bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular pathways associated with micro-vascular invasion HCC.
Authors: Chia Caroline Yun Ling , Tan Wilson Lek Wen , Shannon Nicholas Brian , Foo Roger Sik Yin , Chow Pierce Kah Hoe
Published: February 2017

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Background: Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) has a reported incidence of 15-57%. It is associated with decreased overall and recurrence free survival in post-surgical resection and transplant patients. Currently, the biology of MVI+ HCC remains unknown and the absence of effective adjuvant therapy limits management options to prevent recurrence. Aim: To correlate gene signatures observed at the transcriptomic level with the presence of MVI in HCC, analyze molecular pathways with gene expression tools and validate with TCGA database. Methods: Whole genome expression was studied in two groups of Asian resected HCC tumour specimens: (i) MVI present (MVI+) (n = 14) and (ii) MVI absent (MVI-) (n = 33) both without macrovascular invasion on radiological imaging. 2 distinct pathway analysis tools – gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were performed to identify significantly enriched pathways potentially explaining the observed MVI+ HCC phenotype. Selected gene sets from the identified pathways were subjected to in-silico validation with TCGA data to confirm their enrichment within MVI+ HCC. Results: Within 14 MVI+ and 33 MVI- HCC studied, we have found a total of 1401 significantly differentially expressed genes between them; 766 genes were up-regulated and 635 genes were down-regulated in MVI+ HCC. At p < 0.05 and FDR < 0.25, GSEA and IPA analyses identified enrichment of PI3K/AKT/mTOR, HIF1α, AMPK signaling and actin-mediated cell kinetics pathways: actiny, Cdc42 signaling and actin pathways regulated by Rho. A 90 gene signature derived from these enriched pathways, created on the basis of biological function was used to compare between average expression within the MVI+ vs MVI- HCCs in the TCGA Asian cohort. Genes found differentially expressed at p < 0.05 corresponded with the enriched pathways: actiny, AMPK signaling and PI3K/AKT/mTOR. Conclusions: These pathways underscore functions in regulation of cell metabolism, growth, proliferation, survival, protein synthesis and cytoskeleton organization in MVI+ HCC. Further studies in these pathways may assist in development of molecular targeted therapies for MVI+ HCC. We propose to carry out a prospective study to validate this.
Whole-exome tumor sequencing study in patients with biliary cancer with a response to MEK inhibitors.
Authors: Ahn Daniel H. , Gulcin Ozer Hatice , Hancioglu Baris , Lesinski Gregory B. , Timmers Cynthia Dawn , Bekaii-Saab Tanios S.
Published: February 2017

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Background: We conducted a phase-II study with selumetinib (AZD6244), a small molecule inhibitor of MEK1/2, in advanced biliary tract cancers (BTC). The observed preliminary activity was confirmed with another MEK inhibitor (MEK162) that was tested in a similar patient population. To assess for tumor-specific genetic variants that mediate sensitivity to MEK inhibition in BTC, we performed whole-exome sequencing in patients with an objective response including a complete response to selumetinib. Methods: Normal and tumor DNA from available formalin-fixed paraffin-embedded tissue from biopsies of primary or metastatic tumor from two patients who experienced an objective response underwent whole-exome sequencing. Raw sequence reads were processed with GATK workflow and tumor-specific variants were identified using MuTect and VarScan 2. Following, we assessed the functional consequences of the variants. Copy number changes and potential gene fusion events were also screened. We compared the findings to assess for any commonality between the two samples. Ingenuity Pathway Analysis was used to assess whether the identified somatic variants were intrinsic to the MAPK pathway. Results: 1169 and 628 tumor-specific variants were identified in the two tumor samples. Further analysis demonstrated a similar number of functional and novel variants between the two samples, which were 60 and 53, respectively. No common variants or detectable fusion events were observed between the two samples. Copy number changes were found in chromosomes 1, 5, 6, 9, 10, 12, 17, 20, 21 and 22 in sample one, and in chromosome 11 and 12 on sample two with no common findings. Several variants in genes associated with ERK signaling were present in each tumor sample. Conclusions: Although no common tumor-specific somatic changes of significance several genes associated with ERK signaling were identified in the patients with an objective response. Confirmatory studies investigating the role of the identified genes need to be further investigated.
Correlation of high density of CD8+and FoxP3+ lymphocytes with overall survival in intestinal-type periampullary adenocarcinoma.
Authors: Warfvinge Carl Fredrik , Elebro Jacob , Heby Margareta , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin
Published: February 2017

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Background: Periampullary cancers can be divided into different morphological subtypes where those having an intestinal-type (I-type) morphology have a better prognosis than those with a pancreatobiliary-type (PB-type) morphology. In recent years much focus of antineoplastic research has been directed towards the central role played by various subsets of T-lymphocytes. Yet, very little is known of their role in different subtypes of periampullary cancer. Therefore, the aim of this study was to analyze the density of CD8+ (cytotoxic) and FoxP3+ (regulatory) T-cells in periampullary cancer, with particular reference to their relationship with survival by morphological subtype. Methods: Immunohistochemical expression of CD8 and FoxP3-positive tumor-infiltrating lymphocytes (TILs) was analyzed in tissue microarrays with tumors from 175 consecutive cases of periampullary adenocarcinoma, 110 of PB-type and 65 of I-type morphology, treated with pancreaticoduodenectomy. Kaplan-Meier and univariable and multivariable Cox regression analysis, adjusted for age, T-stage, N-stage, grade, sex, invasion of blood vessels, lymphatic vessels, adjuvant chemotherapy and resection margins were applied to determine the impact of CD8 and FoxP3 expression on 5-year overall survival (OS). Results: In I-type tumors, a high density of CD8+ as well as FoxP3+ TILs was significantly associated with a prolonged overall survival (HR = 0.39, 95% CI 0.19-0.80 and HR = 0.32, 95% CI 0.15 –0.67). The association between high density of FoxP3+ TILs and survival remained significant in multivariable analysis (HR = 0.37, 95% CI 0.17-0.84) while the association between CD8+ TILs and survival did not. The density of CD8+ and FoxP3+ TILs was not prognostic in PB-type tumors. Conclusions: High density of CD8+ and FoxP3+ TILs correlates with a prolonged overall survival in I-type but not in PB-type periampullary adenocarcinomas. Thus, morphological subtype appears to be an important determinant of the prognostic and predictive impact of the inflammatory microenvironment in periampullary carcinoma, and should be considered in future studies.
Tremelimumab, a monoclonal antibody against CTLA-4, in combination with subtotal ablation (trans-catheter arterial chemoembolization [TACE], radiofrequency ablation [RFA] or cryoablation) in patients with hepatocellular carcinoma (HCC) and biliary tract carcinoma (BTC).
Authors: Duffy Austin G. , Makarova-Rusher Oxana V. , Pratt Drew , Kleiner David E , Fioravanti Suzanne , Walker Melissa , Carey Stephanie , Figg William Douglas , Steinberg Seth M. , Anderson Victoria , Levy Elliot , Krishnasamy Venkatesh , Wood Bradford J. , Greten Tim F.
Published: February 2017

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Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA) and cryoablation (CA) have been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced HCC. Methods: Patients with HCC [Childs Pugh A/B7; BCLC B/C; ECOG 0/1; post-sorafenib (BCLC stage C only)] or refractory BTC were enrolled in a study of Tremelimumab combined with subtotal TACE, RFA or CA performed on week 6. All BTC patients received RFA as the immune-stimulant in combination with tremelimumab. Tumor biopsies were performed at baseline and at time of RF/TACE. Results: 34 pts enrolled (28 HCC, 6 BTC). Characteristics: M:F 26:8; Median age 54(range 42-76); In HCC pts cirrhosis present in 17pts, BCLC Stage B/C: 9/19; Hepatitis B/C/neg: 4/15/9. 13 pts received TACE, 16 underwent RFA (inc 6 BTC pts), 3 CA during week 6 of tremelimumab therapy. 2 pts did not receive an ablative procedure. No DLT encountered. Most common toxicity was pruritus. One patient developed pulmonitis and was taken off study but remained disease-free at 16m. Of N = 17 pts evaluable for response outside of TACE/RFA-treated lesion 4 (23.5%) achieved confirmed partial responses. 8 of 9 pts with quantifiable HCV experienced a marked reduction in viral load. 6-week tumor biopsies showed immune cell infiltration on all evaluable patients. Median PFS for the evaluable HCC population (N = 25) was 5.7m. Conclusions: Tremelimumab in combination with subtotal TACE, RFA or CA in patients with advanced HCC and BTC is safe and feasible. Obtaining tumor biopsies at baseline and at the time of RFA/TACE is safe. Evidence of immune cell infiltration was seen on evaluable patients. Encouraging clinical activity seen with objective confirmed responses, PFS 5.7m and possibly surrogate reductions in HCV viral load. Clinical trial information: NCT01853618.
High frequency irreversible electroporation (H-FIRE) as a novel method of targeted cell death.
Authors: Siddiqui Imran A , Kirks Russell C. , Baker Erin H , Latouche Eduardo , Dewitt Matt , Swet Jacob , Vrochides Dionisios , Iannitti David A , Davalos Rafael , Mckillop Iain
Published: February 2017

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Background: Irreversible electroporation unlike ablation is excellent in inducing cell death via apoptosis. It, however, has disadvantages of electrical conduction via cardiac and nervous tissue. This results in requiring cardiac monitoring and general anesthesia and paralytics while performing electroporation. We hypothesized a novel high-frequency IRE (H-FIRE) system employing ultra-short bipolar pulses would obviate the need for cardiac synchronization and paralytics while maintaining measurable effect on cell death. Methods: Female swine (55-65Kg) were used. Two H-FIRE electrodes were inserted into the liver (1.5-cm spacing). In the absence of paralytics H-FIRE pulses were delivered (2250V, 2-5-2 pulse configuration) at different on times (100 vs. 200μs) or number of pulses (100 vs. 300). Next electrodes were placed across major hepatic vascular structures and H-FIRE performed. At conclusion tissue was resected and analyzed histologically. Results: 24 H-FIREs were performed (mean ablation time 275 secs). No EKG abnormalities or changes in vital signs were measured during H-FIRE procedures. In 1/24 H-FIREs minor twitching of the rectus abdominis was recorded coinciding with pulse delivery. Histologically, tissues had effective electroporation as evidenced by cell death and caspase activity. Blinded scoring was performed for necrosis and apoptosis. Areas of cell death were predictable. No significant vascular damage or coagulated/thermally-desiccated blood was detected within major vessels following H-FIRE. Conclusions: H-FIRE is a novel way of liver electroporation. It produces predictable cell apoptosis without the requirement of paralytics and alteration of electrocardiographic signals as compared to traditional electroporation, while preserving underlying vascular integrity. Its application in cancer cell death needs to be further studied, but it has a potential for clinical use in targeting tumors with minimal morbidity and associated cardiac and neurologic side effects.
Adding targeted inhibition of PI3K and MAPK signaling pathways to standard chemotherapy in experimental pancreatic cancer.
Authors: Awasthi Niranjan , Schwarz Margaret A. , Schwarz Roderich
Published: February 2017

278

Background: Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge as gemcitabine (Gem) plus nab-paclitaxel (NPT) represent the current standard for systemic therapy of advanced PDAC. More than 90% of PDAC tumors harbor an activating mutation in the KRAS oncogene. Currently no therapeutics exist that can effectively target this oncogene product, but alternative strategies focus on inhibition of downstream effectors of KRAS signaling pathways. The RAF-MEK-ERK (MAPK) and the AKT-PI3K signaling pathways are well-described mediators of KRAS induced transformation and tumorigenesis and can be explored as targets for combination therapy. Methods: We evaluated combination treatment benefits of NPT+Gem with the MEK inhibitor trametinib (Tra) and the AKT inhibitor MK-2206 (MK) in experimental xenografts to test their therapeutic potential against PDAC. Results: Median animal survival in human intraperitoneal PDAC xenografts in mice revealed that the median survival was 21 days in controls; this was significantly improved by the NPT+Gem combination (35 days, a 67% increase over controls, p = 0.0007). Median survival was further increased by addition of MK-2206 or trametinib to NPT+Gem chemotherapy group: NPT+Gem+MK (39 days, a 86% increase over controls, p = 0.0003), NPT+Gem+Tra (43 days, a 105% increase over controls, p = 0.0003) and NPT+Gem+MK+Tra (48 days, a 129% increase over controls, p = 0.002). In human subcutaneous PDAC xenografts, MK-2206 or trametinib were able to enhance NPT+Gem effects. Compared to controls (100±34.8), the percent net local tumor growth in different therapy groups was: NPT+Gem 21.8±5.9 (p = 0.003), NPT+Gem+MK 17.2±4.8 (p = 0.002), NPT+Gem+Tra 7.1±11.2 (p = 0.002) and NPT+Gem+MK+Tra 5.7±9.1 (p = 0.001). In vivo effects of Tra and MK correlated with reduced expression of phospho-ERK and phospho-AKT in Western blots of tumor samples. Conclusions: These findings suggest that the effects of NPT+Gem can be enhanced through combined inhibition of MAPK and PI3K signaling pathways, which clinically could yield in improved antitumor results.
Molecular profiling of advanced biliary cancer: Lost in translation from bench to bedside.
Authors: Doherty Mark , Chiu Joanne Wing-Yan , McNamara Mairead Geraldine , Horgan Anne M. , Serra Stefano , Kamel-Reid Suzanne , Zhang Tong , Bedard Philippe L. , Hedley David W. , Dhani Neesha C. , Jang Raymond Woo-Jun , Knox Jennifer J.
Published: February 2017

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Background: Advanced Biliary Cancer (ABC) is a collection of diseases which carry poor prognosis, and many patients derive limited benefit from chemotherapy. Identification of molecular drivers of ABC may help to predict treatment response and direct development of targeted therapy. Methods: Formalin fixed paraffin embedded (FFPE) tissue form patients with ABC treated at Princess Margaret Cancer Centre was analysed by MassARRAY Sequenom panel (23 genes, 279 mutations), or by next general sequencing (NGS) using Proton or Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥500x coverage). Clinicopathologic and treatment data were collected from electronic health records. Results: Of 112 tested patients, 16 had insufficient DNA, and 96 had data for analysis: 13 with ampullary cancer (AC), 19 with hilar/distal bile duct (DBD), 43 with gallbladder (GBC), and 21 with intrahepatic (IHC). 13 patients had Sequenom testing, 85 had NGS with Miseq or Proton. 127 mutations were identified in 60 patients, 36 had no mutations detected: 23 in AC, 54 in GBC, 24 in IHC, 26 in DBD. The most frequent mutations were in TP53 (34%) and KRAS (20%). TP53 and SMAD4 mutations appeared most common in GBC, BRAF and KRAS mutations were most common in AC, and IDH1 and FGFR2mutations were seen only in IHC. 14 patients (15%) had a mutation for which targeted treatment could be applied. Conclusions: Profiling of patients with ABC is feasible and can identify some molecular drivers, with different tumour sites demonstrating distinct biological patterns. Only a limited number of patients are shown to have clinically relevant mutations with current NGS techniques, suggesting additional techniques (whole genome/RNA sequencing) may be required to fully characterise these diseases and identify new therapeutic targets. [Table: see text]
Comprehensive genomic analysis in metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Wong Hui-Li , Jones Martin , Eirew Peter , Karasinska Joanna , Schrader Kasmintan A , Lim Howard John , Shen Yaoqing , Jones Steven , Yip Stephen , Laskin Janessa J. , Marra Marco , Schaeffer David F. , Renouf Daniel John
Published: February 2017

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Background: In the absence of defined tumor molecular subtypes and validated predictive markers, PDAC has been largely treated as a single disease. Recent studies of molecular subtyping in PDAC reveal a complex mutational landscape with data suggesting the presence of genomic and gene expression signatures that may have prognostic and therapeutic significance. These studies predominantly focused on resected PDAC and lack data on metastatic tumors. We aim to explore the clinical utility of whole genome sequencing (WGS) and transcriptome analysis from metastatic biopsy samples in patients (pts) with advanced PDAC. Methods: Pts with incurable advanced cancers undergo tumor biopsy for in-depth WGS and RNA sequencing (RNASeq) as part of an ongoing prospective study (NCT02155621). Comprehensive bioinformatics analysis is performed to identify somatic cancer aberrations, gene expression changes and cellular pathway abnormalities. Here we describe clinical and molecular data on the subset of pts with advanced PDAC. Results: Sixteen PDAC pts have been enrolled; median age 59 years, 8 males (50%), 10 with de novo metastases (63%). Full WGS and RNASeq were completed in 11 pts (1 failed biopsy, 4 had insufficient tumor). KRAS codon 12 and TP53 mutations were present in all but one pt. CDKN2A and SMAD4 were also frequently altered (7 and 4 pts respectively). Gene expression analysis for classical and basal subtypes similar to those recently described (PMID 26343385) identified 3 and 6 pts with classical and basal expression patterns respectively, and 2 pts with mixed expression. Overall survival (OS) was significantly worse for the basal subtype vs all others (median OS 7 vs. 13.9 months (ms), p = 0.017). When separated into 3 subtypes a significant difference was still noted (median OS 7 ms in basal, 19.2 ms in classical and 11.8 ms in mixed subtype, p = 0.032). Conclusions: WGS analysis demonstrated a similar mutation pattern to that described in resectable PDAC, with no novel actionable mutations identified. Gene expression analysis demonstrated the presence of distinct gene expression signatures significantly associated with outcome, despite small pt numbers. These results need to be validated prospectively in larger cohorts. Clinical trial information: NCT02155621.
Next Generation Sequencing (NGS) to reveal mutations in IDH1 and its effect on patient (pt) outcomes in advanced biliary tract cancer (aBTC) who received gemcitabine and cisplatin (GC).
Authors: Ahn Daniel H. , Ahn Chul , Jain Apurva , Mikhail Sameh , Wu Christina Sing-Ying , Goldberg Richard M. , Ciombor Kristen Keon , Noonan Anne M. , Sadavartia Priyanka , Shroff Rachna T. , Javle Milind M. , Chen James Lin , Bekaii-Saab Tanios S.
Published: February 2017

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Background: aBTC is uncommon and has a dismal prognosis with limited therapeutic options. First-line therapy for untreated aBTC is GC, with no approved therapies in the refractory setting. To assess for tumor-specific genetic variants that affect outcomes in patients (pts) who received GC in aBTC, we performed NGS in pts treated with who received GC as first-line therapy. Methods: Archival formalin-fixed, paraffin-embedded samples from pts with mBTC from Ohio State University and MD Anderson Cancer Center who received GC in the first-line and underwent NGS as part of routine care. 315 cancer-related genes plus select introns from 28 genes altered in solid tumors were included in the NGS panel. Univariate Cox regression model was used to determine the association between gene mutations with progression free survival (PFS) and (OS). Results: 80 evaluable pts with aBTC treated with first-line GC chemotherapy underwent successful genomic profiling. A total of 414 cancer-specific mutations were identified, where 49 (12%) genes had mutations with > 5% frequency. 17 of the 49 were known mutations. From the comprehensive analysis, somatic mutations in IDH1 (11 of 80 pts; 13%) (HR 0.31; p = 0.035) was associated with improved overall survival (OS) and progression free survival (PFS). Pts wild type for IDH1 had a median OS of 17.7 months and PFS of 4.5 months, while those with an IDH1 mutation had a median OS that was not reached and an improved PFS of 5.7 months. Conclusions: Somatic mutations in IDH1 were associated with improved clinical outcomes in pts with aBTC who received GC as first-line therapy which is consistent with other solid tumor malignancies. IDH1 is a therapeutic target of interest, where future prospective studies will be necessary to validate the predictive utility and its relevance in pt outcomes in aBTC.
Intra and extrahepatic cholangiocarcinoma: An evaluation of adjuvant therapy.
Authors: Wiisanen Jeff , Hubbard Joleen Marie , Bergquist John , Alberts Steven R. , Nagorney David , Truty Mark Joseph
Published: February 2017

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Background: Cholangiocarcinoma (CCA) is a rare malignancy with poor survival. The only curative therapy is resection and the role of adjuvant therapy is not well defined. Despite the unproven benefit, adjuvant therapy is used in resected CCA. The aim of this study is to analyze our institution’s outcomes for peri-operative treatment of resected intrahepatic and extrahepatic CCA. Methods: We retrospectively analyzed 145 intrahepatic (iCCA) and 109 extrahepatic (eCCA) CCA patients who underwent resection at the Mayo Clinic, Rochester. The majority of treated patients received adjuvant chemotherapy; however neo-adjuvant and radiation were also included. Results: In stage 1-2 iCCA patients, the HR indicated worse outcomes for time to recurrence and death. For stage 3-4 or node positive disease, outcomes were not significantly different. Those with node unknown/negative disease had significantly worse time to recurrence but not OS. There was a significant difference in stage and treatment modality between these groups (see table). Among eCCA, for any stage and node positive disease, outcomes were not different. In the node unknown/negative group, neither time to recurrence nor OS differed significantly. In controlling for different features in multi-variable analyses, no significant differences were observed (see table). Conclusions: This retrospective study does not show a significant difference in recurrence free or OS for treated patients. The apparent lack of benefit most likely reflects selection bias among treatment groups. Prospective, randomized trials are needed to make sound recommendations in adjuvant treatment for CCA. [Table: see text] [Table: see text]
Did multiagent chemotherapy improve clinical outcomes of advanced pancreatic cancer? A single center experience of 408 cases.
Authors: Nakai Yousuke , Isayama Hiroyuki , Ishigaki Kazunaga , Takahara Naminatsu , Hamada Tsuyoshi , Mizuno Suguru , Kogure Hirofumi , Matsubara Saburo , Yamamoto Natsuyo , Tada Minoru , Koike Kazuhiko
Published: February 2017

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Background: We previously reported the introduction of S-1 improved overall survival (OS) in advanced pancreatic cancer (PC), but in a pooled analysis of 3 RCTs, a combination of gemcitabine and S-1 (GS) improved OS in locally advanced PC (LAPC), but not in metastatic PC (MPC), compared to gemcitabine (Gem) alone. More recently, FOLFIRINOX, a multiagent chemotherapy, is shown to improve OS in MPC. We conducted clinical trials of a combination of Gem, S-1 and leucovorin (GSL) to further enhance antitumor effects. Herein, we retrospectively studied whether these multiagent regimens, GSL & FOLFIRINOX, affected the prognosis of APC, especially MPC. Methods: A total of 408 pts with APC receiving chemotherapy were grouped by treatment era into 3 groups: Group 1 (Years 2001-5: 53 pts prior to S-1 introduction), Group 2(Years 2005-11: 240 pts post S-1 introduction) and Group 3 (2012-14: 115 pts post multiagent treatment introduction), and clinical outcomes were compared. Results: Patient characteristics and protocol are shown in Table 1. Treatment protocol was single in 233, dual 142, and multiagent in 33. Response rate & disease control rate in Groups 1/2/3 were 2/8/17% & 26/67/73%. In LAPC, PFS was 6.2/8.9/7.9 & OS was 13.4/17.2/19.7 months in Groups 1/2/3. Meanwhile, in MPC, PFS was 2.0/3.5/4.8 & OS was 6.7/8.6/9.6 months in Groups 1/2/3. When treatment protocols were compared, in LAPC, PFS & OS were 7.0/11.7/8.8 & 13.6/22.6/22.6 months in singe/dual/multiagent chemotherapy. In MPC, PFS & OS were 3.1/3.5/6.0 & 8.3/8.1/13.7 months in single/dual/multiagent chemotherapy. Conclusions: While the introduction of S-1 led to longer OS in LAPC, recent introduction of multiagent chemotherapy appeared to improve OS in MPC. Whether multiagent chemotherapy would lead to longer OS than dual chemotherapy in LAPC needs further investigation. Table 1. [Table: see text]
Effect of ablative radiotherapy on survival in patients with inoperable intrahepatic cholangiocarcinoma: A dose response analysis.
Authors: Crane Christopher H. , Tao Randa , Bhosale Priya , Javle Milind M. , Shroff Rachna T. , Aloia Thomas A. , Kaseb Ahmed Omar , Koay Eugene Jon , Bishop Andrew Justin , Swanick Cameron Williams , Hong Theodore S. , Das Prajnan , Krishnan Sunil
Published: February 2017

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Background: Advances in radiotherapy (RT) techniques and image guidance (IGRT) have enabled ablative doses to be delivered to large liver tumors. We evaluated the effects of RT dose escalation in the treatment of intrahepatic cholangiocarcinoma (IHCC). Methods: 79 consecutive patients with inoperable IHCC were treated between 2002–2014. Median tumor size 7.9 cm (range 2.2–17 cm), 57% had nodes+ and 20% had metastatic disease. 89% received gemcitabine and cisplatin before RT (35–100 Gy, median 58.05 Gy) for a median biologic equivalent dose (BED) of 80.5 Gy (range 43.75–180 Gy). 57% were treated with concurrent capecitabine. CT on rails IGRT with gating were used to deliver higher doses. Results: Median FU was 33 months (range 11–93 ). Median overall survival rate (OS) after diagnosis was 30 months; 1, 2, and 3-year OS rates were 87%, 61%, 44%. The median duration of local tumor control (LC) was 23 months; 1, 2, and 3-year LC rates were 81%, 45% and 27%. RT dose was the most important prognostic factor. Higher doses correlated with improved LC and OS. The 3-year OS for a BED greater than 80.5 was 73% versus 38% for those receiving lower doses (P =0.017). Similarly, 3-year LC was significantly higher (78% versus 45%, P= 0.04). On multivariate analysis, RT dose was significant for LC (P= 0.004) and OS (P= 0.006). The majority of patients (32/36, 89%) whose cause of death could be determined died from liver failure related to intrahepatic disease progression. Only 4 patients (11%) died from distant metastatic disease. There were no significant treatment related toxicities. Conclusions: Higher doses of RT improve LC and OS in inoperable IHCC. A BED > 80.5 Gy appears to be ablative for large IHCCs. Long term survival rates compare favorably to resection. RT schedules that achieve a BED > 80.5, such as 67.5 Gy in 15 fractions and 75 Gy in 25 fractions, should be used. Solutions for internal organ motion and IGRT are necessary for safe delivery of high doses near bowel. These findings support the use of 67.5 Gy in 15 fractions (BED = 97.88 Gy) in the current phase III NRG-GI001 randomized trial evaluating whether the addition of RT to chemotherapy affects survival for inoperable IHCC patients.
Clinicopathological features and response to platinum-based chemotherapy in pancreatic neuroendocrine carcinoma: A retrospective multicenter study of 70 patients.
Authors: Hijioka Susumu , Hosoda Waki , Matsuo Keitaro , Ueno Makoto , Furukawa Masayuki , Yoshitomi Hideyuki , Kobayashi Noritoshi , Ikeda Masafumi , Ito Tetsuhide , Nakamori Shoji , Ishii Hiroshi , Kodama Yuzo , Morizane Chigusa , Yanagimoto Hiroaki , Yane Kei , Notohara Kenji , Furuse Junji , Yatabe Yasushi , Mizuno Nobumasa ,   Japan pNEC Study Group
Published: February 2017

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Background: The WHO classified pancreatic neuroendocrine Neoplasms (pNEN) in 2010 as G1, G2, and neuroendocrine carcinoma (NEC). However, pNEC is suspected to include heterogeneous disease entities, but is still not fully studied. We aimed to clarify the clinicopathological and molecular characteristics of NECs. Methods: A total of 100 cases clinical data and pathological slides originally diagnosed as NEC by the WHO in 2010(WHO-NEC) were retrospectively collected from 31 institutes. Expert pathologists were reassessed all cases slide using the designed protocol and reclassified as well differentiated NET (NET-G3), small cell NEC(SCNEC), and large cell NEC(LCNEC) by morphological features. Results: Thirty cases were eliminated mostly because acinar cell carcinoma, NET-G2 and malignant tumor not otherwise specified. Remaining 70 cases were subclassified into 21(30%) NET-G3, 31 (44.3%) SCNEC, 18(25.7%) LCNEC. Comparisons of NET-G3 vs. SCNEC vs. LCNEC revealed the following traits: ENETS stageⅣ: 76%, 81% and 78%; median Ki67 LI: 28.5% (15-53), 85 % (50-100) and 70.0 %(22-90); abnormal Rb expression: 0 %, 59% and 47%; KRAS mutations: 0 %, 48% and 50%; response rates to platinum-based chemotherapy: 0%, 60% and 44.4% ;and median survival(days): 1255, 340 and 196, respectively. When KRAS divided wild (n = 20) and KRAS mutation group (n = 42), response rate to platinum-based chemotherapy was 77% vs 23%.In the same manner, when Rb immune stain divided negative (n = 24) and positive (N = 41), response rate to platinum-based chemotherapy was 80% vs 23.8%. Besides response rate to platinum-based chemotherapy of KRAS mutation(+) and Rb immunopositivity(-) group (n = 7) were 100%, on the other hand, KRAS mutation(-) and Rb immunopositivity(+) group (n = 7) were 18.7%. Conclusions: In this retrospective study, WHO-NEC include 30% NET-G3. NET-G3 are genetically different from SCNEC and LCNEC. As for chemotherapy,Mutated KRAS and/or Rb immunonegativity in tumors with pNEC is associated with response to platinum-based chemotherapy.
Aggressive surgery for advanced colorectal liver metastases in the era of multidisciplinary approaches.
Authors: Mise Yoshihiro , Inoue Yosuke , Ishizawa Takeaki , Takahashi Yu , Saiura Akio
Published: February 2017

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Background: The number of colorectal liver metastases (CLM) is accepted as a strong predictor of survival after surgery. However, recent advances in multidisciplinary approaches have dramatically changed surgical outcomes of CLM. Clinical implications of aggressive surgery for advanced CLM need to be reviewed in relation to the trend in treatment strategies. Methods: We reviewed 581 patients who underwent curative hepatectomy for CLM from 1999 to 2012. One hundred and eighty-nine patients underwent surgery for advanced CLM (n ≥ 4) and were classified according to year of surgery (first: 1999–2003 [n = 30]; second: 2004–2008 [n = 82]; and third: 2009–2012 [n= 77]). The frequency of perioperative chemotherapy for CLM, preoperative gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI), and contrast-enhanced intraoperative ultrasonography (CE-IOUS), and long-term outcomes were compared among the three periods. Results: The frequency of perioperative chemotherapy, EOB-MRI, and CE-IOUS increased with time (P <.001). The 3-/5-year overall survival in the third period (58.7/51.8%) was similar to that in the second period (59.8/43.9%, P =.828) and that of 72 patients who had 1–3 CLM in the first period (70.8/51.0%, P =.991). Advanced CLM was an independent factor in the first (P =.001, hazard ratio: 2.91) and second (P=.040, hazard ratio: 1.56) periods. However, multivariate analysis revealed that advanced CLM was not a predictive factor of overall survival in the third period. Conclusions: The prognostic impact of advanced CLM diminished owing to evolution in multidisciplinary treatment. Aggressive surgery for advanced CLM offers favorable prognosis similar to that of patients with few CLM in the early period.
The role of adjuvant therapy after R0 resection for patients with intrahepatic and perihilar cholangiocarcinoma.
Authors: Kim Young Saing , Park Inkeun , Oh Sung Yong , Go Se-Il , Kang Jung Hun , Song Haa-na , Park Joon Oh , Ji Jun Ho , Hwang In Gyu , Jang JoungSoon
Published: February 2017

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Background: There is still debated regarding the optimal treatment strategy in cholangiocarcinoma (CC) after curative resection. The aim of this study was to analyze the role of adjuvant therapy in R0-resected intrahepatic and perihilar CC. Methods: We retrospectively reviewed the medical records of patients who underwent R0 resection for intrahepatic and perihilar CC between January 2001 and December 2013 at six cancer centers. Adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of our study were recurrence-free survival (RFS) and overall survival (OS). Multivariable Cox proportional hazards model was used to identify prognostic factors for survival. Results: A total of 137 patients were included in the analysis; 58.4% of patients had intrahepatic CC and 25.5% had lymph node involvement. Seventy-three patients (53.3%) received adjuvant therapy (CT/CRT/RT: 48/13/12, respectively). A greater percentage of patients receiving adjuvant therapy had stage III-IVA (P = 0.010), high histologic grade (P = 0.035), and positive lymph nodes (P = 0.088). Multivariable analysis identified positive nodes (hazard ratio (HR), 3.60; P < 0.001), poor tumor differentiation (HR, 2.35, P = 0.048), and high baseline CA 19-9 level (HR, 1.97; P = 0.013) as predictors of decreased OS. The effect of adjuvant therapy varied according to the treatment modality. Adjuvant CRT was significantly associated with longer RFS (HR, 0.44; P = 0.036) but OS benefit was non-significant HR, 0.56; P = 0.245). In node-positive patients, CRT had a trend for longer OS (HR, 0.24; P = 0.097). In contrast, CT did not improve RFS (HR, 1.13; P = 0.617) or OS (HR, 1.70; P = 0.114). RT alone was associated shorter RFS (HR 3.08; P = 0.009) and OS (HR, 6.86, P < 0.001). Conclusions: Adjuvant CT and RT were not associated with a survival advantage in R0-resected intrahepatic and perihilar CC. CRT appears to be appropriate treatment after complete resection especially in lymph node-positive patients.
Randomized clinical trial of the effect of simo decoction plus acupuncture and chewing gum on postoperative ileus in patients with hepatocellular carcinoma after hepatic resection.
Authors: Zhong Jian-Hong , You Xue-Mei , Ma Liang , Li Le-Qun
Published: February 2017

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Background: Postoperative ileus (POI) is a common complication following hepatic resection that delays recovery of bowel function and increases length of hospital stay. Simo decoction (SMD) and acupuncture tsusanli acupoint are used to enhance bowel hypomotility in China. Chewing gum reducing POI is reported. The aim of study is to evaluate the effect of SMD plus acupuncture tsusanli acupoint and chewing gum alone on POI and length of hospital stay in patients with hepatocellular carcinoma (HCC) after hepatic resection. Methods: Primary HCC patients undergoing hepatic resection were randomized to SMD plus acupuncture, chewing gum, or empty control group. Interventions were started on postoperative day 1 for six consecutive days or until flatus. Primary endpoints were POI and length of hospital stay. Secondary endpoints were surgical complications. Results: Between March 2015 and August 2015, 162 patients were randomized to SMD plus acupuncture (55), chewing gum (53), or empty control (54). SMD plus acupuncture or chewing gum group have significantly shorter first peristalsis, flatus, and defaecation time than empty control group (all P< 0.05). The mean (s.d.) length of hospital stay of the three groups was 14.0 (4.9), 14.7 (6.2), and 16.5 (6.8) days. The difference between SMD plus acupuncture and empty control group was significant (P = 0.014). However, chewing gum cannot significantly shorten hospital stay than empty control (P = 0.147). Interventions groups had less grade I and II complications. Conclusions: SMD plus acupuncture or chewing gum is a safe treatment to reduce POI and shorten hospital stay. Registration number: NCT02438436 (https://clinicaltrials.gov). Clinical trial information: NCT02438436.
Efficacy of chemotherapy in patients with pancreatic acinar cell carcinoma.
Authors: Yoo Changhoon , Kim Bumjun , Kim Kyu-Pyo , Lee Jae-Lyun , Kim Tae Won , Ryoo Baek-Yeol , Chang Heung-Moon
Published: February 2017

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Background: Pancreatic acinar cell carcinoma (ACC) is a rare cancer of the exocrine pancreas. Because of its rare incidence, efficacy of chemotherapy in this patient population still remains largely unknown. Therefore, we retrospectively analyzed the outcomes of patients with pancreatic ACC who received chemotherapy. Methods: Between January 1997 and March 2015, a total of 22 patients with histologically confirmed locally advanced unresectable or metastatic pancreatic ACC were identified in Asan Medical Center, Seoul, Korea. Among them, 15 patients received chemotherapy and 2 patients with locally advanced disease underwent concurrent chemoradiotherapy followed by chemotherapy; these 17 patients were included in this analysis. Results: Median age was 58 year old (range, 29-72), and 15 patients (88%) were male. Mixed acinar-neuroendocrine tumor and mixed acinar-adenocarcinoma was found in 1 (6%) and 2 (12%) patients, respectively. The most common metastatic site was liver (n = 9, 53%), followed by intraabdominal lymph nodes (n = 5, 29%), and peritoneum (n = 3, 18%). As 1st-line therapy, 5-FU or its derivative were given in 7 patients (41%), gemcitabine in 6 (35%), gemcitabine plus capecitabine in 2 (12%) and FOLFOX in 2 (12%). Objective response rate (ORR) was 30% and median time-to-progression (TTP) was 5.8 months (95% CI, 2.9-8.6). After progression, 2nd-line chemotherapy was given in 9 patients; 5 and 4 patients received FOLFOX and gemcitabine, respectively. On 2nd-line chemotherapy, ORR was 44% and median TTP was 6.3 months (95% CI, 0.3-12.4); patients with FOLFOX had significantly better TTP compared to those with gemcitabine (median 6.5 vs 1.4 months, p = 0.003). The ratio of TTP at 1st-line chemotherapy to TTP at 2nd-line chemotherapy was significantly higher in patients with FOLFOX (2.10 [range, 0.16-8.30] compared to those with gemcitabine (0.12 [0.08-0.25]; p = 0.03). Median overall survival in all patients was 16.9 months (95% CI, 14.4-19.4). Conclusions: Pancreatic ACC seems to have better prognosis compared to pancreatic adenocarcinoma. Our results suggest that oxaliplatin-containing regimen may have improved activity against pancreatic ACC.
Peri-operative modified FOLFIRINOX (mFOLFIRINOX) in resectable pancreatic cancer (PDAC): A pilot study.
Authors: Marsh Robert de Wilton , Baker Marshall , Catenacci Daniel V.T. , Kozloff Mark , Polite Blase N. , Posner Mitchell C. , Roggin Kevin K. , Talamonti Mark S. , Kindler Hedy Lee
Published: February 2017

312

Background: Surgical resection plus adjuvant gemcitabine or 5-FU is standard therapy for resectable PDAC. Infusional 5-FU, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) has substantial activity in metastatic PDAC. Efficacy and tolerability of peri-operative FOLFIRINOX in resectable PDAC is unknown. Methods: Patients (pts) with ECOG PS 0/1 and resectable PDAC confirmed by multidisciplinary review received 4 cycles of mFOLFIRINOX (mFFX)(oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 day 1, 5-FU 2400 mg/m2 x 48 hours, peg-filgrastim 6 mg SQ day 3) pre- and 4 cycles post- surgery. Results: 21/21 enrolled pts started therapy (median age: 63 (47-78), 81% ECOG 0). 20/21 pts completed 4 cycles of preoperative mFFX (1 withdrew for toxicity), 17/21 pts had successful surgical resection (3 had disease noted in the liver at surgery) and 14/21 completed 4 cycles of postoperative mFFX (2 pts expired prior to postoperative mFFX within 90 days of surgery -1 from an M.I. and 1 from a GI bleed; 1 pt had excessive toxicity after cycle 5). Radiographic response by RECIST following preoperative therapy was 1 CR, 3 PR, 16 SD, 0 PD. Of the 17 (81%) patients undergoing curative-intent surgery, 16/17 (94%) had R0 resections. Treatment effect was seen in 10/17 specimens with 1 pathologic CR. Doses were modified per protocol in 30% pts preoperatively (neuropathy 1; thrombocytopenia 2; neutropenia 3; diarrhea 2) and 26% postoperatively (neuropathy 3; diarrhea 3; allergic reaction 1). Grade III and IV adverse events were observed in 23% and 14% pts (overlapping) in the preoperative, and 26% and 0.06% pts in the postoperative phases. 18 pts are alive with a median follow up of 17.3 months. Conclusions: 17/21 (81%) pts completed neoadjuvant mFFX and surgical resection. 14/21 (66%) pts completed all planned therapy. Radiographic responses were rare but efficacy is suggested by the high R0 resection rate: 16/17 (94%) in pts undergoing resection, and 16/21 (76%) pts overall. Toxicity was manageable and within the expected range. 8 cycles of mFFX is a feasible and tolerable peri-operative regimen in pts with resectable PDAC and ECOG PS 0/1. Definitive assessment of efficacy will require longer follow up and larger studies. Clinical trial information: NCT01660711.
Perioperative decrement of factor XIII as a predictor of anastomotic leakage after esophagectomy in patients with esophageal cancer.
Authors: Takeuchi Hiroya , Inoue Masazumi , Matsuda Satoru , Fukuda Kazumasa , Nakamura Rieko , Takahashi Tsunehiro , Wada Norihito , Kawakubo Hirofumi , Kitagawa Yuko
Published: February 2017

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Background: Factor XIII(F13), or fibrin stabilizing factor, is involved in the last stage of blood coagulation. Although F13 is also known to be activated in wound healing after surgery, the association between F13 levels and postoperative complications after surgery remains unknown. In this study, we hypothesized that the F13 levels during perioperative periods may be related to the postoperative complications after esophagectomy in patients with esophageal cancer. Methods: A prospective study has been conducted for patients with esophageal cancer at our institution (UMIN000011658). Preoperative and postoperative (1st, 3rd, 5th, and 7th postoperative days) F13 levels were examined in 73 patients with primary esophageal cancer who underwent transthoracic esophagectomy. We investigated the association of F13 levels with clinicopathological background factors and the postoperative complications after esophagectomy. Results: The average age of the patients who underwent esophagectomy was 64.8 years, and 66 patients (90%) were males. Major postoperative complications included anastomotic leakage (C-D grade ≥ I: 19%), and pneumonia (C-D grade ≥ I: 34%). F13 level in preoperative esophageal cancer patients ranged from 36 to 155% (median 102%). In general, F13 levels markedly decreased after esophagectomy and gradually recovered after the 5th postoperative day. Preoperative and postoperative F13 levels at each point did not correlate with occurrence of any postoperative complications. However, the patients with 35% or more reduction of F13 level in the 1st postoperative day compared to the preoperative F13 level significantly correlated with higher incidence of anastomotic leakage. The incidence of anastomotic leakage of the patients with F13 change≥35% was 27% while that of the patients with F13 change<35% was only 4% (p = 0.013). Conclusions: This study revealed that perioperative decrement of factor XIII may be a promising predictor of anastomotic leakage after esophagectomy in patients with esophageal cancer.
Stereotactic body radiotherapy for unresectable hepatocellular carcinoma: A population based analysis of tumors up to 15 cm.
Authors: Yeung Rosanna , Rackley Thomas , Weber Britta , Lee Richard , Camborde Marie-Laure , Pearson Moira , Duzenli Cheryl , Loewen Shaun , Liu Mitchell , Ma Roy , Schellenberg Devin
Published: February 2017

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Background: Stereotactic body radiotherapy (SBRT) has an emerging role for patients with hepatocellular (HCC). The purpose of this study is to describe the efficacy of HCC SBRT at a population level without any tumor size restriction. Methods: A retrospective study of the first 49 HCC patients treated with SBRT between March 2011-July 2015 at the British Columbia Cancer Agency was conducted. All patients were either ineligible for or failed standard local therapies (partial hepatectomy, radiofrequency ablation, percutaneous ethanol injection, transarterial chemoembolization, or radioembolization) and discussed in a multidisciplinary rounds setting. Local control (LC), progression free survival (PFS) (defined as freedom from failure elsewhere in the liver) and overall survival (OS) were analyzed at 1 and 2 years. Changes to Child’s Pugh (CP) score at 3 months post-SBRT were also analyzed. Results: Median follow-up was 14 months with 35 patients (71%) alive at last follow-up. Fifty-two separate HCC lesions were treated with a median size of 4.2 cm (range: 1.3-15.6 cm) and a planning treatment volume (PTV) of 114 cm3 (range: 22-1776 cm3). Over half of the lesions (55%) were ≥ 4cm. Thirty-six patients (74%) had previous local therapies. Prior to SBRT, 57% of patients were CP A5, 33% were CP B6, 8% were CP B7, and 1 patient (2%) was CP B8. At 3 months post-SBRT, 35% of patients had an increased CP score, with a mean increase of 1.8 points. The most common dose and fractionation was 45Gy in 3 or 5 fractions. Median V90 (dose to 90% of the PTV) was 99.8% (range: 74.1-100%). LC for all patients was 96% at 1 and 2 years. LC was comparable between moderate to large tumors ( ≥ 4cm) and those < 4cm (1 and 2 year LC: 96% for ≥ 4cm vs 95% for < 4cm). OS for all patients at 1 year was 67% and 62% at 2 years. PFS was 53% and 38% at 1 and 2 years respectively. The median PFS was 13.7 months with 13 patients (27%) undergoing further local treatment due to regional progression including 4 patients who had liver transplants. Conclusions: SBRT provides high local control for patients with HCC of even moderate to large size. Regional progression is prominent in HCC patients and SBRT does not appear to preclude further local treatments.