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Background A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. Patients and methods This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. Results Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). Conclusion In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. Clinical trial number NCT02889978.

Amorphous solid dispersions (ASDs) are used to increase the solubility of oral medicines by kinetically stabilizing the more soluble amorphous phase of an active pharmaceutical ingredient with a suitable amorphous polymer. Low levels of a crystalline material in an ASD can negatively impact the desired dissolution properties of the drug. Characterization techniques such as powder X-ray diffraction (pXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) are often used to detect and measure any crystallinity within ASDs. These techniques are unable to detect or quantify very low levels because they have limits of detection typically in the order of 1–5%. Herein, an ASD of felodipine (FEL) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) prepared via a hot melt extrusion (HME) in a mass ratio of 30:70 was characterized using a range of techniques. No signs of residual crystallinity were found by pXRD, DSC, or FTIR. However, transmission electron microscopy (TEM) did identify two areas containing crystals at the edges of milled particles from a total of 55 examined. Both crystalline areas contained Cl Kα X-ray peaks when measured by energy-dispersive X-ray spectroscopy, confirming the presence of FEL (due to the presence of Cl atoms in FEL and not in PVP/VA). Further analysis was carried out by TEM using conical dark field (DF) imaging of a HME ASD of 50:50 FEL-PVP/VA to provide insights into the recrystallization process that occurs at the edges of particles during accelerated ageing conditions in an atmosphere of 75% relative humidity. Multiple metastable polymorphs of recrystallized FEL could be identified by selected area electron diffraction (SAED), predominately form II and the more stable form I. Conical DF imaging was also successful in spatially resolving and sizing crystals. This work highlights the potential for TEM-based techniques to improve the limit of detection of crystallinity in ASDs, while also providing insights into transformation pathways by identifying the location, size, and form of any crystallization that might occur on storage. This opens up the possibility of providing an enhanced understanding of a drug product’s stability and performance.

89 Background: Combination treatment with regorafenib (80–120 mg/day, PO, 3 wks on/1 wk off) plus nivolumab (480 mg IV Q4W) showed manageable safety but modest efficacy in a phase 2 study of 70 pts from North America with pMMR/MSS chemotherapy-resistant metastatic CRC (mCRC). Five pts had a partial response (PR; objective response rate [ORR]: 7%); all did not have liver metastases at baseline (n = 5/23; ORR: 22%). One pt had a confirmed complete response (CR) after the primary completion analysis of the study (ASCO 2021). This retrospective exploratory analysis investigated the potential association between specific biomarkers and anti-tumor activity, and how those biomarkers are modulated by treatment with regorafenib plus nivolumab. Methods: In formalin-fixed paraffin-embedded tumor samples obtained at baseline and Cycle (C) 2 Day (D) 8, immune-related biomarkers were assessed via immunohistochemistry (IHC), and RNA sequencing was used for gene expression profiling/gene signatures. Pre-/on-treatment blood samples were collected to measure circulating tumor DNA (ctDNA) and soluble biomarkers. Results: A total of 40 and 27 baseline tumor samples and 14 and 5 paired tumor samples at baseline/C2D8 were available for IHC and RNA sequencing, respectively. Higher baseline protein and mRNA expression of biomarkers for pre-existing immune sensitivity (eg, effector T cells) trended with anti-tumor activity. These biomarkers were expressed at lower levels in pts with liver metastases vs those without liver metastases at baseline. Cytotoxic T cell density was elevated on C2D8 but did not correlate with anti-tumor activity. Increased mean variant allelic frequency in ctDNA at C2D1 predominated in pts with progressive disease (PD), while clearance of ctDNA at C2D1 was only noted for the one pt with a CR. High clonal tumor mutational burden in ctDNA showed a numerical trend with anti-tumor activity (PD vs. SD/PR; P=0.058) and PFS (P = 0.072). Baseline serum levels of select markers related to angiogenesis (eg, vascular endothelial growth factor [VEGF] D) were associated with inferior anti-tumor activity (P = 0.002). Serum levels of immune-related soluble biomarkers (eg, tumor necrosis factor alpha) increased on treatment (P < 0.005), while levels of soluble VEGF receptor 2 decreased (P < 0.001). Conclusions: This study of pts with MSS mCRC treated with regorafenib plus nivolumab suggests that baseline tumor biomarkers for pre-existing immune sensitivity trended with anti-tumor activity, whereas select baseline peripheral biomarkers related to angiogenesis trended with inferior anti-tumor activity. Pharmacodynamics effects were observed, yet no significant correlation with anti-tumor activity was found. Due to the small sample size and retrospective nature, these analyses are hypothesis-generating. Clinical trial information: NCT04126733.

Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients ≥18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma, gallbladder or ampullary cancer); randomized (1:1) to NUC-1031 (725 mg/m2)/cisplatin (25 mg/m2) or gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2), on days 1/8, Q21-days. Primary objectives are overall survival and objective response rate. Secondary objectives: progression-free survival, safety, pharmacokinetics, patient-reported quality of life and correlative studies. (Investigational new drug (IND) number: 139058, European Clinical Trials database: EudraCT Number 2019-001025-28, ClinicalTrials.gov identifier: NCT04163900).

During drug development control of polymorphism, particle properties and impurities are critical for ensuring a good quality, reproducible, and safe medicine. A wide variety of analytical techniques are employed in demonstrating the regulators control over the drug substance and product manufacturing, storage, and supply. Transmission electron microscopy (TEM) offers the opportunity to analyze in detail pharmaceutical systems at a length scale and limit of detection not readily achieved by many traditional techniques. However, the use of TEM as a characterization tool for drug development is uncommon due to possible damage caused by the electron beam. This work outlines the development of a model, using molecular descriptors, to predict the electron beam stability of active pharmaceutical ingredients (API). For a given set of conditions and a particular imaging or analytical mode, the total number of electrons per unit area, which causes observable damage to a sample in the TEM, can be defined as the critical fluence ( C

Summary Background Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding Merck & Co, Inc.

INTRODUCTION: Luxeptinib (CG-806) is a potent, non-covalent oral inhibitor of BTK and FLT3. It suppresses BCR signaling pathways (LYN, SYK, BTK, AKT, ERK) and other oncogenic pathways in cell lines and primary CLL cells, kills malignant B-cells insensitive to ibrutinib or venetoclax at low nM concentrations, and shows enhanced activity in combination with venetoclax. Luxeptinib is currently being evaluated in a Phase 1a/b trial in patients with relapsed or refractory B-cell malignancies (NCT03893682). AIMS: Primary objectives are to assess the safety and tolerability of luxeptinib and determine the recommended expansion dose for future clinical trials in patients with R/R CLL/SLL or B-NHL. Key secondary objectives include elucidation of the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and evidence of antitumor activity. METHODS: Luxeptinib is administered continuously as oral capsules BID in 28-day cycles, in ascending cohorts of 3 patients. Treatment emergent adverse events (TEAEs) and tumor responses are evaluated per disease specific guidelines. RESULTS: As of June 7, 2021, a total of 23 patients (median age 64.0 years, 11 CLL/SLL, 4 follicular lymphoma (FL), 1 Richter's transformation lymphoma, 2 Waldenstrom's macroglobulinemia (WM), 2 mantle cell lymphoma, 3 diffuse large B cell lymphoma (DLBCL)) with a median of 3 prior systemic regimens (range of 1 - 12) have been treated with luxeptinib at doses of 150 mg (n=1), 300 mg (n=1), 450 mg (n=9), 600 mg (n=4) and 750 mg (n=8). Drug related grade ≥ 3 TEAEs included neutropenia (n=5, 21.7%), leukocytosis (n=2, 8.7%), decreased white blood cell count, decreased platelet count, anemia, increased alanine aminotransferase, diarrhea, hypertension, and headache (n=1, 4.3 % each). One patient, who experienced progressive hypertension before receiving luxeptinib, developed grade 1 hypertension during screening evolving to grade 2 prior to dosing on C1D1, experienced grade 4 hypertension after luxeptinib treatment at 750 mg BID for 5 days. While this was considered a DLT per protocol, luxeptinib plasma levels in this patient were lower than those observed in patients at this and lower dose levels, and no drug-related hypertension has been observed in any other patient treated to date. The average steady-state (C min) plasma levels of luxeptinib in patients treated with 750 mg BID were > 1µM and were sustained over multiple cycles. PD analysis demonstrated that C min of luxeptinib in the plasma of patients treated with doses of 300 mg or higher significantly reduced levels of phosphorylated BTK, SYK, ERK and FLT3 in EOL-1 reporter cells in a plasma inhibitor activity assay, demonstrating multi-target engagement. Response evaluations were available for 12 patients who had at least one imaging study or IgM measurements (WM patients) after starting treatment. Eight out of these 12 patients had various reductions of lesion size or IgM measurements compared to baseline (3 SLL, 2 FL, 1 CLL, 1 WM and 1 DLBCL), demonstrating anti-tumor activity. FDG PET-CT scans in one FL patient, who had 2 prior regimens, revealed lesion growth during treatment with luxeptinib at 450 mg BID for 7 cycles. After dose-escalation to 600 mg BID in Cycle 8, lesion measurements demonstrated continuous reduction. By C15D1, target lesions decreased by 42.5% and 11.3% when compared with peak tumor size and baseline measurements, respectively. One WM patient in Cohort 5 (750 mg BID), who had 2 prior regimens including ibrutinib, has had a 24.9% reduction in IgM level by C3D1 compared with baseline as her best response so far. CONCLUSIONS: Luxeptinib has a favorable safety profile in patients treated with 150 mg to 600 mg BID over multiple cycles. A single apparent DLT (grade 4 hypertension in one patient with pre-existing hypertension) led to expansion of the 750 mg dose level to 6 patients. Pharmacodynamic studies documented inhibition of SYK, BTK and ERK in the BCR signaling pathway. Anti-tumor activity was observed in multiple B-NHL subtypes and CLL/SLL patients. Enrollment of patients with R/R CLL/SLL and B-NHL at dose level 5 (750 mg) is ongoing and updated clinical data will be presented at the meeting. Disclosures Samaniego: Arog: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees. Burke: AstraZeneca: Consultancy; Verastem: Consultancy; Bristol Myers Squibb: Consultancy; Epizyme: Consultancy; Kura: Consultancy; Kymera: Consultancy; SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy; Beigene: Consultancy, Speakers Bureau; AbbVie: Consultancy; MorphoSys: Consultancy; Roche/Genentech: Consultancy. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Cherry: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sadiq: Dava Oncology: Honoraria. Reid: ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator, Research Funding. Roeker: TG Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company; Pharmacyclics: Consultancy. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Benbatoul: Aptose Biosciences, Inc.: Current Employment. Haney: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Bejar: Astex: Consultancy; Silence Therapeutics: Consultancy; Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Epizyme: Consultancy, Honoraria; Takeda: Research Funding; Gilead: Consultancy, Honoraria; BMS: Consultancy, Research Funding.

3560 Background: The role of immunotherapy in the treatment of pMMR/MSS metastatic CRC is not established. A Japanese phase 1b trial in this setting showed the combination of regorafenib (multikinase inhibitor with immunomodulatory activity) plus nivolumab (anti PD-1) had encouraging activity and manageable safety (Fukuoka, 2020). This study further assessed the safety and efficacy of this combination. Methods: Patients (pts) from the US aged ≥18 years who progressed on/were intolerant to standard chemotherapy were enrolled. Regorafenib was given orally, once daily in 28-day (D) cycles (21D on/7D off) plus IV nivolumab 480 mg on D1. Regorafenib starting dose was 80 mg; if well tolerated, it could be escalated to 120 mg in Cycle 2. Primary endpoint was overall response rate (ORR; RECIST 1.1); secondary aims included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety (NCI-CTCAE v5.0 grade). Biomarker analysis was exploratory. Results: 70 pts (59% male) started treatment. At baseline, median age was 57 years (range 34–85), ECOG PS 0/1 was 51%/49%, 67% had liver metastases (mets), and the primary tumor site was right-sided colon in 36% and rectum in 17%. Median number of cycles was 3.0 (range 1–13); 41% of pts escalated regorafenib to 120 mg. Five pts (7.1%) had a partial response (PR) lasting ≥16 weeks (wks) and 22 (31.4%) had stable disease (SD); pts without liver mets had a higher ORR (21.7%). In pts with tumor samples (n = 40), higher baseline expression (IHC) of cytotoxic T cells (CD3+/CD8+/GranzymeB+), Tregs (FoxP3+), and macrophages (CD68+) trended with clinical benefit (PR/SD ≥16 wks/PFS); pts with liver mets had lower expression. Lower plasma levels of biomarkers of vascular biology (e.g. VEGF-D, Ang-2, VWF) trended with longer PFS. Grade (Gr) 3 treatment-emergent adverse events (TEAEs) occurred in 53% of pts and Gr 4 in 10%. Three pts had a Gr 5 TEAE: n = 1 related to the combination (sepsis); n = 1 related to nivolumab only by investigator (sepsis); n = 1 unrelated to treatment (respiratory failure). Most common Gr 3/4 TEAEs: maculopapular rash (14%), fatigue (7%), pneumonia (6%), increased bilirubin (6%). Conclusions: Combination treatment with regorafenib (up to 120 mg/day) and nivolumab (480 mg every 28D) has manageable safety. Efficacy of this combination in the North American population did not emulate results in the Japanese population. Absence of liver mets and expression of specific biomarkers indicate a better response and may warrant further analysis. Clinical trial information: NCT04126733. [Table: see text]

We present here the first update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography with a focus on the assessment of diffuse liver disease. The short version provides clinical information about the practical use of elastography equipment and interpretation of results in the assessment of diffuse liver disease and analyzes the main findings based on published studies, stressing the evidence from meta-analyses. The role of elastography in different etiologies of liver disease and in several clinical scenarios is also discussed. All of the recommendations are judged with regard to their evidence-based strength according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. This updated document is intended to act as a reference and to provide a practical guide for both beginners and advanced clinical users.Dies ist die erste Überarbeitung der 2013 publizierten EFSUMB-Leitlinien zur klinischen Anwendung der Elastografie und konzentriert sich auf die diffusen Lebererkrankungen. Der klinische Teil dieser Leitlinien erläutert die praktische Anwendung der Elastografie bei der Beurteilung diffuser Lebererkrankungen unter Berücksichtigung der Geräteausstattung und Interpretation der Ergebnisse. Die aktuelle Literatur wurde analysiert unter besonderer Beachtung von Metaanalysen. Die klinische Anwendung der Elastografie wird unter Reflexion unterschiedlicher klinischer Szenarien und der unterschiedlichen Ätiologien diffuser Lebererkrankungen erläutert. Alle Empfehlungen erfolgten gemäß der Evidenz basierten Methodik der Oxford-Klassifikation. Das hier vorgestellte Update soll dem Anfänger und fortgeschrittenen Nutzer eine praktische Hilfe darstellen.

TPS351 Background: Biliary tract cancer (BTC) carries a poor prognosis and no first-line treatments are approved. The accepted global standard of care is gemcitabine + cisplatin (GemCis). NUC-1031 is a phosphoramidate transformation of gemcitabine designed to overcome key cancer resistance mechanisms that are associated with gemcitabine. Promising efficacy has been observed with single-agent NUC-1031 in a phase I study in advanced solid tumors and in the phase Ib ABC-08 study of NUC-1031 + cisplatin for first-line treatment of advanced BTC. Of 14 patients enrolled in 2 cohorts (NUC-1031 625 mg/m2 or 725 mg/m2 + cisplatin 25 mg/m2 on Days 1 and 8 of 21-day cycle), 1 had a CR and 6 had PRs, resulting in an unconfirmed ORR of 50%. This represents an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected AEs or DLTs. The RP2D of NUC-1031 with cisplatin was 725 mg/m2. The tolerability profile, together with encouraging efficacy, suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global registrational study. Methods: NuTide:121 is a Phase III, open-label, randomized study of NUC-1031 + cisplatin vs GemCis for first-line treatment of advanced BTC. Patients ≥18 years with histologically- or cytologically-confirmed BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease, are eligible. A total of 828 patients are being randomized (1:1) to either 725 mg/m2 NUC-1031 or 1000 mg/m2 gemcitabine, both with 25 mg/m2 cisplatin, administered on days 1 and 8 of 21-day cycles. Primary objectives are OS and ORR. Secondary objectives include PFS, safety, PK and patient-reported quality of life. In addition to the final analysis, three interim analyses, including two designed to support accelerated approval, are planned. The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.

Background: Mipsagargin (G-202; (8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin)-Asp-γ-Glu-γ-Glu-γ-GluGluOH)) is a novel thapsigargin-based targeted prodrug that is activated by PSMA-mediated cleavage of an inert masking peptide. The active moiety is an inhibitor of the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump protein that is necessary for cellular viability. We evaluated the safety of mipsagargin in patients with advanced solid tumours and established a recommended phase II dosing (RP2D) regimen. Methods: Patients with advanced solid tumours received mipsagargin by intravenous infusion on days 1, 2 and 3 of 28-day cycles and were allowed to continue participation in the absence of disease progression or unacceptable toxicity. The dosing began at 1.2 mg m−2 and was escalated using a modified Fibonacci schema to determine maximally tolerated dose (MTD) with an expansion cohort at the RP2D. Plasma was analysed for mipsagargin pharmacokinetics and response was assessed using RECIST criteria. Results: A total of 44 patients were treated at doses ranging from 1.2 to 88 mg m−2, including 28 patients in the dose escalation phase and 16 patients in an expansion cohort. One dose-limiting toxicity (DLT; Grade 3 rash) was observed in the dose escalation portion of the study. At 88 mg m−2, observations of Grade 2 infusion-related reaction (IRR, 2 patients) and Grade 2 creatinine elevation (1 patient) led to declaration of 66.8 mg m−2 as the recommended phase II dose (RP2D). Across the study, the most common treatment-related adverse events (AEs) were fatigue, rash, nausea, pyrexia and IRR. Two patients developed treatment-related Grade 3 acute renal failure that was reversible during the treatment-free portion of the cycle. To help ameliorate the IRR and creatinine elevations, a RP2D of 40 mg m−2 on day 1 and 66.8 mg m−2 on days 2 and 3 with prophylactic premedications and hydration on each day of infusion was established. Clinical response was not observed, but prolonged disease stabilisation was observed in a subset of patients. Conclusions: Mipsagargin demonstrated an acceptable tolerability and favourable pharmacokinetic profile in patients with solid tumours.

Objectives At diagnosis, 30% of patients with pancreatic cancer are unresectable stage 3 locally advanced. The standard treatment for locally advanced pancreatic cancer (LAPC) is not defined. The current study was conducted to assess the roles of chemotherapy and chemoradiation for LAPC treatment. Materials and methods Between June 2006 and March 2011, 100 patients with LAPC were treated at the Johns Hopkins Hospital. Retrospective analysis was performed to compare cumulative incidence of progression (CIP) and overall survival (OS) among different subgroups. Results For the 100 patients, the median OS was 15.8 months and the median CIP was 8.4 months. The combination of chemotherapy and chemoradiation before disease progression was significantly associated with improved CIP (P=0.001) and improved OS when compared with chemoradiation alone (median OS: 16.4 vs. 11.1 mo, P=0.03). Among patients receiving combination treatment, patients who received chemotherapy first followed by chemoradiation had a trend toward lower CIP (P=0.09) and improved OS (median OS: 18.1 vs. 11.0 mo, P=0.09). Patients who received >2 cycles of chemotherapy before chemoradiation had a significantly decreased CIP (P=0.008) and a trend toward better OS (median OS: 19.4 vs. 15.7 mo, P=0.10). On multivariate analysis, receiving >2 cycles of chemotherapy before chemoradiation was associated with improved CIP. Conclusions Although combination chemotherapy and chemoradiation is favored in the treatment of LAPC, longer induction chemotherapy may play a more important role in sensitization of tumors to subsequent chemoradiation. Our results support treating patients with induction chemotherapy for at least 3 cycles followed by consolidative chemoradiation. These results merit further validation by a prospective study.

To determine the efficacy of combined continuous sorafenib therapy and drug-eluting bead (DEB) transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC).This study was conducted in accordance with the principles of the Declaration of Helsinki, and all patients provided written informed consent prior to enrollment. Inclusion criteria included unresectable HCC, a treatment naïve status, an Eastern Cooperative Oncology Group score of 0-1, and a Child-Pugh score of A-B7. Continuous sorafenib therapy (400 mg twice daily) was started 1 week before the first round of DEB TACE, which was performed in 6-week cycles. Up to four rounds of DEB TACE therapy were allowed on demand within 6 months. The primary end point was safety. Secondary end points were time to progression (TTP), response rate, and overall survival (OS) and were stratified by the Barcelona Clinic Liver Cancer (BCLC) stage and the duration of sorafenib therapy. OS was assessed with Kaplan-Meier estimates, and the Mantel-Cox log-rank test was used to determine differences in survival. A two-sided P value of less than .05 was considered to indicate a significant difference. The study was approved by the Johns Hopkins institutional review board and remained open from March 2009 to January 2012.Fifty patients--of whom 76% were male, 92% had a Child-Pugh score of A, and 62% had BCLC stage C disease--underwent a median of three cycles of therapy. The 6-month disease control rate (defined as complete response plus partial response plus stable disease) was 94% according to the response evaluation criteria in solid tumors. Median TTP and OS were 13.9 and 20.4 months, respectively, and 81% of toxicities were grades 1-2. There was one death that was possibly treatment related.Combined continuous sorafenib therapy and on-demand DEB TACE provided excellent local disease control and did not lead to multiplicative toxicities. Long-term administration of sorafenib therapy in combination with DEB TACE may have a survival benefit in patients with advanced HCC.

BACKGROUND Colorectal cancer is one of the most common cancers and causes of cancer-related death. Up to approximately 70% of patients with metastatic colorectal cancer (mCRC) have metastases to the liver at initial diagnosis. Second-line systemic treatment in mCRC can prolong survival after development of disease progression during or after first-line treatment and in those who are intolerant to first-line treatment. OBJECTIVE The objective of this study is to evaluate the efficacy and safety of transarterial radioembolization (TARE) with TheraSphere yttrium-90 (90Y) glass microspheres combined with second-line therapy in patients with mCRC of the liver who had disease progression during or after first-line chemotherapy. METHODS EPOCH is an open-label, prospective, multicenter, randomized, phase 3 trial being conducted at up to 100 sites in the United States, Canada, Europe, and Asia. Eligible patients have mCRC of the liver and disease progression after first-line chemotherapy with either an oxaliplatin-based or irinotecan-based regimen and are eligible for second-line chemotherapy with the alternate regimen. Patients were randomized 1:1 to the TARE group (chemotherapy with TARE in place of the second chemotherapy infusion and subsequent resumption of chemotherapy) or the control group (chemotherapy alone). The addition of targeted agents is permitted. The primary end points are progression-free survival and hepatic progression-free survival. The study objective will be considered achieved if at least one primary end point is statistically significant. Secondary end points are overall survival, time to symptomatic progression defined as Eastern Cooperative Oncology Group Performance Status score of 2 or higher, objective response rate, disease control rate, quality-of-life assessment by the Functional Assessment of Cancer Therapy-Colorectal Cancer questionnaire, and adverse events. The study is an adaptive trial, comprising a group sequential design with 2 interim analyses with a planned maximum of 420 patients. The study is designed to detect a 2.5-month increase in median progression-free survival, from 6 months in the control group to 8.5 months in the TARE group (hazard ratio [HR] 0.71), and a 3.5-month increase in median hepatic progression-free survival time, from 6.5 months in the control group to 10 months in the TARE group (HR 0.65). On the basis of simulations, the power to detect the target difference in either progression-free survival or hepatic progression-free survival is >90%, and the power to detect the target difference in each end point alone is >80%. RESULTS Patient enrollment ended in October 2018. The first interim analysis in June 2018 resulted in continuation of the study without any changes. CONCLUSIONS The EPOCH study may contribute toward the establishment of the role of combination therapy with TARE and oxaliplatin- or irinotecan-based chemotherapy in the second-line treatment of mCRC of the liver. CLINICALTRIAL ClinicalTrials.gov NCT01483027; https://clinicaltrials.gov/ct2/show/NCT01483027 (Archived by WebCite at http://www.webcitation.org/734A6PAYW) INTERNATIONAL REGISTERED REPOR RR1-10.2196/11545

Background: Colorectal cancer is one of the most common cancers and causes of cancer-related death. Up to approximately 70% of patients with metastatic colorectal cancer (mCRC) have metastases to the liver at initial diagnosis. Second-line systemic treatment in mCRC can prolong survival after development of disease progression during or after first-line treatment and in those who are intolerant to first-line treatment. Objective: The objective of this study is to evaluate the efficacy and safety of transarterial radioembolization (TARE) with TheraSphere yttrium-90 (90Y) glass microspheres combined with second-line therapy in patients with mCRC of the liver who had disease progression during or after first-line chemotherapy. Methods: EPOCH is an open-label, prospective, multicenter, randomized, phase 3 trial being conducted at up to 100 sites in the United States, Canada, Europe, and Asia. Eligible patients have mCRC of the liver and disease progression after first-line chemotherapy with either an oxaliplatin-based or irinotecan-based regimen and are eligible for second-line chemotherapy with the alternate regimen. Patients were randomized 1:1 to the TARE group (chemotherapy with TARE in place of the second chemotherapy infusion and subsequent resumption of chemotherapy) or the control group (chemotherapy alone). The addition of targeted agents is permitted. The primary end points are progression-free survival and hepatic progression-free survival. The study objective will be considered achieved if at least one primary end point is statistically significant. Secondary end points are overall survival, time to symptomatic progression defined as Eastern Cooperative Oncology Group Performance Status score of 2 or higher, objective response rate, disease control rate, quality-of-life assessment by the Functional Assessment of Cancer Therapy-Colorectal Cancer questionnaire, and adverse events. The study is an adaptive trial, comprising a group sequential design with 2 interim analyses with a planned maximum of 420 patients. The study is designed to detect a 2.5-month increase in median progression-free survival, from 6 months in the control group to 8.5 months in the TARE group (hazard ratio [HR] 0.71), and a 3.5-month increase in median hepatic progression-free survival time, from 6.5 months in the control group to 10 months in the TARE group (HR 0.65). On the basis of simulations, the power to detect the target difference in either progression-free survival or hepatic progression-free survival is >90%, and the power to detect the target difference in each end point alone is >80%. Results: Patient enrollment ended in October 2018. The first interim analysis in June 2018 resulted in continuation of the study without any changes. Conclusions: The EPOCH study may contribute toward the establishment of the role of combination therapy with TARE and oxaliplatin- or irinotecan-based chemotherapy in the second-line treatment of mCRC of the liver. Trial Registration: ClinicalTrials.gov NCT01483027; https://clinicaltrials.gov/ct2/show/NCT01483027 (Archived by WebCite at http://www.webcitation.org/734A6PAYW) International Registered Report Identifier (IRRID): RR1-10.2196/11545

More and more evidences suggest that primary colon and rectum tumors should not be considered as a single disease entity. In this manuscript, we evaluate the metastatic patterns of colon and rectum cancers and analyze the potential distribution of metastatic disease in these two malignancies. Data queried for this analysis include colorectal adenocarcinoma (2010-2011) from the Surveillance, Epidemiology, and End Results Program (SEER) database. Metastatic distribution information was provided for liver, lung, bone and brain. All of statistical analyses were performed using the Intercooled Stata 13.0 (Stata Corporation, College Station, TX). All statistical tests were two-sided. Totally, there were 46,027 eligible patients for analysis. We found that colon cancer had a higher incident rate of liver metastasis than rectum cancer (13.8% vs 12.3%), while rectum cancer had a higher incident rate of lung (5.6% vs 3.7%) and bone (1.2% vs 0.8%) metastasis than colon cancer, P

We sought to estimate the cost-effectiveness of hepatic resection (HR) (strategy A) relative to surveillance plus 6 months of additional systemic chemotherapy (sCT) (strategy B) for patients with colorectal disappearing liver metastases (DLM). A Markov model was developed using data from a systematic literature review. Three base cases were evaluated: (1) a 60-year-old patient with three lesions in the right hemi-liver who underwent 6 months of sCT, had normalized carcinoembryonic antigen (CEA), and was diagnosed with DLM through a computed tomography (CT) scan; (2) a 60-year-old patient with three lesions in the right hemi-liver who underwent 6 months of sCT, had normalized CEA, and was diagnosed with DLM through a magnetic resonance imaging (MRI) scan; and (3) a 60-year-old patient with three lesions in the right hemi-liver who underwent 6 months of sCT plus hepatic artery infusion (HAI), had normalized CEA, and was diagnosed with DLM through a MRI scan. The outcomes evaluated were quality-adjusted life months (QALMs), incremental cost-effectiveness ratio (ICER), and net health benefit (NHB). The NHB of strategy A versus strategy B was positive in base case 1 (7.7 QALMs, ICER $34.449/quality-adjusted life year (QALY)) and base case 2 (1.6 QALMs, ICER $43,948/QALY). In contrast it was negative (−0.2 QALMs, ICER $72,474/QALY) for base case 3. Monte Carlo simulation showed that strategy B is acceptable only in old patients (>60 years) with normalized CEA and MRI-based diagnosis. In younger patients, strategy B may reach cost-effectiveness only after sCT plus HAI. Surveillance of DLM after sCT was more beneficial and cost-effective among patients >60 years with multiple factors predictive of true complete pathological response, such as normalization of CEA, HAI therapy, BMI ≤30 kg/m2, and diagnosis of DLM made through MRI.

The breast section of these Guidelines and Recommendations for Elastography produced under the auspices of the World Federation of Ultrasound in Medicine and Biology (WFUMB) assesses the clinically used applications of all forms of elastography used in breast imaging. The literature on various breast elastography techniques is reviewed, and recommendations are made on evidence-based results. Practical advice is given on how to perform and interpret breast elastography for optimal results, with emphasis placed on avoiding pitfalls. Artifacts are reviewed, and the clinical utility of some artifacts is discussed. Both strain and shear wave techniques have been shown to be highly accurate in characterizing breast lesions as benign or malignant. The relationship between the various techniques is discussed, and recommended interpretation based on a BI-RADS-like malignancy probability scale is provided. This document is intended to be used as a reference and to guide clinical users in a practical way.

There are no conclusive cost-effectiveness studies measuring the efficacy of salvage LT after liver resection (LR) and radiofrequency ablation (RFA) in patients with early hepatocellular carcinoma (HCC) and compensated cirrhosis. The aim of the present study is to compare liver transplantation (LT) versus locoregional therapy plus salvage LT (to treat tumor recurrence) in patients with early HCC and compensated cirrhosis. Reference case: 55-year old male with HCC within Milan criteria and Child-Pugh A cirrhosis. The analysis was performed in two geographical cost settings: USA and Italy. Survival benefit measured in quality-adjusted life years (QALYs), costs (C) in US$, incremental cost-effectiveness, willingness to pay, and net health benefit (NHB). In the base-case analysis, NHB of LT vs. LR and RFA was −1.7 and −1.3 years for single tumor ≤3 cm, −1.2 and −0.7 for single nodules measuring 3.1–5 cm and −0.7 and −0.7 for multi-nodular tumor ≤3 cm in Italy. In USA, NHB of LT versus LR and RFA were −1.2 and −0.8 years for single tumor ≤3 cm, −0.9 and −0.5 for single nodules measuring 3.1–5 cm, and −0.5 and −0.4 for multi-nodular tumor ≤ 3 cm. On the Monte Carlo simulation, only young patients with multi-nodular HCC and short waiting list time had a positive NHB. Salvage LT proved to be an ineffective cost strategy after RFA or LR. In patients with HCC within Milan criteria and Child-Pugh A cirrhosis, LR and RFA were more cost-effective than LT. Salvage LT was not cost-effective.

The aim of this study was to investigate the predictive value of enhanced intensity on double contrast-enhanced sonography in assessing lymph node metastasis of gastric cancer.A total of 357 patients with gastric cancer were enrolled in this study. Double contrast-enhanced sonography, in which an oral ultrasound contrast agent is combined with an intravenous contrast agent, was performed preoperatively, and the data were analyzed quantitatively. The predictive ability of enhanced intensity, a quantitative double contrast-enhanced sonographic measure, for lymph node metastasis was evaluated retrospectively.Compared to negative lymph node metastasis cases, the presence of thicker lesions, deeper invasion, poorer differentiation, and higher enhanced intensity were found in positive cases (P.05). An enhanced intensity cutoff value of 16.91 dB was the best point for balancing the sensitivity and specificity (71.50% and 79.30%, respectively) for prediction of lymph node metastasis, with the highest Youden index of 0.508. The area under the receiver operating characteristic curve was 0.828 (P.001; 95% confidence interval, 0.786-0.870). In cases in which the lesions were hyperenhanced (enhanced intensity16.91 dB), the lesions were significantly thicker and had deeper invasion, poorer differentiation, and more positive metastasis findings compared to non-hyperenhanced cases (enhanced intensity ≤16.91 dB; P.05). On logistic regression analysis, the enhanced intensity of primary tumors and the invasion depth were significantly associated with lymph node metastasis.Double contrast-enhanced sonography with quantitative analysis may be considered a novel alternative imaging modality for noninvasive preoperative evaluation of lymph node metastasis with good reliability.

Background: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). Methods: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. Results: Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg−1 every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. Conclusions: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.

To prospectively assess treatment response using volumetric functional magnetic resonance imaging (MRI) metrics in patients with hepatocellular carcinoma (HCC) treated with the combination of doxorubicin-eluting bead-transarterial chemoembolization (DEB TACE) and sorafenib.A single center study enrolled 41 patients treated with systemic sorafenib, 400 mg twice a day, combined with DEB TACE. All patients had a pre-treatment and 3-4 week post-treatment MRI. Anatomic response criteria (RECIST, mRECIST and EASL) and volumetric functional response (ADC, enhancement) were assessed. Statistical analyses included paired Student's t-test, Kaplan-Meier curves, Cohen's Kappa, and multivariate cox proportional hazard model.Median tumour size by RECIST remained unchanged post-treatment (8.3 ± 4.1 cm vs. 8.1 ± 4.3 cm, p = 0.44). There was no significant survival difference for early response by RECIST (p = 0.93). EASL and mRECIST could not be analyzed in 12 patients. Volumetric ADC increased significantly (1.32 × 10(-3) mm(2)/sec to 1.60 × 10(-3) mm(2)/sec, p 0.001), and volumetric enhancement decreased significantly in HAP (38.2% to 17.6%, p 0.001) and PVP (76.6% to 41.2%, p 0.005). Patients who demonstrated ≥ 65% decrease PVP enhancement had significantly improved overall survival compared to non-responders (p 0.005).Volumetric PVP enhancement was demonstrated to be significantly correlated with survival in the combination of DEB TACE and sorafenib for patients with HCC, enabling precise stratification of responders and non-responders.• PVP enhancement is significantly correlated with survival in responders (p 0.005). • There was no significant survival difference for early response using RECIST (p = 0.93). • mRECIST or EASL could not assess tumour response in 29% of patients.

Cholangiocarcinoma (CCA) is the second most common primary malignancy of the liver arising from malignant transformation and growth of biliary ductal epithelium. Approximately 50-70 % of CCAs arise at the hilar plate of the biliary tree, which are termed hilar cholangiocarcinoma (HC). Various staging systems are currently employed to classify HCs and determine resectability. Depending on the pre-operative staging, the mainstays of treatment include surgery, chemotherapy, radiation therapy, and photodynamic therapy. Surgical resection offers the only chance for cure of HC and achieving an R0 resection has demonstrated improved overall survival. However, obtaining longitudinal and radial surgical margins that are free of tumor can be difficult and frequently requires extensive resections, particularly for advanced HCs. Pre-operative interventions may be necessary to prepare patients for major hepatic resections, including endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, and portal vein embolization. Multimodal therapy that combines chemotherapy with external beam radiation, stereotactic body radiation therapy, bile duct brachytherapy, and/or photodynamic therapy are all possible strategies for advanced HC prior to resection. Orthotopic liver transplantation is another therapeutic option that can achieve complete extirpation of locally advanced HC in judiciously selected patients following standardized neoadjuvant protocols.

Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.

The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.

Surgery remains the only potentially curative option for patients with hepatocellular carcinoma (HCC) and fibrolamellar carcinoma (FLC). We sought to investigate the differences over time in surgically managed FLC compared with conventional HCC using population-based data.Using SEER data, we identified 7,225 patients with surgically managed FLC or HCC from 1986 to 2008. We examined differences in clinicopathologic and surgical factors associated with long-term survival.Of the 7,225 patients, the majority had HCC (n = 7,135; 99%) vs FLC (n = 90; 1%). Patients with FLC were younger (25 years vs 59 years) and more often were women (44% vs 27%) than patients with HCC (both p0.001). Regional disease was more common among patients with FLC (42.2%) vs patients with HCC (22.1%) (p0.001). More than one-third of patients with FLC (36.9%) were operatively managed with a hemihepatectomy compared with patients with HCC, who were more often managed with a liver transplant (p0.001). On univariable analysis, there was a marked difference in overall survival, with patients with FLC surviving a median of 75 months vs 43 months for HCC (hazard ratio [HR]: 0.59; p = 0.001). There was a marked difference in survival when patients were stratified by localized (FLC, 78 months vs HCC, 49 months; p = 0.012) vs regional disease (FLC, 46 months vs HCC, 23 months; p = 0.002.Patients with FLC have many clinicopathologic features that are different from those of patients with HCC, including younger age and female sex. Despite a higher likelihood of advanced disease at the time of diagnosis, surgically treated FLC patients had better long-term outcomes than patients with conventional HCC.

Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts—we designate this variant as ‘chromophobe hepatocellular carcinoma with abrupt anaplasia’. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P = 0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

Patterns of care of physician specialists may differ for patients with hepatocellular carcinoma (HCC). Reasons underlying variations are poorly understood. One source of variation may be disparate referral rates to specialists, leading to differences in cancer-directed treatments.Surveillance, Epidemiology, and End Results (SEER)-linked Medicare database was queried for patients with HCC, diagnosed between 1998 and 2007, who consulted 1 or more physicians after diagnosis. Visit and procedure records were abstracted from Medicare billing records. Factors associated with specialist consult and subsequent treatment were examined.There were 6,752 patients with HCC identified; 1,379 (20%) patients had early-stage disease. Median age was 73 years; the majority were male (66%), white (60%), and from the West region (56%). After diagnosis, referral to a specialist varied considerably (hepatology/gastroenterology, 60%; medical oncology, 62%; surgery, 56%; interventional radiology [IR], 33%; radiation oncology, 9%). Twenty-two percent of patients saw 1 specialist; 39% saw 3 or more specialists. Time between diagnosis and visitation with a specialist varied (surgery, 37 days vs IR, 55 days; p = 0.04). Factors associated with referral to a specialist included younger age (odds ratio [OR] 2.16), Asian race (OR 1.49), geographic region (Northeast OR 2.10), and presence of early-stage disease (OR 2.21) (all p0.05). Among patients with early-stage disease, 77% saw a surgeon, while 50% had a consultation with medical oncologist. Receipt of therapy among patients with early-stage disease varied (no therapy, 30%; surgery, 39%; IR, 9%; chemotherapy, 23%). Factors associated with receipt of therapy included younger age (OR 2.48) and early-stage disease (OR 2.20).After HCC diagnosis, referral to a specialist varied considerably. Both clinical and nonclinical factors were associated with consultation. Disparities in referral to a specialist and subsequent therapy need to be better understood to ensure all HCC patients receive appropriate care.

Assessment of patient performance status is often subjective. Sarcopenia--measurement of muscle wasting--may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT).Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IAT of hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors.Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm(2)/m(2)) was greater than women (413 mm(2)/m(2)). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3-year survival was 39 %. Factors associated with risk of death were tumor size (HR = 1.84) and Child's score (HR = 2.15) (all P 0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR = 1.84; P = 0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients.Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies.

Little is known about the patterns of utilization of surveillance imaging after treatment of hepatocellular carcinoma (HCC). We sought to define population-based patterns of surveillance and investigate if intensity of surveillance impacted outcome following HCC treatment.The Surveillance, Epidemiology, and End Results-Medicare database was used to identify patients with HCC diagnosed between 1998 and 2007 who underwent resection, ablation, or intra-arterial therapy (IAT). The association between imaging frequency and long-term survival was analyzed.Of the 1,467 patients, most underwent ablation only (41.5%), while fewer underwent liver resection only (29.6 %) or IAT only (18.3%). Most patients had at least one CT scan (92.7%) during follow-up, while fewer had an MRI (34.1%). A temporal trend was noted with more frequent surveillance imaging obtained in post-treatment year 1 (2.5 scans/year) vs. year 5 (0.9 scans/year; P = 0.01); 34.5% of alive patients had no imaging after 2 years. Frequency of surveillance imaging correlated with procedure type (total number of scans/5 years, resection, 4.7; ablation, 4.9; IAT, 3.7; P 0.001). Frequency of surveillance imaging was not associated with a survival benefit (three to four scans/year, 49.5 months vs. two scans/year, 71.7 months vs. one scan/year, 67.6 months; P = 0.01) CONCLUSION: Marked heterogeneity exists in how often surveillance imaging is obtained following treatment of HCC. Higher intensity imaging does not confer a survival benefit.

To assess whether volumetric functional magnetic resonance (MR) results 3-4 weeks after initial intraarterial therapy can aid accurate distinction between responders and nonresponders, to determine whether overall survival (OS) is improved, and to compare volumetric functional MR response with anatomic response criteria (Response Evaluation Criteria in Solid Tumors [RECIST], modified RECIST [mRECIST], European Association for the Study of the Liver [EASL]), as well as α1-fetoprotein [AFP] level.In this single-institution HIPAA-compliant retrospective, institutional review board-approved study, informed consent was waived; 143 patients with hepatocellular carcinoma underwent intraarterial therapy between October 2005 and February 2011. Volumetric functional MR response (25% or more increase in apparent diffusion coefficient, 65% or more decrease in enhancement) was stratified as follows: Dual-parameter responders fulfilled both criteria, single-parameter responders fulfilled one criterion, and those with stable disease (SD) fulfilled neither. RECIST, mRECIST, EASL, and AFP response criteria were determined. Kaplan-Meier technique, log-rank tests, and the Cox proportional hazards model were used to test whether OS was different per response.OS differed significantly between single-parameter responders and dual-parameter responders (P = .01) and between single-parameter responders and those with SD (P = .001). Dual-parameter responders' response improved OS compared with single-parameter responders; risk of death decreased (hazard ratio [HR] = 0.28, P = .01). In those with SD compared with single-parameter responders, risk of death increased (HR = 2.09, P = .001). RECIST, mRECIST, and EASL stratification was short of significant; most lesions were classified as SD. Baseline AFP level increased in 55 patients; AFP responders versus AFP nonresponders had decreased risk of death (HR = 0.36, P = .002). Agreement between anatomic response criteria and volumetric functional MR findings (κ = 0.06-0.12) and between AFP response and imaging criteria (κ = -0.04 to 0.14) was low.Volumetric functional MR response 3-4 weeks after initial intraarterial therapy showed improved OS. Volumetric functional MR was superior to current imaging (RECIST, mRECIST, and EASL) and biochemical (AFP level) response criteria.

Effects of chronic cadmium exposure on liver disease and liver-related mortality are unknown. We evaluated the association of creatinine-corrected urinary cadmium levels with hepatic necroinflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver-related mortality, and liver cancer mortality in the US general population.We analyzed the relationship of individuals in the top quartile for urinary cadmium measured in 12,732 adults who participated in the Third National Health and Nutrition Examination Survey in 1988-1994 (NHANES III), and hepatic necroinflammation, NAFLD, and NASH. Associations between cadmium, liver-related mortality, and liver cancer mortality were evaluated in the NHANES III mortality follow-up study.The cutoffs for highest quartile of urinary cadmium per gram of urinary creatinine were 0.65 and 0.83 μg/g for men and women, respectively (P 0.001). After multivariate adjustment for other factors including smoking, the odds ratios [95 % confidence intervals (CI)] for hepatic necroinflammation, NAFLD, and NASH associated with being in the top quartile of cadmium levels by gender, were 2.21 (95 % CI, 1.64-3.00), 1.30 (95 % CI, 1.01-1.68) and 1.95 (95 % CI, 1.11-3.41) for men and 1.26 (95 % CI, 1.01-1.57), 1.11 (95 % CI, 0.88-1.41) and 1.34 (95 % CI, 0.72-2.50) for women, respectively. The hazard ratios for liver-related mortality and liver cancer mortality for both genders were 3.42 (95 % CI, 1.12-10.47) and 1.25 (95 % CI, 0.37-4.27).Environmental cadmium exposure was associated with hepatic necroinflammation, NAFLD, and NASH in men, and hepatic necroinflammation in women. Individuals in the top quartile of creatinine-corrected urinary cadmium had over a threefold increased risk of liver disease mortality but not in liver cancer related mortality.

The World Federation for Ultrasound in Medicine and Biology (WFUMB) has produced guidelines for the use of elastography techniques including basic science, breast and liver. Here we present elastography in thyroid diseases. For each available technique, procedure, reproducibility, results and limitations are analyzed and recommendations are given. Finally, recommendations are given based on the level of evidence of the published literature and on the WFUMB expert group's consensus. The document has a clinical perspective and is aimed at assessing the usefulness of elastography in the management of thyroid diseases.

Objective Yttrium-90 (Y-90) radioembolization is an emerging treatment option for unresectable neuroendocrine liver metastases (NELM). However, the data regarding this treatment are currently limited. This study evaluates the efficacy and tolerability of Y-90 radioembolization and identifies prognostic factors for radiographic response and survival. Methods and materials Thirty-eight patients underwent Y-90 radioembolization for NELM at our institution between April 2004 and February 2012. Patients were assessed radiographically (RECIST criteria, enhancement), serologically, and clinically at 1 month, and then at every 3 months after treatment for tumor response, toxicity, and survival outcomes. Results Median length of follow-up was 17.0 months (IQR, 9.0–37.0). Median survival was 29.2 months. Three patients (9%) had a radiographic complete response to treatment, 6 (17%) had a partial response, 21 (60%) had stable disease, and 5 (14%) developed progressive disease. Two factors were significantly associated with a good radiographic response (complete/partial response): islet cell histological subtype (p = 0.043) and hepatic tumor burden ≥ 33% (p = 0.031). Multivariate analysis revealed that patients requiring multiple Y-90 treatments (HR 2.9, p = 0.035) and patients who had previously failed systemic therapy with octreotide/chemotherapy (HR 4.4, p = 0.012) had worse survival. Grade 3 serologic toxicity was observed in 2 patients (5%; hyperbilirubinemia, elevated alkaline phosphatase) after treatment. Grade 3 non-serologic toxicities included abdominal pain (11%), fatigue (11%), nausea/vomiting (5%), ascites (5%), dyspnea (3%), diarrhea (3%), and peripheral edema (3%). No grade 4 or 5 toxicity was reported. Conclusions Y-90 radioembolization is a promising treatment option for inoperable NELM and is associated with low rates of grade ≥ 3 toxicity.

Trainee exposure to clinical oncology during residency training is heterogeneous and often modest. The steep learning curve upon entry into fellowship can result in undue stress for fellows and their patients. Simulation-based training has been shown to be superior to classical didactic approaches. We have introduced several innovative simulation-based workshops into the curriculum for the Johns Hopkins Hematology/Oncology Fellowship Training Program in order to address this unmet need. During the first months of training, fellows were engaged in activities emphasizing essential clinical and procedural skills. Specific workshops included the following: (1) chemotherapy writing, (2) cadaveric and simulation-based bone marrow biopsy and intrathecal chemotherapy administration, and (3) simulation-based communication skills training. All first-year fellows in our program participated in these exercises. Pre- and post-workshop surveys were administered to assess knowledge, attitudes, and behaviors; additional distant post-workshop evaluations were disseminated to assess the durability/impact of the curricula and for program evaluation. Overall, participating fellows indicated that the workshops improved patient care and comfort with procedures and patient-centered communication. Continued implementation of these workshops was recommended for program improvement. To the best of our knowledge, ours is amongst the first oncology fellowship training programs to systematically implement simulation-based curricula into our schema for fellowship training. We hypothesize that proactively introducing fellows to these high-yield activities will translate into improved patient care and reduced stress for trainees. Additional investigation into the long-term impact of such curricula remains an area of ongoing need.

Criteria for resectability of colon cancer liver metastases (CLM) are evolving, yet little is known about how physicians choose a therapeutic strategy for potentially resectable CLM.Physicians completed a national Web-based survey that consisted of varied CLM conjoint tasks. Respondents chose among three treatment strategies: immediate liver resection (LR), preoperative chemotherapy followed by surgery (C → LR), or palliative chemotherapy (PC). Data were analyzed by multinomial logistic regression, yielding odds ratios (OR).Of 219 respondents, 79 % practiced at academic centers and 63 % were in practice ≥10 years. Median number of cases evaluated was four per month. Surgical training varied: 51 % surgical oncology, 44 % hepato-pancreato-biliary/transplantation, 5 % no fellowship. Although each factor affected the choice of CLM therapy, the relative effect differed. Hilar lymph node disease predicted a strong aversion to LR with surgeons more likely to choose C → LR (OR 8.92) or PC (OR 49.9). Solitary lung metastasis also deterred choice of LR, with respondents favoring C → LR (OR 4.43) or PC (OR 6.97). After controlling for clinical factors, surgeons with more years in practice were more likely to choose PC over C → LR (OR 1.94) (P = 0.005). Surgical oncology-trained surgeons were more likely than hepatobiliary/transplant-trained surgeons to choose C → LR (OR 2.53) or PC (OR 4.15) (P 0.001).This is the first nationwide study to define the relative impact of key clinical factors on choice of therapy for CLM. Although clinical factors influence choice of therapy, surgical subspeciality and physician experience are also important determinants of care.

Perihilar cholangiocarcinoma (CCA) is the second most common primary malignant tumor of the liver. In the USA, there are approximately 3000 cases of CCA diagnosed annually, with approximately 50-70% of these tumors arising at the hilar plate of the biliary tree. Risk factors include advanced age, male gender, primary sclerosing cholangitis, choledochal cysts, cholelithiasis, parasitic infection, inflammatory bowel disease, cirrhosis and chronic pancreatitis. Patients typically present with jaundice, abdominal pain, pruritus and weight loss. The mainstays of treatment include surgery, chemotherapy, radiation therapy and photodynamic therapy. Specific preoperative interventions for patients with perihilar CCA include endoscopic retrograde cholangiopancreatography, percutanteous transhepatic cholangiography and portal vein embolization. Surgical resection offers the only chance for curative therapy in perihilar CCA. R0 resection is of utmost importance and has been linked to improved survival. Major hepatic resection is needed to achieve both longitudinal and radial margins negative for tumor. Fractionated stereotactic body radiotherapy has shown promising results in CCA. Perihilar CCA typically presents with advanced disease, and many patients receive systemic therapy; however, the response to current regimens is limited. Orthotopic liver transplantation offers complete resection of locally advanced tumors in select patient groups.

Molecular packing in two polymorphs of sibenadet hydrochloride (AR-C68397AA, Viozan™) is investigated using a combined experimental 1H double-quantum (DQ) solid-state magic-angle spinning nuclear magnetic resonance and computational (gauge including projected augmented wave calculation of chemical shifts) approach. For Form I, NH–NH and NH–OH 1H DQ peaks are observed corresponding to nearest distances of 2.62 and 2.87 A, respectively, for the intermolecular hydrogen-bonding arrangement in the single-crystal X-ray diffraction structure. The same 1H DQ peaks at the same 1H chemical shifts are observed for Form II, for which there is no single-crystal diffraction structure, indicating the same intermolecular hydrogen-bonding arrangement of the benzothiazolone moieties as in Form I. 1H DQ build-up (as a function of the DQ recoupling time) curves are presented for the resolved NH–NH and NH–OH DQ peaks for the two polymorphs. For Form I, the ratio of the maximum intensity for the NH–OH and NH–NH DQ peaks is in excellent agreement with the ratio of the summed squares of the H–H dipolar couplings, as determined using H–H distances from the crystal structure up to 4 A. Small differences in the 1H DQ build-up behaviour for the two polymorphs are attributed to differences in the longer-range NH–OH distances associated with different inter-layer arrangements. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1821–1830, 2012

To analyze a single-center experience with locally advanced pancreatic cancer (LAPC) patients treated with chemoradiation (CRT) and to evaluate predictive variables of outcome.LAPC patients at our institution between 1997 and 2009 were identified (n = 109). Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier analysis. Cox proportional hazard models were used to evaluate predictive factors for survival. Patterns of failure were characterized, and associations between local progression and distant metastasis were explored.Median OS was 12.1 months (2.5-34.7 months) and median PFS was 6.7 months (1.1-34.7 months). Poor prognostic factors for OS include Karnofsky performance status ≤80 (LAPC patients who suffer local progression following definitive CRT may experience inferior OS and increased risk of metastasis, warranting efforts to improve control of local disease. However, patients with poor pretreatment performance status, elevated CA19-9 levels, and treatment interruptions may experience poor outcomes despite aggressive management with CRT, and may optimally be treated with induction chemotherapy or supportive care. Novel therapies aimed at controlling both local and systemic progression are needed for patients with LAPC.

Purpose To evaluate safety and efficacy of combined transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) and sorafenib in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods A prospective single-center phase II study was undertaken involving patients with unresectable HCC. The protocol involved sorafenib 400 mg twice per day combined with DEB-TACE. Safety and response were assessed. Results DEB-TACE in combination with sorafenib was successfully administered in 35 patients: mean age, 63 years; Child's A, 89%; Barcelona Clinic Liver Cancer stage C, 64%; Eastern Cooperative Oncology Group performance status of 0 and 1, 46% and 54%, respectively; and mean index tumor size, 7.7 cm (standard deviation, ± 4.2 cm). Patients underwent 128 cycles of therapy (sorafenib plus DEB-TACE, 60 cycles; sorafenib alone, 68 cycles). Median number of cycles per patient was two (range, one to five cycles); median number of days treated with sorafenib was 71 (range, 4 to 620 days). The most common toxicities during cycle one were fatigue (94%), anorexia (67%), alterations in liver enzymes (64%), and dermatologic adverse effects (48%). Although most patients experienced at least one grade 3 to 4 toxicity, most toxicities were minor (grade 1 to 2, 83% v grade 3 to 4, 17%). Toxicity during cycle two was decreased. Over the course of the study, there were 40 sorafenib dose interruptions and 25 sorafenib dose reductions. Sorafenib plus DEB-TACE was associated with a disease control rate of 95% (Response Evaluation Criteria in Solid Tumors Group)/100% (European Association for the Study of the Liver [EASL]), with an objective response of 58% (EASL). Conclusion The combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib. Toxicity is manageable with dose adjustment of sorafenib. Preliminary efficacy data are promising.

Tumor recurrence remains a main limitation to the long-term survival of patients following liver transplantation for hepatocellular carcinoma (HCC). While the majority of patients recur in the first two years after transplantation, late recurrence is not infrequent.Most common sites of recurrence in order of decreasing frequency are liver graft, lung, bone, abdominal lymph nodes, adrenal glands and peritoneum. Reported five-year survival after surgical resection ranges from 27-88%. Few patients, however, are candidates for surgical resection. Other therapeutic options for recurrent HCC include systemic therapy, intra-arterial therapy, or radiation therapy. Although systemic molecular targeted therapy is generally tolerated with very few interactions with immunosuppressive medications, there is only modest success regarding prolongation of survival. Utilization of radiation therapy for extrahepatic recurrences similarly has minimal impact on overall survival, but may effectively in palliate symptoms. While late recurrence is associated with a more favorable prognosis than early recurrences, prognosis is still poor.Late recurrence of HCC following transplantation should be borne in mind even after many years from transplant. Surgical salvage, when feasible, remains a viable treatment option in select patients with a chance for long-term survival. A multi-disciplinary approach is critical as different therapeutic modalities have a role in treating recurrent HCC following transplant.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. It is traditionally difficult to cure, especially when discovered at later stages, making early diagnosis and intervention of paramount importance. HCC typically arises in the background of chronic liver disease and can have various morphologic appearances. One of the most difficult of these to recognize on early surveillance imaging is the infiltrative subtype, which can account for up to 13% of all HCC cases, and may be more closely associated with background hepatitis B infection.Certain imaging characteristics can provide vital clues, including differing signal intensity on the T1 and T2 sequences of magnetic resonance imaging (MRI) and the presence/appearance of portal vein thrombus. Owing to the diffuse and infiltrating properties of this tumor, surgical resection and transplantation are rarely if ever viable therapeutic options. Other forms of liver-directed therapy have been attempted with limited success, having minimal efficacy and high morbidity. To date, there is no data available to determine if the various HCC subtypes respond to systemic therapy differently, so this may be the most reasonable approach. Left untreated, observed patients commonly progress to hepatic failure fairly rapidly.Infiltrative HCC can be extremely subtle, and therefore difficult to detect, especially in the background of cirrhosis. Providers caring for patients with hepatitis, chronic liver disease, and cirrhosis must be extremely vigilant in the evaluation of surveillance imaging in order to potentially discover this HCC subtype as early as possible and initiate a multidisciplinary treatment plan.