In the course of radiotherapy for 5 weeks, hepatic arterial infusion of 5-fluorouracil (500mg/day) via implanted port was applied during the first 5 days and the last 5 days of radiotherapy. Four weeks after localized CCRT, sorafenib (400mg bid) was maintained. The primary endpoint was overall survival. Results: A total of 47 patients were enrolled. After the completion of localized CCRT, the objective response rate was 31.9%. During the overall treatment course, the objective response rate was 46.8% respectively. Overall, 7 patients (14.9%) underwent curative resection or transplantation after down-staging. The median overall survival was 18.4 months and the progression-free survival was 6.8 months. Adverse events were predictable and manageable with conservative care. Conclusions: Localized CCRT followed by sequential sorafenib treatment in patients with advanced HCC showed significant activity and good tolerability. Furthermore, such a treatment modality, when compared to the use of sorafenib alone, might provide the additional therapeutic benefit through initial tumor reduction, allowing curative treatment after down-staging in 14.9% of patients, Further randomized trial should be required to make the more robust evidence. Clinical trial information: NCT02425605.
A novel and validated inflammation-integrated prognostic model for hepatocellular carcinoma (HCC).
Authors: Chan Anthony W.H. , Chong Charing C.N. , Lai Paul B.S. , Yeo Winnie , To Ka Fai , Chan Stephen Lam
Published: September 2018

e15679

Background: Various serum inflammatory factors are implicated in pathogenesis and prognostication of HCC but none of them is incorporated into a HCC prognostic model. We aim to build an inflammation-integrated prognostic model without any radiological feature. Methods: A prospective-retrospective cohort of patients with HCC was accrued from 2001 to 2013, and was randomly spitted into training and validation cohorts. Cox proportional hazards model was used for univariable and multivariable survival analyses. The risk score was constructed by factors and their coefficients identified by multivariable Cox model. Results: The entire cohort was composed of 1315 patients (BCLC 0/A/B/C/D 73/533/237/425/47; Surgery/Locoablation/TACE/Systemic agent/BSC 538/128/318/122/209). In the training cohort (n=657), a novel model, PANALA score, was generated by using6 independent prognostic factors: 1.488*(Performance status >0) – 0.057*Albumin + 0.098*Neutrophil – 50.4*Alkaline phosphatase-1 – 0.269*Lymphocyte + 0.11*ln(Alpha fetoprotein). PANALA outperformed other staging systems (Table) and allowed the prediction of survival of an individual patient. In the validation cohort (n=658), the prognostic performance of PANALA was still the most superior one. The goodness of fit of PANALA score in prediction of survival was evaluated by dividing patients into 4 equal quartiles by PANALA. In the quartile 1, overall survival between actual observation and prediction was highly comparable (6m survival: 100% vs. 95%, 3y survival: 80% vs. 79%, 5y survival: 72% vs. 74%; P=0.71). Discrepancies between observed and predicted survival were also insignificant in other quartiles. Moreover, PANALA was able to stratify each BCLC stage into 3 prognostically different subgroups. Conclusions: PANALA is a novel and validated model with high prognostic performance. [Table: see text]
Multi-omic molecular profiling of pancreatic neuroendocrine tumors.
Authors: Patel Rishi , Bender R Joseph , Li Quanlin , Pan Dana , Tuli Richard , Pishvaian Michael J. , Hendifar Andrew Eugene
Published: September 2018

e15685

Multi-omic Molecular profiling of Pancreatic Neuroendocrine Tumors Authors: Rishi R Patel, Joseph Bender, Quanlin, Dana Pan, Lynn Matrisian, David Halverson, Emanuel Petricoin, Subha Madhavan, Richard Tuli, Michael Pishvaian, Andrew Hendifar; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA Background: Pancreatic Neuroendocrine Tumors (pNETs) are a rare malignancy with an incidence of 2 per 1,000,000. In 2016, the Pancreatic Cancer Action Network and Perthera initiated the Know Your Tumor (KYT) initiative in an effort to improve coordination across clinical spectrums in regards to multi-omic molecular profiling and clinical outcomes data pertaining to pancreatic tumors. We used data collected as part of the KYT effort to describe demographic, clinical and genomic data for pNETs. Methods: From 2015 - 2016, 15 patients with pNET were enrolled in the KYT program, which helped facilitate tissue acquisition, clinical data collection, and multi-omic molecular profiling. Using the data collected, we performed Fisher’s Exact to assess for statistical significance between genetic alterations and histology. Results: 11/15 of our patients were female. 8/15 had metastatic disease at the time of diagnosis, while 5/15 had locally advanced disease at the time of diagnosis. 29 genetic alterations were pathogenic. KMT2D and MEN1 were jointly found in 6/15 of our patients. 5/15 with pathogenic alterations in p53, 2/15 with DAXX, 5/15 with alteration in RB1, and 2/15 with alterations in PTEN and TSC2. 2 patients had pathologic alterations in mismatch repair genes, MLH1 and MSH1. Two genes had a statistically significant relationship to pNET histology. Alterations in MEN1 (p = 0.0097) and SPTA1 (p = 0.0333) were associated with high grade tumors (p = 0.0097). Of note, both of the patients under the age of 35 shared an alteration in ATR, which none of the other enrollees expressed. Conclusions: In PNETS, multi-omic profiling through the KYT program identified targetable alterations in several key pathways. Outcome data will be explored.
Periprocedural management of patients undergoing liver resection or liver-directed therapy for neuroendocrine tumor metastases.
Authors: Kwon Daniel , Mulvey Claire , Paciorek Alan T , Chan Hilary , Meng Lingzhong , Zhang Li , Nakakura Eric K. , Fidelman Nicholas , Bergsland Emily K. , Van Loon Katherine
Published: September 2018

e15689

Background: Carcinoid crisis is a life-threatening event caused by release of vasoactive substances from neuroendocrine tumors (NETs). Octreotide is often used in the periprocedural setting as prophylaxis against carcinoid crisis; however, there is no standardized protocol for its use. We aimed to describe the periprocedural management of patients with metastatic NETs who underwent liver-directed procedures at UCSF. Methods: We identified 54 patients with NETs with hepatic metastases who underwent either liver resection/ablation (n = 30) or liver-directed embolization (n = 24) between 2012 and 2016. Anesthesia records and clinical data were abstracted. Carcinoid crisis was defined by physician documentation. Hemodynamic instability was defined as ≥10 minutes of systolic blood pressure < 80 mmHg or > 180 mmHg or heart rate > 120. Pearson chi-squared tests were used to test associations with three outcomes: crisis, instability, or none. Results: Three (6%) patients were documented to have developed carcinoid crisis. Another 14 (26%) patients developed hemodynamic instability. Of 16 patients who received preprocedural octreotide, 1 (6%) had a carcinoid crisis and 5 (31%) developed hemodynamic instability. History of carcinoid syndrome, degree of hepatic involvement, and use of pre or intraprocedural octreotide were not associated with carcinoid crisis or at least hemodynamic instability. Patients undergoing embolization were less likely to develop hemodynamic instability versus those undergoing liver resection (17% vs 43%, Pearson chi-squared p = 0.04). Conclusions: Occurrence of documented carcinoid crisis was low in this high-risk population. However, a significant proportion of patients developed hemodynamic instability, suggesting that carcinoid crisis is a spectrum diagnosis and may be clinically under-recognized. Use of octreotide was not associated with risk of carcinoid crisis or hemodynamic instability; however, this analysis was limited by our modest sample size at a single institution. There remains a need to establish an objective definition of carcinoid crisis and to inform standardization of periprocedural use of octreotide for at-risk patients.
Association of weight change with telotristat ethyl in the treatment of carcinoid syndrome.
Authors: Weickert Martin O , Kaltsas Gregory , Hörsch Dieter , Lapuerta Pablo , Pavel Marianne , Valle Juan W. , Caplin Martyn E. , Bergsland Emily K. , Kunz Pamela L. , Anthony Lowell Brian , Grande Enrique , Oberg Kjell E. , Warner Richard R. P. , Lombard-Bohas Catherine , Welin Staffan , Fleming Rosanna , Kittur Ashwin , Arnold Karie , Yang Qi Melissa , Kulke Matthew H.
Published: September 2018

e15692

Background: In the Phase 3 TELESTAR study, the oral tryptophan hydroxylase inhibitor telotristat ethyl (TE) significantly reduced bowel movement (BM) frequency compared with placebo (pbo) over a 12-week Double-blind Treatment (DBT) period in patients with carcinoid syndrome (CS). Weight loss has previously been associated with uncontrolled CS and may result in reduced survival, so it is important to examine weight changes in patients with neuroendocrine tumors (NETs). Methods: We conducted an analysis, prespecified in the statistical analysis plan, of the incidence of weight change of ≥3% at Week 12 in TELESTAR. Patients with metastatic NETs, CS, and ≥4 BMs per day were randomly assigned to receive pbo, TE 250 mg 3x/day (tid), or TE 500 mg tid for 12 weeks, in addition to somatostatin analog therapy. Results: There were 45 patients in each group. Mean baseline age was 63.5 years, with 5.8 BMs/day and mean body mass index 24.87 kg/m2. Weight gain ≥3% at Week 12 was observed in 2/39 (5.1%), 7/41 (17.1%), and 13/40 (32.5%) patients on pbo, TE 250 tid, and TE 500 mg tid, respectively. The Cochrane–Armitage test for trend in weight gain incidence across groups yielded p = 0.0017. Among the 20 patients with a ≥3% weight gain on TE, 10 patients experienced a reduction of at least 30% in BM frequency at Week 12 (maximum reduction 75%). Weight loss ≥3% at Week 12 was observed in 5 (12.8%), 4 (9.8%), and 6 (15.0%) patients on pbo, TE 250 tid, and TE 500 mg tid. Adverse events of vomiting, decreased appetite, cachexia, and performance status decreased were reported during the DBT period among those with weight loss but not those with weight gain. Conclusions: The incidence of weight gain was dose-related on TE and was greater than that on pbo. It was possibly related to a reduction in diarrhea severity, and it may be a relevant aspect of TE efficacy among patients with functioning metastatic NETs. Clinical trial information: NCT01677910.
Association between duration of somatostatin analogs (SSAs) use and quality of life in patients with carcinoid syndrome in the United States based on the FACT-G instrument.
Authors: Halperin Daniel M. , Huynh Lynn , Beaumont Jennifer L , Cai Beilei , Totev Todor , Bhak Rachel , Duh Mei Sheng , Vekeman Francis , Neary Maureen , Cella David
Published: September 2018

e15693

Background: Carcinoid syndrome (CS) results from the secretion of bioactive amines by functional neuroendocrine tumors. The only FDA-approved agents to treat carcinoid syndrome symptoms (CSS) are SSAs. This study assessed the association of duration of SSA use and quality of life (QoL) among patients with CSS usingthe validated Functional Assessment of Cancer Therapy-General (FACT-G) instrument. Methods: Patients with CSS in the US were recruited by NCAN for a two-part online, anonymous survey (~6 months apart). The first survey was fielded between July-October 2016 and results are reported here. Eligible patients were ≥18 years old with CSS and received either SSA or non-SSA treatment for CSS control. The survey consisted of demographic, clinical and QoL questions, including FACT-G. Descriptive and multivariable regression analyses, adjusting for demographic and clinical characteristics, were performed to assess predictors of FACT-G QoL scores. Duration of SSA use was categorized into quartiles ( < 2.7, 2.7-4.42, 4.43-8.0, and > 8.0 years). Results: Among 117 patients who completed the first survey, 76.9% were female and 87.2% Caucasian with a mean age of 58.0 years. A predominant number of patients (98.3%) received SSAs in the past month. The mean ± SD FACT-G total score was 67.6 ± 20.0 (possible range: 0-108), lower than that of the general US population (80.1 ± 18.1). The mean ± SD duration of SSA use was 6.1 ± 4.7 years. Descriptive analysis suggested that patients receiving SSA treatment for > 8 years had higher (better) FACT-G subscale and total scores than reference group < 2.7 years. Multivariable models showed that FACT-G total score was 11.3 points ( P= 0.033) higher for patients treated with SSA > 8 years compared to those treated for < 2.7 years. Similar patterns were observed for two FACT-G subscales - Physical Well Being and Functional Well Being. Conclusions: The duration of SSA use was positively associated with QoL benefit among CS patients. This may be explained by long-term effectiveness of SSAs or selection bias favoring patients with more indolent disease. Future studies will be needed to distinguish between these possibilities.
Microarray analysis of cytokine expression in the gastrointestinal stromal tumors with different malignant potential.
Authors: Zhang Bo
Published: September 2018

e15701

Background: Nowadays, a variety of prognostic criteria, which established merely based on clinicopathologic features, have been proposed, validated and widely used in practice. Numerous studies have confirmed tumor location, size and mitotic index were closely associated with the prognoses of GISTs. However, no method has yet been proven sufficient power to discriminate malignant potential and to predict biological behavior in all cases. In fact, the changes in cytokine level may result in alteration of tumor's microenvironment, which is considered to be related in the course of malignization for many tumors. Methods: The expression profile of cytokine in 4 patients with gastric GISTs (low malignant potential in 2 cases: 2x2cm, 3/50HPF; 2x1.8cm, 2/50HPF. high malignant potential in 2 cases: 12x10cm, 14/50HPF; 15x12cm, 16/50HPF), along with matched normal gastric tissue was evaluated by microarray. Results: The majority of cytokines expression between adjacent tissue of low and high malignant potential GISTs was similar. The high malignant potential GISTs exhibiting a notable upregulation of 41 cytokines, whereas a total of 23 cytokines with decreased expression in comparison to those with low malignant potential, after considering the expression level of cytokines among matched normal tissue. The cytokines expressed differentially including SPARCL1, MMP13 and FAP have been proven enormously valuable for assessing the prognoses of many tumors. Conclusions: Abnormally expressed cytokines in GISTs may play a vital role in promoting tumor progression, and detection of these cytokines proteins is useful to understand GISTs- malignization mechanisms and is also helpful to evaluate risk of recurrence in the treatment of GISTs patients.
Effect of palliative surgery, chemotherapy, and radiation in stage IV pancreatic cancer.
Authors: Vuong Brooke , Dehal Ahmed , Graff-Baker Amanda N , Chang Shu-Ching , Foshag Leland , Bilchik Anton , Goldfarb Melanie R
Published: September 2018

e15707

Background: Despite significant advances in multi-modality treatment for pancreatic adenocarcinoma (PC), prognosis for stage IV PC remains poor. While reducing suffering and optimizing quality of life are the primary goals of palliative therapies, these interventions may extend overall survival. We examined the impact on survival when aggressive palliative treatments including surgery, chemotherapy, or radiation were employed in end-of-life care. Methods: The 2004-2014 National Cancer Data Base (NCDB) was queried to identify patients with stage IV PC that did not undergo primary surgical resection. Univariate (Kaplan Meier and log-rank) and multivariable (Cox proportional hazard) analyses were used to assess the associations between patient characteristics, use of palliative therapies, and overall survival. Results: Of 72,736 patients identified with metastatic stage IV PC, 2,097 (3%) underwent surgical palliation (ST), 5,615 (8%) received palliative chemotherapy (CT), 940 (1%) received palliative radiation (RT), 1,163 (2%) received multimodality treatment (MMT), and 62,921 (87%) had no aggressive palliative intervention (NT). The choice of palliative therapy, if any, was influenced by all demographic and tumor variables except for gender (all p < 0.001). Median OS was greatest after CT (5.09 months, p < 0.001) compared to any other modality (NT: 3.45months, ST: 3.71months, RT: 3.25months, MMT: 4.47months). This remained true regardless of age, gender, race/ethnicity, insurance, and facility type. After adjusting for all demographic and tumor factors, use of CT decreased the annual risk of death by 20% (HR = 0.8; 95%CI [0.77, 0.82]) and MMT by 10% (HR = 0.9; 95%CI [0.84, 0.96]). Employment of RT increased risk of death by 9% (HR = 1.09; 95%CI [1.01, 1.17]) and ST did not affect OS (HR = 1.01; 95%CI [0.96,1.06]). Conclusions: Despite advances in palliative treatments, Stage IV PC arries a dismal prognosis. Palliative RT may shorten survival. Equivalent survival for ST versus NT suggests that this may be beneficial in the appropriate patient. Palliative CT independently improved survival by approximately 6 weeks and should be considered in patients that want to extend survival and can tolerate the toxicity.
BP-C1 in the treatment of primary inoperable pancreatic cancer.
Authors: Larsen Stig Einride , Ibrahim Tarek M.M.
Published: September 2018

e15708

Background: The aim was to estimate the efficacy and tolerability of intramuscular administration of a new benzene-poly-carboxylic acids complex with cis-diammineplatium (II) (BP-C1) in treatment of primary inoperable pancreatic cancer patients Methods: The study was an open, single center, non-randomized trial with security sequential design. The study sample consists of 12 patients with a mean age 61.8 years, BMI 23.9 and disease duration 1.8 months. The patients received daily intramuscular injection of 0.035 mg/kg bw BP-C1 for 32 days. NCI Bethesda (CTC-NCI) and EORTC QOL-C30 were recorded at screening, after every 16 days of treatment and 28 days follow-up. CT-scans performed at screening, after 32-days BP-C1 treatment and follow-up. The RECIST criteria used for tumor evaluation and the sum diameters of the three largest lesions measured. Patient classified as responding to treatment if Stable Disease (SD) or better was obtained. Results: The number of target lesions was unchanged from screening to Day 32. The sum lesion diameters declined from 47.3 mm at screening to 46.3 after 32 days of BP-C1. During follow-up, the sum diameters declined significantly (p = 0.03) to 14.0 mm. After 32 days of treatment, three patients classifies as Progressive Disease (PD) and nine as SD: A responds rate of 75% (95% CI: 42.8 – 94.5%). After 28 days follow-up, five patients classifies as PD, three as SD and four as PR: A responds rate of 58.3% (95% CI: 27.7 – 84.8%). “Discomfort last week” and “Physical activity problem” declined significantly (p < 0.01) and “Health and life quality” increases significantly (p < 0.01) from screening to Day 16 and Day 32. Sum CTC score increase non-significantly from 9.8 at screening to 12.3 and 13.4 after 16 and 32 days of treatment, respectively. During follow-up, the score decreased to 8.8. Thirty AE recorded. Ten classified as “Unrelated”, seven as “Possibly”, 12 as “Probably” and one as “Definite” related to the trial treatment. Of the 20 AE, which might be related to the treatment, 12 classifie as “Mild”, six as “Moderate”, one as “Severe “and one as “Life-threatening”. Conclusions: BP-C1 reduce the cancer growth, improve quality-of-life and well tolerated with only few mild to moderate AE.
Comparison of standard versus reduced-dose pegfilgrastim on clinical outcomes and chemotherapy dose intensity in patients with advanced pancreatic cancer receiving cytotoxic combination chemotherapy (NAPPCG) in an outpatient oncology infusion clinic.
Authors: Hicks Krystal , Odeh Adam
Published: September 2018

e15710

Background: Pegfilgrastim use has been shown to reduce the incidence of febrile neutropenia when given at recommended dosage (6 mg) following myelosuppressive chemotherapy. Despite lack of supportive data, many prescribers have adopted the practice of utilizing reduced dosages (3-4 mg) of pegfilgrastim, often citing bone pain as reason for dose reduction. We sought to explore the impact of reduced-dose pegfilgrastim on chemotherapy dose intensity in patients with pancreatic cancer treated with the triplet combination of nab-paclitaxel, cisplatin and gemcitabine (NabPlagem) at our facility. Methods: A retrospective analysis was conducted on all patients who received NabPlagem chemotherapy in combination with pegfilgrastim during the period of 1/1/16 - 9/30/16. Patients who received at least 2 cycles were considered evaluable. Chemotherapy was administered on Days 1 and 8 of a 21-day cycle with pegfilgrastim administered Days 2 and 9. Chemotherapy doses were considered full-intensity if no reduction made from original treatment schema (i.e. 125 mg/m2 nab-paclitaxel, 25 mg/m2 cisplatin and gemcitabine 1000 mg/m2) with no doses delayed or omitted from treatment plan. Results: A total of 54 chemotherapy cycles were administered, with patients receiving between 5-13 cycles. Of these 54 cycles, 14 were given with reduced-dose pegfilgrastim (26%) and 40 at full dosage (74%). In the patients receiving full dose pegfilgrastim, treatment delays and omissions were observed in 5% cycles (n = 2), with no dose reductions required. Full dose-intensity was obtained in 90% cycles (36/40). In comparison, treatment delays and omissions were observed in 14% cycles given with reduced-dose pegfilgrastim. Dose reductions were required in 10/14 cycles (71%). Full dose-intensity was observed in 28.5% cycles (4/14). Conclusions: Based on this data, dosage of pegfilgrastim dose is an important factor in maintaining dose-intensity of chemotherapy, and full dosing (6 mg) should be preferred dosing schedule when used with myelosuppressive chemotherapy.
A phase IIb of eryaspase in combination with gemcitabine or FOLFOX as second-line therapy in patients with metastatic pancreatic adenocarcinoma (NCT02195180).
Authors: Hammel Pascal , Bachet Jean-Baptiste , El-Hariry Iman , Portales Fabienne , Mineur Laurent , Metges Jean-Philippe , De La Fouchardiere Christelle , Louvet Christophe , El Hajbi Farid , Faroux Roger , Guimbaud Rosine , Tougeron David , Volet Julien , Lecomte Thierry , Tournigand Christophe , Rebischung Christine , Berlier Willy , Gupta Anu , Cros Jerome , Andre Thierry
Published: September 2018

e15718

Background: L-asparaginase (L-ASP) hydrolyses asparagine (ASN) leading to depletion of this amino acid. While normal cells are protected from ASN requirement due to their ability to produce ASN,.leukemic lymphoblasts and most cancer cells have a very low level or even lack of L-asparagine synthetase (ASNS), and thus depend on serum ASN for their proliferation and survival. L-ASP depletes serum ASN, which in turn inhibits the protein synthesis, resulting in cell cycle arrest and apoptosis in susceptible cancer cells, especially pancreatic cancer cells Eryaspase, which is L-ASP encapsulated in red blood cells, recently showed an encouraging activity and improved safety profile compared to L-ASP in patients (pts) with relapsed ALL. Knowing that up to 70% of pancreatic adenocarcinomas (PC) have low or null ASNS expression (Bachet Pancreas 2015), prompted us to evaluate the efficacy and safety of eryaspase in combination with chemo in PC. Methods: This open label, multicenter phase II randomized study (2:1) enrolled pts with second-line metastatic PC. Pts eligible to gemcitabine or FOLFOX regimen (according to first line chemo) were randomized to chemo +/- eryaspase (100 IU/Kg D3 and D17 of 4-wk regimen) until disease progression Primary end point: progression free survival in pts with ASNS negative tumors (0/1+). ASNS expression was measured using immunohistochemistry and optical density. Key secondary endpoints: PFS in ASNS positive pts (2+/3+), overall survival, biomarkers ( KRASmutation, cell free DNA), and safety. Results: 141 pts were enrolled. Treatment was generally well tolerated, with no safety concerns based on IDMC reviews. ASNS expression was negative in 69%, and positive in 31% of the pts At the time of submission, PFS and OS analysis and the correlation of ASNS expression with clinical outcomes were not yet available but will be presented at the meeting. Conclusions: This is the largest set of PC pts tested for the expression of ASNS and treated in second line with an asparaginase combined with chemotherapy. The ASNS expression levels may be a potential therapeutic target and therefore predictive of response to eryaspase for the treatment of advanced PC. Clinical trial information: NCT02195180.
Prognostic influence of waiting time in management of pancreatic ductal adenocarcinoma.
Authors: Suzuki Rei , Takagi Tadayuki , Hikichi Takuto , Ohira Hiromasa
Published: September 2018

e15726

Background: Since pancreatic ductal adenocarcinoma (PDAC) showed aggressive progression, we hypothesized that waiting time in management might have prognostic influence on patients’ prognosis. Methods: Data on PDAC patients who underwent either chemotherapy or surgical resection in our hospital (2006 – 2016) were collected. Waiting time was classified into two groups as detection-to-diagnosis waiting time (WT1) and diagnosis-to-treatment waiting time (WT2). Median disease free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method and utilized as cut-off points to divide patients into 2 groups (short- and long-survival group). Clinical characteristics including age, sex, tumor size, location of tumor, stage of disease, the levels of serum tumor markers, waiting times, use of adjuvant chemotherapy and resectability were compared between the two survival groups. Results: In total, 149 patients were included. Seventy-two patients who underwent chemotherapy (median OS: 9.7 months) were divided into long survival group (n = 42) and short survival group (n = 30). We did not find significant differences in both WT1 (20.0 days vs. 19.0 days, P = 0.98) and WT2 (17.0 days vs. 18.5 days, P = 0.93), while proportion of patients with locally advanced disease ( P = 0.02) and combination chemotherapy ( P = 0.003) was significantly associated with long survival. Among 79 patients underwent surgical resection, median DFS after pancreatic resection was 16.4 months and OS was 35.0 months. The patients were divided into short DFS (n = 47) versus long DFS (n = 30) and short OS (n = 57) versus long OS (n = 20). We did not find significant differences in both WT1 (short vs. long DFS: 21.0 days vs. 21.0 day, P = 0.65, short vs. long OS: 21.0 days vs. 23.0 days, P = 0.45) and WT2 (short vs. long DFS: 46.0 days vs. 44.5 days, P = 0.45, short vs. long OS: 46.0 vs. 41.0 days, P = 0.36). Both advanced T- and N-stage was significantly associated with poor DFS ( P = 0.049, P = 0.03, respectively) while only advanced T-stage was significantly associated with poor OS ( P = 0.02). Conclusions: Our findings suggested that both detection-to-diagnosis waiting time and diagnosis-to-treatment waiting time might not influence on prognosis of patients with PDAC.
Clinical predictors of second-line chemotherapy (ChT) benefit in pancreatic cancer (PC).
Authors: Pokataev Ilya , Bazin Igor , Fedyanin Mikhail , Tryakin Alexey , Popova Anna , Rumyantsev Alexey , Sekhina Olga , Patutko Yury , Fainstein Igor , Tjulandin Sergei
Published: September 2018

e15733

Background: Second line ChT is shown to improve outcome in selected patients with PC; however there are no approved models predicting its benefit. This retrospective study was aimed to evaluate prognostic factors in patients with PC who had disease progression following 1st line ChT and their value in prediction of 2nd line ChT benefit. Methods: Records of PC patients treated in N.N. Blokhin Russian Cancer Research Center since 2000 to 2015 were analyzed. Inclusion criteria for this retrospective analysis were: morphologically confirmed PC, disease progression after 1st line ChT or adjuvant / induction ChT with ChT-free interval <6 months. The most common clinical factors were evaluated for prognostic significance in the Cox proportional hazards model with overall survival (OS) as the end-point. OS was calculated from the date of progression following previous ChT. Cutoff values for quantitative variables were determined using ROC curve analyses. Results: Records of 172 patients matched the inclusion criteria. Second line ChT was administered in 110 (64%) patients (47% of them received gemcitabine- and/or platinum-based doublets). The Cox multivariate analysis identified two independent prognostic factors: Karnofsky performance status (KPS) ≤70% and neutrophil-to-lymphocyte ratio (NLR) >5 at the time of disease progression after 1st line ChT (Table). Administration of 2nd line ChT improved outcome of patients with favorable prognosis (score ≤1): median OS increased from 1.7 to 5.5 months in groups without (n=23) and with (n=90) ChT, respectively (p=0.02). In patients with poor prognosis (score>1) there were no benefit by administration of 2nd line ChT: medians OS were 2.3 and 1.7 months in groups with (n=20) and without (n=39) ChT, respectively (p=0.23). Conclusions: This novel prognostic model can potentially predict 2nd line ChT benefit in patients with PC, however it needs to be validated in further trials. [Table: see text]
NAMPT expression in stage I/II pancreatic ductal adenocarcinoma.
Authors: Davis Katelynn , Dunseth Craig , Mott Sarah L , Bellizzi Andrew , Chan Carlos Hou Fai
Published: September 2018

e15735

Background: NAD (nicotinamide adenine dinucleotide), a vital cofactor in redox reactions and a substrate for many enzymes, plays a critical role in cellular metabolism. NAMPT (nicotinamide phosphoribosyltransferase) is a key enzyme that regenerates NAD from its metabolites. NAMPT has been shown to be overexpressed in some cancers, and inhibition of NAMPT in pancreas cancer cell lines and xenografts has been shown to decrease cell growth, making it an attractive potential therapeutic target. Here we correlate NAMPT expression in a large cohort of stage I/II pancreatic ductal adenocarcinomas (PDA) with clinical outcomes and pathologic features. Methods: NAMPT immunohistochemistry (IHC) was performed on tissue microarrays of 250 PDAs. Tumors had been arrayed in triplicate. Each core was evaluated for staining intensity of cancer cells (0 = no staining, 1+ = weak, 2+ = moderate, 3+ = strong), and a mean score was calculated for each case; cases with fewer than 2 cores were excluded. Fisher’s exact and Wilcoxon rank sum tests were used for categorical and continuous variables, respectively. Recurrence-free survival (RFS) and overall survival (OS) differences were evaluated using Cox regression. This study was conducted under an approved IRB protocol. Results: 197 PDAs had at least 2 TMA cores with identifiable cancer cells. The mean IHC score was 0.53 (range 0 to 2.33). While 121/197 PDAs (61%) were positive, only 18/197 (9%) had a score > 1. Stage II tumors had a higher mean score than stage I tumors (0.57 vs 0.31; P = 0.03) and were more likely to be positive (66% of 148 vs 41% of 22; P = 0.03). However, RFS and OS were not significantly different between NAMPT-positive vs NAMPT-negative PDAs. Conclusions: NAMPT expression was detected in 61% of stage I/II PDAs. Frequency and extent of expression correlated with overall stage, suggesting a role in cancer progression. Although NAMPT expression did not correlate with RFS and OS in this study, given its frequent expression in PDA, it represents a potential therapeutic target.
Early-onset pancreatic ductal adenocarcinoma (PDAC) at Memorial Sloan Kettering Cancer Center (MSKCC).
Authors: Kunte Siddharth , Sangli Swathi , Lemor Alejandro , Lowery Maeve Aine , Yu Kenneth H. , Abou-Alfa Ghassan K. , Varghese Anna M. , O'Reilly Eileen Mary
Published: September 2018

e15736

Background: PDAC is a leading and rising cause of cancer-related mortality. There is infrequent description of patients and outcomes with PDAC diagnosed aged <=50 years old (Early onset PC: EOPC). We reviewed the epidemiology, risk factors, oncologic outcomes and genomic data of EOPC pts at MSKCC. Methods: Using an institutional dataline search, N=364 patients were identified with EOPC between 2008-2014 at MSKCC. N= 282 were included in final analysis based on data completeness. Results: Baseline characteristics are summarized in table 1. The average patient was male, aged between 40- 50 years, BMI 24 and had metastatic disease at diagnosis. Family history of malignancy was present in N= 216 patients. The median overall survival (OS) for stages IIA, IIB, III and IV was 19.2, 21.8, 18.8 and 9.7 months respectively. Age, gender, diabetes and smoking history did not have a significant impact on OS. No difference in OS was noted between the groups who received gemcitabine based first-line chemotherapy compared to those with 5-fluorouracil based regimen in metastatic disease (9.9 vs 12 months, p= 0.315). Conclusions: EOPC represents a small subset of patients with PDAC and very rarely arises < 30 years of age. For this MSKCC cohort, outcomes appear similar to patients with average age onset PDAC. Further analyses on genomic characteristics may provide insight into outcomes and genetic underpinnings of EOPC. [Table: see text]
Modified FOLFIRINOX (mFOLFIRINOX) as second-line chemotherapy in pancreatic adenocarcinoma.
Authors: Dean Andrew Peter , Higgs Domenic , James Alex , Van Gemert Tegan , James Alena Talia
Published: September 2018

e15747

Background: FOLFIRINOX is a highly effective combination chemotherapy regimen with the reputation of only being tolerable to young patients with good performance status. As the original ACCORD study was carried out at specific French university hospitals with patients performance status 0 or 1 many oncologists feel uncomfortable administering mFOLFIRINOX as a second-line therapy. We have previously reported our experience in 24 patients ages 27 - 84 where we concluded that dose modified FOLFIRINOX can be safely administered to elderly patients with appropriate initial dose reductions and subsequent escalation. There is a lack of consensus on a standard second-line regimen for metastatic pancreatic cancer. We conducted a review of dose intensity and outcome for all patients treated with 2nd or 3rd-line mFOLFIRINOX for pancreatic adenocarcinoma at St John of God Hospital, Subiaco, Western Australia in order to assess efficacy and tolerability Methods: Electronic records were used to identify 35 patients who had received 1st-line gemcitabine-based chemotherapy who then went on to receive 2nd or 3rd line mFOLFIRINOX. Case files, laboratory and radiology records were then examined to determine outcomes and toxicities. Results: 35 patients were identified with an age range of 27- 85, both locally advanced and metastatic disease, with 12 over the age of 70. All patients except 2 had gemcitabine plus abraxane in the first line setting. Dose intensity was 65% for oxaliplatin, 68% for irinotecan, 18% for bolus 5-FU and 68% fir infusional 5FU. Toxicity was acceptable with a grade 3 toxicity rate of 10%. Overall survival in this group ranged from 5-67 months (median 23 months for locally advanced / 15 months for metastatic). Notably, 20 patients received greater than 6 cycles of treatment and 8 patients received more than 12 cycles. One patient has received 70 cycles. Conclusions: Our experience demonstrates the safety, tolerability and efficacy of mFolfirinox as a second-line therapy after gemcitabine failure. The disease control rate, even with the reduction in dose intensity, suggests that modified Folfirinox should be formally tested in the 2nd line setting in a clinical trial.