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Abstract Background The randomized, dose-optimization, open-label ReDOS study in US patients with metastatic colorectal cancer (CRC) showed that, compared with a standard dosing approach, initiating regorafenib at 80 mg/day and escalating to 160 mg/day depending on tolerability increased the proportion of patients reaching their third treatment cycle and reduced the incidence of adverse events without compromising efficacy. Subsequently, the ReDOS dose-escalation strategy was included as an alternative regorafenib dosing option in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. A retrospective analysis was conducted using a US claims database to assess whether inclusion of this dose-escalation strategy in NCCN Guidelines has influenced the use of flexible dosing in routine US clinical practice, and to describe clinical outcomes pre- and post-inclusion in NCCN Guidelines. Methods Patients with CRC in the Optum’s de-identified Clinformatics® Data Mart database initiating regorafenib for the first time between January 2016 and June 2020 were stratified based on whether they initiated regorafenib pre- or post-inclusion of ReDOS in NCCN Guidelines, and in two groups: flexible dosing (

Aim: The objective of this study was to compare adverse event (AE) management costs for fruquintinib, regorafenib, trifluridine/tipiracil (T/T) and trifluridine/tipiracil+bevacizumab (T/T+bev) for patients with metastatic colorectal cancer (mCRC) previously treated with at least two prior lines of therapy from the US commercial and Medicare payer perspectives. Materials & methods: A cost-consequence model was developed to calculate the per-patient and per-patient-per-month (PPPM) AE costs using rates of grade 3/4 AEs with incidence ≥5% in clinical trials, event-specific management costs and duration treatment. Anchored comparisons of AE costs were calculated using a difference-in-differences approach with best supportive care (BSC) as a common reference. AE rates and treatment duration were obtained from clinical trials: FRESCO and FRESCO-2 (fruquintinib), RECOURSE (T/T), CORRECT (regorafenib) and SUNLIGHT (T/T, T/T+bev). AE management costs for the commercial and Medicare perspectives were obtained from publicly available sources. Results: From the commercial perspective, the AE costs (presented as perpatient, PPPM) were: $4015, $1091 for fruquintinib (FRESCO); $4253, $1390 for fruquintinib (FRESCO-2); $17,110, $11,104 for T/T (RECOURSE); $9851, $4691 for T/T (SUNLIGHT); $8199, $4823 for regorafenib; and $11,620, $2324 for T/T+bev. These results were consistent in anchored comparisons: the differencein-difference for fruquintinib based on FRESCO was -$1929 versus regorafenib and -$11,427 versus T/T; for fruquintinib based on FRESCO-2 was -$2257 versus regorafenib and -$11,756 versus T/T. Across all analyses, results were consistent from theMedicare perspective. Conclusion: Fruquintinib was associated with lower AE management costs compared with regorafenib, T/T and T/T+bev for patients with previously treated mCRC. This evidence has direct implications for treatment, formulary and pathways decision-making in this patient population.

Abstract Background Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). Methods/design INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator’s choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. Discussion INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. Trial registration INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

Summary: Background: Compared with normal cells, tumour cells contain elevated levels of reactive oxygen species (ROS). Increased levels of the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) correlate negatively with the survival of patients with pancreatic cancer. Napabucasin is an investigational, orally administered ROS generator bioactivated by NQO1. Methods: In the open-label, phase 3 CanStem111P study (NCT02993731), adults with previously untreated metastatic pancreatic adenocarcinoma (mPDAC) were randomised (1:1) to napabucasin plus nab-paclitaxel with gemcitabine or nab-paclitaxel with gemcitabine alone. The primary endpoint was overall survival (OS). In exploratory analyses, OS was evaluated in the subgroup of patients with tumours positive for pSTAT3 (biomarker-positive). Findings: Between 30 January 2017 and 20 February 2019, a total of 1779 patients were screened across 165 study sites in Austria, Australia, Belgium, Canada, China, Czech Republic, France, Germany, Italy, Japan, Korea, Netherlands, Poland, Portugal, Russia, Singapore, Spain, Taiwan, Ukraine, and the US. Of the 565 and 569 patients randomised to the napabucasin and control treatment arms, respectively, 206 and 176 were biomarker-positive. Median (95% confidence interval [CI]) OS in the napabucasin and control treatment arms was 11.4 (10.5–12.2) and 11.7 (10.7–12.7) months, respectively (hazard ratio, 1.07; 95% CI, 0.93–1.23). Due to the lack of OS improvement in the napabucasin arm, CanStem111P was terminated due to futility. In the biomarker-positive subgroup, no difference between treatment arms was found for OS. Grade ≥3 adverse events were reported in 85.4% and 83.9% of napabucasin-treated and control-treated patients, respectively. The incidence of gastrointestinal-related grade ≥3 events was higher with napabucasin (diarrhoea: 11.6% vs 4.9%; abdominal pain: 10.0% vs 4.8%). Interpretation: Our findings suggested that although the addition of napabucasin to nab-paclitaxel with gemcitabine did not improve efficacy in patients with previously untreated mPDAC, the safety profile of napabucasin was consistent with previous reports. CanStem111P represents the largest cohort of patients with mPDAC administered nab-paclitaxel with gemcitabine in the clinical trial setting. Our data reinforce the value of nab-paclitaxel plus gemcitabine as a platform for novel therapeutics approaches in mPDAC. Funding: The Sumitomo Pharma Oncology, Inc.

Abstract Liposomal irinotecan is a liposomal formulation of irinotecan, which prolongs circulation of irinotecan and its active metabolite SN‐38. A population pharmacokinetic (PK) model was developed based on data from seven studies (N = 440). Adequacy of the model was assessed using multiple methods, including visual predictive check. Associations between PK exposure and the incidence of diarrhea (grade ≥3) and neutropenia adverse events (AEs) (grade ≥3) at first event in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) were investigated using logistic regression based on data from two studies (the phase III NAPOLI‐1 [N = 260] and phase I/II NCT02551991 [N = 56] trials). The PKs of total irinotecan was described by a two‐compartment model with first‐order elimination, with SN‐38 formed directly by a first‐order constant from the central compartment of irinotecan or after using a transit compartment. Clearance was 17.9 L/week (0.107 L/h) and 19,800 L/week (118 L/h) for total irinotecan and SN‐38, respectively. The UGT1A1*28 7/7 homozygous genotype had no significant impact on SN‐38 clearance. Model evaluation was satisfactory for both irinotecan and SN‐38. The incidence of diarrhea (grade ≥3) at first event was significantly higher with increasing average concentrations of total irinotecan and SN‐38; there was no significant association between an increased risk of neutropenia AEs (grade ≥3) at first event and average SN‐38 concentrations. In summary, the PKs of total irinotecan and SN‐38 after administration of liposomal irinotecan were well‐described by the model. The UGT1A1*28 status had no significant impact on the PKs of liposomal irinotecan.

Objectives Female physicians in medicine are increasing, but disparities in female authorship exist. The aim of this study was to characterise factors associated with female first (FF) and female senior (SF) authorship in later phase systemic oncological clinical trials in biliary tract cancer (BTC) and identify any changes over time.Setting Embase/Medline identified trial publications in BTC (2000–2020) were included. χ2 tests and log regression were used (assessed factors associated with FF and SF authorship, including changes over time (STATA V.16)).Primary outcome measure FF and SF authorship in later phase systemic oncological clinical trials in BTC.Secondary outcome measure Any changes over time?Results Of 501 publications, 163 met inclusion criteria. The median percentage of female author representation in publications was 25%; there were no female authors in 13% of publications. Geographic location of the home institution of the first and senior authors was Asia (42%/42%), Europe (29%/29%), USA (24%/22%) and other (4%/6%), respectively. Overall, FF and SF author representation was 20% and 10%, respectively. The median position of the first female author was second in all the publication author lists. The phase of trial, journal-impact factor, industry funding or whether the study met its primary endpoint did not impact FF/SF author representation. More SF authors had home institutions in ‘other’ geographic locations (40% in 10 trials) (p=0.02) versus Asia (6%), Europe (8%) and USA (14%). There were no significant changes in FF/SF representation over time (p=0.61 and p=0.33 respectively).Conclusions FF and SF author representation in later phase systemic clinical trial publications in BTC is low and has not changed significantly over time. The underlying reasons for this imbalance need to be better understood and addressed.

Biliary tract cancers are a diverse and aggressive malignancy that carry a poor chance for curative treatment and significant associated mortality. Current first-line treatment only extends median overall survival to roughly 1 year and is associated with a significant adverse event profile. Recently, advancements in genetic sequencing have opened new avenues of targeted treatment. In cholangiocarcinoma, FGFR2 alterations have been shown to be present in roughly 10–15% of intrahepatic cholangiocarcinoma. Pemigatinib, a FGFR1–4 inhibitor, has been shown to significantly extend survival in the second-line setting to over 20 months in patients who harbor FGFR2 fusions. Here, we outline the development and future direction of pemigatinib and other FGFR2 inhibitors in the field of advanced biliary tract cancers.

Abstract DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression. Comprehensive genomic profiling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classified patients into 3 groups based on TMB level: low (

Abstract No approved therapy exists for cancer‐associated cachexia. The colon‐26 mouse model of cancer cachexia mimics recent late‐stage clinical failures of anabolic anti‐cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx‐024. The histone deacetylase inhibitor (HDACi) AR‐42 exhibited anti‐cachectic activity in this model. We explored combined SARM/AR‐42 therapy as an improved anti‐cachectic treatment paradigm. A reduced dose of AR‐42 provided limited anti‐cachectic benefits, but, in combination with GTx‐024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR‐42 suppressed the IL‐6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx‐024‐mediated β‐catenin target gene regulation was apparent in cachectic mice only when combined with AR‐42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx‐024 therapy and a blockade of GTx‐024‐mediated anabolic signaling. AR‐42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx‐024. Combining GTx‐024, a clinically established anabolic therapy, with AR‐42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making.

Therapeutic blockade of PD-1/PD-L1 signaling with monoclonal antibodies (mAbs) has shown clinical success and activity across a broad set of cancer subtypes. However, monotherapy with PD-1/PD-L1 inhibitors are only effective in a subset of patients and ongoing studies show efficacy of treatment depends on a combinatorial approach. Contrary to mAbs chimeric B-cell cancer vaccines incorporating a “promiscuous” T-cell epitope have the advantage of producing a polyclonal B-cell antibody that can potentially induce memory B- and T-cell responses, while reducing immune evasion and suppression. Here, we describe a novel PD-1 B-cell peptide epitope vaccine (amino acid 92–110; PD1-Vaxx) linked to a measles virus fusion peptide (MVF) amino acid 288–302 via a four amino acid residue (GPSL) emulsified in Montanide ISA 720VG that aims to induce the production of polyclonal antibodies that block PD-1 signaling and thus trigger anticancer effects similar to nivolumab. In preclinical studies, the PD1-Vaxx outperformed the standard anti-mouse PD-1 antibody (mAb 29F.1A12) in a mouse model of human HER-2 expressing colon carcinoma. Furthermore, the combination of PD1-Vaxx with combo HER-2 peptide vaccine (B-Vaxx) showed enhanced inhibition of tumor growth in colon carcinoma BALB/c model challenged with CT26/HER-2 cells. The PD-1 or combined vaccines were safe with no evidence of toxicity or autoimmunity.

Purpose: Intensity modulated radiation therapy (IMRT) has been rapidly incorporated into clinical practice because of its technological advantages over 3-dimensional conformal radiation therapy (CRT). We characterized trends in IMRT utilization in trimodality treatment of locally advanced rectal cancer at National Comprehensive Cancer Network cancer centers between 2005 and 2011. Methods and materials: Using the prospective National Comprehensive Cancer Network Colorectal Cancer Database, we determined treatment patterns for 976 patients with stage II-III rectal cancer who received pelvic radiation therapy at contributing centers between 2005 and 2011. Multivariable logistic regression was used to identify factors associated with IMRT versus 3-dimensional CRT. Radiation therapy compliance and time to completion were used to compare acute toxicity. Results: A total of 947 patients (97%) received 3-dimensional CRT (80%) or IMRT (17%). Ninety-eight percent of these patients received radiation therapy preoperatively, and 81% underwent definitive resection. IMRT use increased from 30% in 2010 and thereafter, with significant variability among institutions (range, 0%-43%). Other factors associated with IMRT use included age ≥65 years, dose >50.4 Gy, African-American race, and no transabdominal surgery. Rates of and time to radiation therapy completion were similar between the groups. Conclusions: Although most patients with stage II-III rectal cancer at queried National Cancer Institute–designated cancer centers between 2005 and 2011 received 3-dimensional CRT, significant and increasing numbers received IMRT. IMRT utilization is highly variable among institutions and not uniform among sociodemographic groups but may be more consistently embraced in specific clinical settings. Given this trend, comparative-effectiveness research is needed to evaluate the benefits of IMRT for rectal cancer.

Lynch syndrome is characterized by predisposition to colorectal cancer and mutations in genes involved in mismatch repair. Here, the authors use whole genome sequencing and immunohistochemistry of mismatch repair proteins to show a high prevalence of Lynch syndrome in the Icelandic population.

Abstract Background Outcomes in younger (

Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, potency and safety. Specifically, we postulate that novel combination treatments targeting members of the EGFR family and IGF-1R will yield significant anti-tumor effects in in vitro models of EC and TNBC possibly overcoming mechanisms of resistance. We show that the combination of HER-1 and HER-2 or HER-1 and IGF-1R peptide mimics/vaccine antibodies exhibited enhanced antitumor properties with significant inhibition of tumorigenesis in OE19 EC and MDA-MB-231 TNBC cell lines. Our work elucidates the mechanisms of HER-1/IGF-1R and HER-1/HER-2 signaling in these cancer cell lines, and the promising results support the rationale for dual targeting with HER-1 and HER-2 or IGF-1R as an improved treatment regimen for advanced therapy tailored to difference types of cancer.

Background: Treatment with nab-paclitaxel with gemcitabine demonstrates a survival advantage when compared with single-agent gemcitabine. However, the combination is associated with significant toxicities, leading to a high rate of drug discontinuation. We implemented a modified regimen of gemcitabine and nab-paclitaxel (mGNabP) in an attempt to minimize toxicities while maintaining efficacy. Methods: A total of 79 evaluable patients with metastatic pancreatic adenocarcinoma (mPC) treated with a modified regimen of gemcitabine (1000 mg/m 2 ) and nab-paclitaxel (125 mg/m 2 ) on days 1, 15 of every 28-day cycle were identified from our prospective database. A total of 57 patients received this regimen as first-line treatment and were evaluated for toxicities, progression-free survival (PFS), and overall survival (OS). Overall, 22 patients with advanced or metastatic PC treated with the modified regimen outside the first-line setting were only evaluated for toxicities. Results: The median OS and PFS were 10 months [95% confidence interval (CI) 5.9–13 months] and 5.4 months (95% CI 4.1–7.4 months) for patients that received the modified regimen as first-line therapy. Neurotoxicity occurred in 27% with only 1.6% of patients experiencing grade ⩾3 toxicity. The incidence of grade ⩾3 neutropenia was 19%, resulting in growth factor support in 12% of patients. This rate was similar in patients who received the modified regimen for first-line treatment of mPC versus the overall group. Conclusions: A modified regimen of biweekly nab-paclitaxel with gemcitabine is associated with a lower cost, acceptable toxicity profile and appears to be relatively effective in pancreatic cancer. Prospective randomized studies confirming its potential benefits compared with standard weekly mGNabP are warranted.

Cancer stem cells (CSCs) are thought to be a distinct population of cells within a tumor mass that are capable of asymmetric division and known to have chemoresistant characteristics. The description and identification of CSC models in cancer growth and recurrence has inspired the design of novel treatment strategies to overcome treatment resistance by targeting both CSCs and non-CSC tumor cells. Several cellular signaling pathways have been described as playing a role in the induction and maintenance of stemness in CSCs, such as the Wnt/β-catenin, Notch, STAT3, and Hedgehog pathways. In this review, we aim to review some of the ongoing CSC therapeutic targeting strategies in gastrointestinal malignancies.

Genotype, particularly Ras status, greatly affects prognosis and treatment of liver metastasis in colon cancer patients. This pilot aimed to apply word frequency analysis and a naive Bayes classifier on radiology reports to extract distinguishing imaging descriptors of wild-type colon cancer patients and those with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. In this institutional-review-board-approved study, we compiled a SNaPshot mutation analysis dataset from 457 colon adenocarcinoma patients. From this cohort of patients, we analyzed radiology reports of 299 patients (> 32,000 reports) who either were wild-type (147 patients) or had a KRAS (152 patients) mutation. Our algorithm determined word frequency within the wild-type and mutant radiology reports and used a naive Bayes classifier to determine the probability of a given word belonging to either group. The classifier determined that words with a greater than 50% chance of being in the KRAS mutation group and which had the highest absolute probability difference compared to the wild-type group included: “several”, “innumerable”, “confluent”, and “numerous” (p < 0.01). In contrast, words with a greater than 50% chance of being in the wild type group and with the highest absolute probability difference included: “few”, “discrete”, and “[no] recurrent” (p = 0.03). Words used in radiology reports, which have direct implications on disease course, tumor burden, and therapy, appear with differing frequency in patients with KRAS mutations versus wild-type colon adenocarcinoma. Moreover, likely characteristic imaging traits of mutant tumors make probabilistic word analysis useful in identifying unique characteristics and disease course, with applications ranging from radiology and pathology reports to clinical notes.

Oncolytic virotherapy represents a novel therapeutic strategy in the treatment of gastrointestinal malignancies. Oncolytic viruses, including genetically engineered and naturally occurring viruses, can selectively replicate in and induce tumor cell apoptosis without harming normal tissues, thus offering a promising tool in the armamentarium for cancer therapy. While this approach has garnered much interest over the past several decades, there has not been significant headway across various tumor types. The recent approval of talimogene laherparepvec, a second-generation oncolytic herpes simplex virus type-1, for the treatment of metastatic melanoma, confirms the therapeutic potential of oncolytic viral therapy. Herein, we will highlight and review the role of oncolytic viral therapy in gastrointestinal malignancies while discussing its limitations and potential alternative mechanisms to improve its treatment efficacy.

Angiogenesis is a tightly regulated process that is mediated by a group of angiogenic factors such as vascular endothelial growth factor and its receptors. Given the widespread use of antiangiogenic agents, there has been considerable interest in developing methods to identify subgroups of patients who would preferentially benefit from those treatments. The overlap between the various angiogenic factors, vascular endothelial growth factor, and its multiple isoforms or splice variants presents a significant challenge to assessing the consequences of activation or inhibition of the angiogenesis pathway and thus represent a challenge to biomarker discovery. Multiple biomarkers are in various phases of development and include tissue and serum biomarkers, as well as novel imaging techniques. Patient selection for angiogenesis inhibitors, however, continues to depend mostly on risk-factor assessment as it relates to their anticipated side-effect profile. In this review we discuss the state of biomarker discovery for agents that target the angiogenesis pathway, with a main focus on currently approved therapies. [ABSTRACT FROM AUTHOR]

Purpose: Phase II multicenter study investigated the efficacy and toxicity of the novel halogenated derivative of sulfaquixonaline Chloroquinoxaline Sulfonamide (CQS) in metastatic colorectal cancer. Experimental design: Eligible patients with metastatic or recurrent colorectal cancer received CQS at a dose schedule of 2000 mg/m2 over an hour weekly for 4 weeks every 42 days. Treatment was continued until unexpected toxicity or disease progression. Results: A total of seventeen patients were enrolled on this study. 94% of all patients enrolled had prior treatment. Sixteen patients were evaluable for response with fifteen patients showing evidence of disease progression and one patient with prolonged stable disease. One patient had non-evaluable disease. Following this interim analysis, the drug was considered ineffective and the study was terminated early. The most frequent adverse event was anemia. No patients discontinued the treatment because of toxicity. Conclusion: CQS, when given at a dose of 2000 mg/m2 weekly for 4 weeks every 42 days to patients with metastatic colorectal cancer, does not result in significant tumor regression. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma is an epithelial malignancy of the intrahepatic or extrahepatic biliary tree, primarily driven by chronic inflammation and fibrosis. Fibrosis has been shown to correlate with malignancy, and the aminotransferase-platelet ratio index (APRI) score, a marker for hepatic fibrosis, has proved useful in prognosticating hepatocellular carcinoma. This study aimed to assess the utility of APRI score in predicting post-surgical outcomes in cholangiocarcinoma patients., Methods: Clinical data from a total of 152 cholangiocarcinoma patients who underwent surgical resection at the Mayo Clinic were collected. The data were subsequently analyzed to determine if there was a relationship between APRI score and the demographic, laboratory, pathologic and outcome data, including overall survival. To determine the relationship between quantitative and qualitative data and the APRI score, a P-value <0.05 was considered as statistically significant., Results: No relationship between APRI score and demographic factors was identified. There were correlations between APRI score and alanine transaminase, albumin and bilirubin, but the remaining laboratory parameters showed no correlation. APRI score did not prove to be useful as a prognostic tool, as it did not correlate with tumor pathology features (tumor grade t -test P=0.86, N stage ANOVA P=0.94, vascular invasion t -test P=0.59, and perineural invasion t -test P=0.14), or with post-surgical recurrence ( t -test P=0.22) and mortality ( t -test P=0.39)., Conclusion: APRI score is not a prognostic tool for post-surgical outcomes in patients with cholangiocarcinoma., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Purpose: FGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown., Patients and Methods: Patients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher's exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis., Results: Three hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/II v III/IV: 35.8% v 22%, respectively; P = .001), and were associated with a longer OS compared with patients without FGFR GAs (37 v 20 months, respectively; P < .001). This difference remained significant after excluding 36 patients treated with FGFR inhibitors. There was no OS difference ( P = .60) between CCA with FGFR2 fusions (n = 63) versus other FGFR GAs (n = 29). Patients with FGFR GAs had a better OS with FGFR-targeted therapy compared with standard treatment ( P = .01). BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 ( P = .04) and CDKN2A/B ( P = .04) were correlated with a shorter OS., Conclusion: CCA with FGFR GAs represents a unique subtype occurring in younger patients with an indolent disease course. FGFR-targeted therapy may have a positive impact on OS in this subgroup.

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

Improvements in screening and preventive measures have led to an increased detection of early stage colorectal cancers (CRC) where patients undergo treatment with a curative intent. Despite these efforts, a high proportion of patients are diagnosed with advanced stage disease that is associated with poor outcomes, as CRC remains one of the leading causes of cancer-related deaths in the world. The development of next generation sequencing and collaborative multi-institutional efforts to characterize the cancer genome has afforded us with a comprehensive assessment of the genomic makeup present in CRC. This knowledge has translated into understanding the prognostic role of various tumor somatic variants in this disease. Additionally, the awareness of the genomic alterations present in CRC has resulted in an improvement in patient outcomes, largely due to better selection of personalized therapies based on an individual's tumor genomic makeup. The benefit of various treatments is often limited, where recent studies assessing the genomic diversity in CRC have identified the development of secondary tumor somatic variants that likely contribute to acquired treatment resistance. These studies have begun to alter the landscape of treatment for CRC that include investigating novel targeted therapies, assessing the role of immunotherapy and prospective, dynamic assessment of changes in tumor genomic alterations that occur during the treatment of CRC.