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In the original article, the following author name was incorrectly published and the corrected name is given below.

537 Background: Treatment of unresectable liver cancer or liver metastases (mets) by stereotactic body radiotherapy is well tolerated but limited by the need to preserve liver function. Increasing energy deposition in the tumor while at the same time maintaining the dose in healthy tissue remains a major challenge in radiation oncology that could be achieved by NBTXR3 (hafnium oxide nanoparticles) when activated by radiotherapy (RT). NBTXR3 augments energy dose deposit within tumor cells, increasing tumor cell death compared to RT alone, while sparing healthy tissues. Patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets) may benefit from the mode of action of NBTXR3. A phase I/II clinical trial has been conducted to evaluate NBTXR3 activated by SBRT in these pts [NCT02721056]. Methods: The Phase I used a 3+3 dose escalation scheme with 5 NBTXR3 dose levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 was administered by intratumoral injection (ITI) followed by SBRT (45 Gy / 3 fractions / 5 to 7 days or 50 Gy / 5 fractions / 15 days). Primary endpoints were identification of the recommended Phase II Dose and early DLTs. Secondary endpoints included safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and early efficacy by response rate (mRECIST/RECIST 1.1). Results: The dose escalation levels of 10, 15, 22 and 33% are completed (n = 17): 6 pts at 10% (2 SBRT doses tested due to organ constraints), 4 pts each at 15% and 22% (due to fiducial displacement and ITI shift) and 3 pts at 33%. No early DLT was observed and only one SAE (bile duct stenosis) related to NBTXR3 and RT occurred. CPS and APRI did not show clinically meaningful changes post-treatment and CT-scan showed no leakage of NBTXR3 into surrounding tissues. Best response for HCC (n = 8) were 5CR, 3PR and for mets (n = 6) the results were: 3 PR, 3SD. Conclusions: ITI of NBTXR3 is feasible, demonstrated a very good safety and tolerability profile up to the 33% dose level. Recruitment needs to be finalized at the 42% dose level. Based on early efficacy results NBTXR3 has the potential to address an unmet medical need in pts with unresectable primary or metastatic liver cancer. Clinical trial information: NCT02721056.

516 Background: 90Y loaded microsphere SIRT (radioembolization) is a treatment option in advanced HCC. However, no personalized dosimetric endpoints are currently used. The goal of this study was to compare the efficacy of 90Y loaded glass microsphere SIRT in HCC using a standard versus a personalized dosimetric approach. Methods: DOSISPHERE-01 was a multicenter, randomized phase 2 trial in unresectable HCC patients with at least one tumor ≥7cm. Treatment arm was randomly assigned (1:1) to standard dosimetry arm (SDA), with a goal to deliver 120±20Gy to the treated volume or to personalized dosimetry arm (PDA) with a goal to deliver at least 205Gy to the index lesion. The primary endpoint was the response rate (RR) of the index lesion according to EASL criteria. Secondary endpoints included dose response evaluation, safety and overall survival (OS). Results: Sixty HCC patients were randomized (PDA 31, SDA 29, intent to treat population-ITTP-), and 56 treated (28 in each arm). RR was significantly increased in the PDA versus the SDA, in the ITTP, respectively 64.5% versus 31% (p=0.0095) as in the safety population -SP- (treatment effectively received, personalized 35, standard 21), respectively 74.3% versus 14.3% (p

To evaluate the survival outcomes of percutaneous thermal ablation (RFA + microwaves) for patients presenting N0 non-small-cell lung cancer (NSCLC) ineligible for surgery.Eighty-seven patients from two comprehensive cancer centers were included. Eighty-two patients were treated with RFA electrodes and five with microwave antenna. Overall survival (OS) and disease-free survival (DFS) were estimated and predictive factors of local tumor progression, OS and DFS identified and compared by univariate and multivariate analysesMedian follow-up was 30.5 months (interquartile range 16.7-51) and tumor size was 21 mm (range 10-54 mm). Treatment was incomplete for 14 patients with a local tumor progression of 11.5, 18.3, and 21.1 % at 1, 2, and 3 years, respectively. Two patients presented with neurological (grade III or IV) complications, and one died of respiratory and multivisceral failure as a result of the procedure at 29 days. In univariate analysis, increasing tumor size (P = 0.003) was the only predictive factor related to risk of local tumor progression. 5-year OS and DFS were 58.1 and 27.9 %, respectively. Sex (P = 0.044), pathology (P = 0.032), and tumor size2 cm (P = 0.046) were prognostic factors for DFS. In multivariate analysis, pathology (P = 0.033) and tumor size2 cm (P = 0.032) were independent prognostic factors for DFS.Oversized and overlapping ablation of N0 NSCLC was well tolerated, effective, with few local tumor progressions, even over long-term follow-up. Increasing tumor size was the main prognostic factor linked to OS, DFS, and local tumor progression.

Modern oncology requires precise tumor assessment to drive effective therapies. Image-guided biopsies are the current standard of care to characterize molecular alterations safely and effectively, but have inherent limitations due to tumor heterogeneity and accessibility, as well as from procedure related risks. Advancements in radiomics analysis provide the potential to retrieve useful incremental information to characterize molecular alterations from standard imaging data in a cost-effective and non-invasive manner, but currently suffers from lack of validation and standardization. The combination of techniques may provide the optimal solution for patient-tailored care, ultimately through the development of accurate and reliable virtual biopsy. In the advancement towards that goal, image-guided biopsy can prove radiomic suspicions and conversely radiomics can guide image-guided biopsy to improve tissue yield. Joint development of these two methods will improve cancer understanding and patient outcomes.

Background: Molecular alterations involving FGFR family genes (FGFR 1-4) are emerging driver events in a variety of solid tumors, mainly represented by urothelial carcinoma (UC) and intrahepatic cholangiocarcinoma (CC). Several tyrosine kinase inhibitors (TKI) are in clinical development to counteract FGFR-driven diseases, being especially active against activating gene mutations and rearrangements. Progression on these targeted agents eventually appears and the understanding of molecular mechanisms of resistance is crucial to develop novel strategies. Methods: In the MATCH-R prospective study (NCT02517892), patients with unresectable or metastatic cancer are included upon acquired resistance to targeted therapies or immunotherapy, defined as progressive disease after complete/partial response or stable disease for six months. Serial blood samples are collected and tumor biopsy is performed upon progression. Targeted NGS, CGH, WES and RNAseq are performed on the tissue samples. PDX models and patient-derived cell lines are developed to fully investigate the underlying mechanisms of resistance. Only patients receiving TKI for FGFR-mutated or -rearranged tumors were included (i.e. FGFRamplifications were excluded) in the analysis. Results: From June 2015 to November 2018, 113 patients treated with a TKI were included in the MATCH-R study, of which 17 (15%) had received an FGFR inhibitor. Tumor types and corresponding molecular aberrations were as follows: 8 CC (n=6 FGFR2-rearranged, n=1 FGFR2:C383R, n=1 FGFR3:S249C), 7 UC (n=5 FGFR3:S249C, n=1 FGFR3:R248C, n=1 FGFR3:Y373C), 1 breast (FGFR3-rearranged) and 1 ovarian (FGFR2-rearranged) cancers. Evaluable tumor biopsies were taken upon progression to treatment with erdafitinib (n=12), pemigatinib (INCB54828) (n=3) or TAS-120 (n=4). Two patients underwent multiple biopsies as progressing on sequential FGFR inhibitors. Resistance mechanisms consisted of polyclonal secondary mutations (n=5), bypass pathways activation (n=3) and the remaining nine cases are still under investigation. PDX models/patient-derived cell lines were obtained in eight cases and extensively characterized in three. Adaptive treatment with novel FGFR TKI or combinatorial strategies aiming to block the bypass pathways allowed to restore sensitivity in both cell lines (readouts: IC50 and Western Blots) and PDX (readout: median tumor growth). Novel mutations potentially implicated in resistance to FGFR TKI were characterized by infecting Ba/F3 cells with respective lentiviral vectors, as well as the inhibitory potential of the differential FGFR inhibitors. Conclusions: Novel mechanisms of resistance to FGFR inhibitors in solid tumors were identified and consequent treatment strategies allowed to regain sensitivity in both patient-derived cell lines and PDX. Updated results will be presented at the Meeting. Citation Format: Francesco Facchinetti, Rastislav Bahleda, Antoine Hollebecque, Yohann Loriot, Gonzalo Recondo, Ludovic Bigot, Ken A. Olaussen, Gilles Vassal, Stefan Michiels, Rosa L. Frias, Justine Galissant, Tony Sourisseau, Claudio Nicotra, Maud Ngo-Camus, Linda Mahjoubi, Ludovic Lacroix, Etienne Rouleau, Catherine Richon, Aurélie Abou-Lovergne, Olivier Deas, Nathalie Auger, Thierry De Baere, Frederic Deschamps, Eric Solary, Jean-Yves Scoazec, Eric Angevin, Alexander Eggermont, Fabrice André, Benjamin Besse, Jean-Paul Thiery, Jean-Charles Soria, Christophe Massard, Luc Friboulet. Mechanisms of acquired resistance to FGFR inhibitors in molecularly-selected solid tumors: A prospective cohort from the MATCH-R study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 318.

Background: ALK rearrangements occur in 3-6% of patients (pts) with lung adenocarcinoma. Lorlatinib, is a novel third generation ALK tyrosine kinase inhibitor (TKI) with proven efficacy for patients previously treated with second generation ALK TKI. Methods: The MATCH-R study is a prospective single-institution trial aiming to identify mechanisms of resistance to targeted agents and immunotherapy in pts with advanced cancer (NCT02517892). Patients that achieve an initial partial or complete response or stability of disease for at least 6 months with selected agents are included upon disease progression. Tumor biopsies are performed and serial blood samples are collected. Extensive molecular profiling with panel next-generation sequencing (NGS), whole exome sequencing (WES) and RNA sequencing (RNAseq) is performed on tumor samples. Patient-derived xenografts (PDX) in NOD scid gamma (NSG) or nude mice and patient-derived cell lines are developed. We report mechanisms of resistance in a cohort of pts with ALK-rearranged lung cancer treated with lorlatinib. Results: From June 29th 2015 to November 15th 2018, 113 pts treated with a TKI were included in the MATCH-R study, of which 14 (12%) received treatment with ALK TKI, 6 pts treated with lorlatinib and with adequate tumor biopsies for molecular analysis were included. Tumor types studied were lung adenocarcinoma (n=4), anaplastic thyroid carcinoma (ATC, n=1) and myofibroblastic inflammatory tumor (MIT, n=1). An NF2 frame-shift deletion was detected by NGS in the ATC sample and a TNIK Q674 missense mutation was detected in the MIT sample. In the four pts with lung cancer treated with lorlatinib, we identified novel ALK G1202R/F1174L compound mutations from the tumor biopsy in one case and characterized them with Ba/F3 models (ctDNA analysis will be presented). Induction of epithelial mesenchymal transition (EMT) with lorlatinib exposure was responsible for resistance in one patient-derived model and susceptible to combined ALK/SRC inhibition. This cell line also had ALK C1156Y/G1269A compound mutations, not contributing to lorlatinib resistance. In a third case, double deleterious events in NF2 were identified in temporo-spatial distinct tumor biopsies on progression to lorlatinib. We further validated the effect of these events in patient-derived cell lines developed from two different biopsies. Downstream mTOR pathway activation conferred resistance to lorlatinib, and was reversible with mTOR inhibitors. We performed NF2 knockout in H3122 cells using Crispr-Cas9 gene editing to validate these findings. The resistance mechanism to lorlatinib treatment is yet to be elucidated in one patient-derived model. Conclusions: Mechanisms of resistance to lorlatinib can be diverse and complex, involving compound mutations, EMT and bypass activation. The present evidence could provide new insights for the development of tailored treatments for patients. Citation Format: Gonzalo Recondo, Laura Mezquita, David Planchard, Anas Gazzah, Francesco Facchinetti, Ludovic Bigot, Ahsan Z. Rizvi, Jean-Paul Thiery, Jean-Yves Scoazec, Rosa L. Frias, Tony Sourisseau, Linda Mahjoubi, Justine Galissant, Aurelie Abou-Lovergne, Gilles Vassal, Rastislav Bahleda, Antoine Hollebecque, Claudio Nicotra, Maud Ngocamus, Stefan Michiels, Ludovic Lacroix, Catherine Richon, Nathalie Auger, Thierry De Baere, Frederic Deschamps, Eric Solary, Ken A. Olaussen, Eric Angevin, Alexander Eggermont, Fabrice André, Christophe Massard, Jean-Charles Soria, Benjamin Besse, Luc Friboulet. Diverse biological mechanisms drive resistance to Lorlatinib in ALK-rearranged Lung Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 311.

e15642 Background: Hafnium oxide nanoparticles, NBTXR3, increase the effect of radiotherapy (RT) by enhancing local energy dose deposit within tumor cells, resulting in increased cell death compared to the same dose of RT alone. NBTXR3 efficacy was demonstrated in a phase II/III study in soft tissue sarcoma (NCT02379845) and is currently evaluated in other solid tumors including liver cancers. The use of this radio enhancer is particularly relevant in liver cancer management, a difficult to treat heterogenous population, due to the presence of underlying liver dysfunction. Methods: Phase I/II study of NBTXR3 activated by RT in patients (pts) with HCC (with/without portal vein tumor thrombus) or liver metastasis (mets) [NCT02721056]. The dose escalation part followed a 3+3 design with tested dose levels equivalent to 10%, 15%, 22% and 33% of baseline tumor volume. Patients were treated with a single intralesional injection (ILI) of NBTXR3 followed by Stereotaxic Body RT (SBRT: 45 Gy/3 fractions/5 to 7 days). Determination of recommended dose(s) and early dose limiting toxicities (DLT) were primary endpoints. Secondary endpoints include assessment of global safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST 1.1). Results: The 4 levels of ILI dose escalation were finalized (n = 17): 6 pts at 10% (2 SBRT doses tested due to organs constraints), 4 pts at 15% and 22% (due to fiducial displacement and ILI shift) and 3 pts at 33% were included. ILIs were successful and SBRT was delivered as planned with no observed DLT or NBTXR3-related SAE at all levels. Only one grade 1 AE (fatigue) related to NBTXR3 was reported at dose level 33%. No relevant change of CPS or APRI was observed over time. Among 7 evaluable HCC pts the best target lesion responses by mRECIST were: 3 CR and 4 PR and among 5 evaluable mets pts: 2 PR, 1 SD and 2 PD. Conclusions: This study demonstrated the feasibility and good tolerance of the first in class NBTXR3 ILI. These results have supported a protocol amendment adding a higher dose of NBTXR3 (42% of the tumor volume). This innovative approach might constitute a valuable solution for patients with unresectable liver tumors and liver dysfunction. Clinical trial information: NCT02721056.

Acquired EGFR Mutation as the Potential Resistance Driver to Crizotinib in a MET-Mutated Tumor Marc-Antoine Benderra, MD, Sandrine Aspeslagh, PhD, Sophie Postel-Vinay, PhD, Ludovic Bigot, MD, Thierry De Baere, PhD, Yohann Loriot, PhD, Ludovic Lacroix, PhD, Christophe Massard, PhD, Gilles Vassal, PhD, Fabrice Andre, PhD, Jean-Charles Soria, PhD* DITEP (Departement d’Innovations Therapeutiques et Essais Precoces), Gustave Roussy Cancer Campus, Villejuif, France Faculte de medicine Paris-Sud XI, Kremlin-Bicetre, France U981 INSERM, Gustave Roussy Cancer Campus, Villejuif, France Radiologie interventionnelle, Gustave Roussy Cancer Campus, Villejuif, France Departement de Medecine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France Laboratoire de Recherche Translationnelle et Centre de Ressources Biologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Villejuif, France Departement de Biologie et Pathologie Medicales, Gustave Roussy Cancer Campus, Villejuif, France Direction de la recherche clinique, Gustave Roussy Cancer Campus, Villejuif, France

STUDY DESIGN Retrospective assessment of risk factors using univariate and multivariate analyses. OBJECTIVE To evaluate risk factors retrospectively for cement leakage (CL), including vascular cement leakage (vCL) and cortical cement leakage (cCL), in percutaneous vertebroplasty of spinal metastasis. SUMMARY OF BACKGROUND DATA Complications of vertebroplasty for spine metastasis are rare but related to extravertebral cement leakage that is pulmonary embolism and medullary compression. Better understanding of the risk factors for vascular and cortical types of cement leakage is necessary to prevent these complications. METHODS Fifty-six cancer patients (30 females, 26 males; age, 56 ± 12 yr) (81 vertebrae) were treated in 58 sessions under fluoroscopy or computed tomography-fluoroscopy guidance. Leakage rates were reported. The following items were assessed for occurrence of CL, vCL, and cCL: primary tumor site, prior radiotherapy or local tumor ablation or embolization, appearance on computed tomography, cortical osteolytic destruction, vertebral collapse, operator's experience, guidance modality, and cement filling. RESULTS CL, vCL, and cCL rates were 53%, 25%, and 32%. History of prior treatment correlated with a decrease in CL (P = 0.018). vCL decreased when lung was the primary tumor site (P = 0.036), in osteolytic vertebrae (P = 0.033) or when there was a vertebral collapse (P = 0.037). cCL correlated with operator's experience (P = 0.021) and vertebral collapse (P < 0.001). Superior discal cCL correlated with superior endplate cortical destruction (P = 0.012). Although history of prior treatment seemed to be an independent protective factor (odds ratio = 0.24; 95% confidence interval, 0.087-0.7; P = 0.001), vertebral collapse was isolated as a risk factor for cCL (odds ratio = 32; 95% confidence interval, 6.7-161; P = 0.001). CONCLUSION Risk factors for cCL and vCL are distinct. Vertebral collapse and cortical destruction are risk factors for cCL. History of prior treatment is a protective factor for CL. LEVEL OF EVIDENCE 4.

Transcatheter hepatic arterial administration of irinotecan-loaded drug-eluting beads (DEBIRI) is used to treat liver-only or liver-dominant metastatic disease from colorectal cancer (CRC). Eligibility for DEBIRI should be established in each individual patient by a multidisciplinary team based on comprehensive clinical, imaging, and laboratory assessment. Standardization of DEBIRI technique and protocols would be expected to lead to improved efficacy and safety. The present article provides a set of technical recommendations for the use of DEBIRI in the treatment of hepatic CRC metastases.

Purpose Improved prognostic accuracy for treatment response and a wider understanding of drug effects in humans are crucial for enhancing the utility of sorafenib and other promising targeted therapies. We developed a strategy of global genomic investigation of sequential tumor biopsy samples at baseline and 21 days post treatment, and applied this approach in a phase I study of sorafenib plus dacarbazine in patients with solid tumors. The objective of this study was also to validate functional parameters of DCE-US as surrogate markers to predict earlier response. Experimental design Patients received 21-day cycles of oral sorafenib, 400 mg twice daily and dacarbazine, 1,000 mg/m2 in a 1-h intravenous infusion on day 1. Efficacy was assessed using response evaluation criteria in solid tumors. Sequential biopsy samples (baseline and day 21) were obtained from the same tumor. Changes from baseline in global gene expression (GE) measured by genomic microarrays and in tumor vascularity at baseline, D8, D21, D 42 and every 2 cycles using dynamic contrast-enhanced ultrasonography (DCE-US) were analyzed for patients with and without a clinical response to treatment at 3 months. Results Among 23 patients evaluable for treatment efficacy, 17 were eligible for gene expression and DCE-US analyses. One patient achieved a partial response; 14 exhibited stable disease. Ten patients were defined as exhibiting stable disease (SD) and 7, progressive disease (PD) at 3 months. Genomic analyses identified a 237-gene signature that distinguished SD from PD at 3 months. Of note, CDK4 overexpression and PDGFR downregulation were associated with PD. Functional parameters of DCE-US representing the blood volume at baseline, day 8, and day 21 were correlated with disease progression at 3 months. Conclusions This novel approach of sequential investigations in a phase I trial was feasible, detecting early changes in gene expression and tumor vascularity evaluated using DCE-US that may be predictive of clinical outcome.

Percutaneous lung thermo-ablation has steadily been developed over the past 15years. Main indications are early stage non-small cell lung carcinoma (NSCLC) for non-surgical patients and slow evolving localized metastatic disease, either spontaneous or following a general treatment. Radiofrequency, being the most evaluated technique, offers a local control rate of about 80-90% for tumors3 cm in diameter. With excellent tolerance and very few complications, radiofrequency may be proposed for patients with a chronic disease. Other ablation techniques under investigation such as microwaves and cryotherapy could allow overcoming radiofrequency limits. Furthermore, stereotactic radiotherapy proposed for the same indications is efficient. Comparative studies are warranted to differentiate these techniques in terms of efficacy, tolerance and cost-effectiveness.

Background We studied Y-STRUT® (Hyprevention, France), a new percutaneous internal fixation device, in combination with bone cementoplasty to prevent hip fracture. Methods Between February 2013 and February 2015, a total of 16 femoral necks in 4 osteoporotic and 12 oncologic patients have been considered for prophylactic consolidation in this prospective multicentre pilot study involving 4 different hospitals. These consolidations were performed percutaneously under fluoroscopic guidance using Y-STRUT®, a dedicated internal fixation device. For osteoporotic patients, orthopaedic surgeons performed the prophylactic consolidations immediately after surgical treatment of a hip fracture (same anaesthesia) in the opposite side. For oncologic patients, without current hip fracture but considered at risk (Mirels score ≥8), interventional radiologists performed the procedures. We report the preliminary results of feasibility, safety and tolerance of these preventive consolidations using Y-STRUT®. Results Four patients (mean 83 years old) had prophylactic consolidation because of a severe osteoporosis (mean T-score −3.30) resulting in first hip fractures. Ten patients (mean 61 years old) were treated because of impending pathological fractures (mean Mirels score 9) related to femoral neck osteolytic metastases. All the procedures were performed with success. Wound healing was achieved in all cases with no access site complication. Radiographic exams performed at 3 months follow-up revealed that Y-STRUT® was well integrated in the bone. For the osteoporotic cohort, mean pain was 0.9 ± 0.7 at 3 weeks. For the oncologic cohort, it decreases from 3.6 ± 2.9 at baseline to 2.4 ± 0.9 at 2 months. Conclusions Preliminary results demonstrate the feasibility and safety of Y-STRUT® implantation as well as the tolerance of the device.

Interferon-alpha (IFN-alpha) is recommended in neuroendocrine tumors (NET). Malignant pheochromocytoma and paragangliomas (MPPGLs) constitute a rare subgroup of NET with few treatment options. IFN-alpha efficacy in patients with MPPGLs was evaluated in a single-center retrospective study. Progression-free survival (PFS) was the primary endpoint according to RECIST 1.1 and/or PERCIST 1.0, and response rate, safety, and symptomatic efficacy were secondary endpoints. Fourteen patients received peginterferon alfa-2a (90 to 180 μg/week) or interferon alfa-2b (1.5 to 3 million units × 3/week) at our institution between December 2005 and February 2014 as the first (n = 7), second (n = 3), or subsequent line (n = 4) of treatment. Most of the patients had a slowly progressive disease before IFN-alpha initiation. Eight patients were men (57%); the median age was 44. At the beginning of treatment, 12 patients had progressive disease demonstrated by FDG-PET (n = 9), MIBG (n = 1), or CT scan (n = 2). Most of the patients treated (64%) had metastatic disease limited to or predominantly located in the bones. During IFN-alpha therapy, bone-directed loco-regional treatments were performed in 9 patients (range 1-4). Median PFS was 17.2 months (95% CI [12.1-58.3]). We observed 3 partial metabolic responses, 9 stable diseases, and 2 progressive diseases. No partial response according to RECIST 1.1 was observed. Symptomatic relief of pain, headaches, diarrhea, or sweating occurred in 6 out of 10 symptomatic pts. Most frequent all grade IFN-α-related toxicities were asthenia (n = 10), lymphopenia (n = 7), thrombopenia (n = 6), and anemia (n = 5). Median overall survival was 7.5 years (95% CI [4-NR]). This study suggests symptomatic response and tumor control effect with interferon-alpha in progressive MPPGLs.

Purpose Despite high response rates, feasibility of hepatic artery infusion (HAI) is impaired by frequent malfunctions of surgically implanted catheters (SIC). The aim of this study is to analyze the incidence and the types of malfunctions affecting the SIC and the success rate of interventional revisions (IR) in restoring patency to these catheters. Methods In a single center, 101 consecutive patients treated with HAI through SIC over 10 years were retrospectively reviewed. The studied group (+ IR ) was composed of patients referred to interventional radiology for repair of catheter malfunctions. The overall patency of catheters in the + IR group was compared with the overall patency of a control group composed of patients without catheter malfunction ( no IR ). Results 86 patients were included with no difference in baseline characteristics between + IR ( n = 40) and no IR ( n = 46). There were no significant differences in overall patency between both groups (8.4 courses vs. 8.4 courses, p = 0.99). Furthermore, with an overall success rate of 72.5%, IR significantly improved the mean primary patency from 2.4 to 8.4 courses ( p 0.0001) in the + IR group. Conclusion By restoring a normal patency to SIC affected by different types of malfunctions, IR improves feasibility of HAI.

Metastatic liver disease is the most common cause of death in cancer patients. Complete surgical resection is currently considered the only curative treatment, with only about 25% of patients being amenable to surgery. Therefore, a variety of interventional oncologic techniques have been developed for treating secondary liver malignancies. The aim of these therapies is either to allow patients with unresectable tumors to become surgical candidates, provide curative treatment options in nonsurgical candidates, or improve survival in a palliative or even curative approach. Among these interventional therapies are transcatheter therapies such as portal vein embolization, hepatic artery infusion chemotherapy, transarterial chemoembolization, and radioembolization, as well as interstitial techniques, particularly radiofrequency ablation as the most commonly applied technique. The rationale, application and clinical results of each of these techniques are reviewed on the basis of the current literature. Future prospects such as gene therapy and immunotherapy are introduced.

To prospectively evaluate a novel implant, Y-STRUT® (Hyprevention, Pessac, France), designed to provide prophylactic reinforcement of the proximal femur in metastatic patients. Ten patients presenting lytic lesions of the proximal femur were to be treated. The device consisted of two components implanted in the proximal femur, combined with bone cement. Patients were followed at 2, 6 and 12 months to record technical feasibility, safety and efficacy parameters of the procedure. All patients (62 years, 67% male) presented a pertrochanteric lesion shown on imaging with an average Mirels’ score of 9.42 (range 8–11). Procedures were performed by interventional radiologists, under general anesthesia in 97 ± 28 min, with 9.2 ± 3.1 ml of cement injected. Hospitalization duration was 2.3 ± 1.4 days. A median follow-up of 237 days (range 24–411) was reported. Wound healing was achieved in all patients, with no case of wound infection, bleeding, leakage or inflammation. Among the patients evaluated, 86% could resume walking at hospital discharge. Visual Analogue Scale decreased from 3.6 ± 2.9 before treatment to 1.3 ± 0.8 at 1 year. OHS-12 score increased from 30 ± 10 at baseline to 37 ± 6 at 1 year. Results from this first-in-man study conducted in patients with metastatic bone disease show the feasibility and the safety of the intervention, with a short hospitalization, when performed following the operating instructions. Initial data showing pain-level diminution and increase in OHS-12 score indicate that both symptomatic and functional conditions of the patients were improved 1 year after the implantation of this novel implant. Level 4, Case Series.

To assess whether fusion imaging-guided percutaneous microwave ablation (MWA) can improve visibility and targeting of liver metastasis that were deemed inconspicuous on ultrasound (US). MWA of liver metastasis not judged conspicuous enough on US was performed under CT/US fusion imaging guidance. The conspicuity before and after the fusion imaging was graded on a five-point scale, and significance was assessed by Wilcoxon test. Technical success, procedure time, and procedure-related complications were evaluated. A total of 35 patients with 40 liver metastases (mean size 1.3 ± 0.4 cm) were enrolled. Image fusion improved conspicuity sufficiently to allow fusion-targeted MWA in 33 patients. The time required for image fusion processing and tumors’ identification averaged 10 ± 2.1 min (range 5–14). Initial conspicuity on US by inclusion criteria was 1.2 ± 0.4 (range 0–2), while conspicuity after localization on fusion imaging was 3.5 ± 1 (range 1–5, p

Background Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m 2 ) and triplet hepatic artery infusion (HAI) within European trial OPTILIV. Methods Irinotecan (180 mg/m 2 ), 5-fluorouracil (2800 mg/m 2 ) and oxaliplatin (85 mg/m 2 ) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models. Results Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33–76 years, with a median of 12 liver metastases (LMs) (2–50), involving five segments (1–8). Ten patients had a late response, and 31 patients had no response. Grade 3–4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation—odds ratio (OR): 6.0 (1.2–29.8; p = 0.029)—and LM diameter ≤57 mm—OR: 5.3 (1.1–25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection—OR: 11.8 (1.4–100.2; p = 0.024) and overall survival—hazard ratio: 0.39 (0.17–0.88; p = 0.023) in multivariate analyses. Conclusions Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making. Protocol numbers : EUDRACT 2007-004632-24 NCT00852228.

Hepatic intra-arterial port Indications Because hepatic artery infusion chemotherapy (HAIC) is a local treatment, it is most often used in case of liver cancer without extrahepatic disease, or in patients with predominant hepatic disease. Such treatment has been used mostly as salvage therapies after failure of intravenous (IV) standard-of-care therapies for metastases, and because response rate remains interesting even when using the same drug that was or became inefficient with IV administration. Due to the high response rate of HAIC, there are some recent reports and ongoing study using such therapies in first line. The goal of such therapies in first line, as a so-called induction treatment, is to obtain as early as possible in the disease the highest response possible in order to downstage a non-surgical candidate to a surgical candidate. Indeed, it has been demonstrated that the increase in response rate of colorectal liver-only metastases (CRLM) to treatment is linearly correlated with an increase in resection rate, and consequently with an increased chance of cure. Such induction chemotherapy targeting specifically the liver is obviously even more interesting in patients with liver-limited disease which demonstrated a steeper slope of the linear correlation between response and downstaging from non-operable to surgical candidates. HAIC used in an adjuvant setting after liver resection has been demonstrated to increase survival. For primary tumors, and namely hepatocellular carcinoma, the use of HAIC is less common due to the high efficacy of transarterial chemoembolization (TACE). Indications are probably in patients not responding to TACE or not candidates for TACE due to portal vein thrombosis or advanced liver insufficiency. HAIC is technically more challenging than systemic chemotherapy, because it requires the implantation of an indwelling catheter in the hepatic artery that is connected to a subcutaneous port for the administration of repeated courses of HAIC. The main drawbacks that hampered the use of HAIC were that, until recently, the implantation of such a device required a laparotomy, and additionally, frequent catheter dysfunction led to discontinued treatment. For example, in a randomized controlled study comparing HAIC with 5-fluorouracil (5-FU) to systemic 5-FU in 290 cases, 50 (37%) patients allocated to HAIC did not start their treatment, and another 39 (29%) had to stop before receiving six cycles of treatment because of catheter failure. Only 33% of patients received at least six courses of HAIC vs. 78% for the IV route.

Purpose: This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS). Experimental Design: Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion. Results: Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6–40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10%–90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible. Conclusions: A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. Clin Cancer Res; 23(4); 908–17. ©2016 AACR.

Two clinical strains, NF 296 and NF 931, present in our collection, were identified biochemically as members of CDC group II-i. Determination of the 16S rRNA gene sequence revealed highest similarity with strains of Sphingobacterium mizutaii . Because these strains produced indole, whereas S. mizutaii has been described as indole-negative, we also investigated the type strain and a reference strain of S. mizutaii , LMG 8340T ( = CCUG 15907T) and LMG 8341 ( = CCUG 15908), and found both strains also to be positive for indole production. These data warrant inclusion of some of the CDC group II-i strains into S. mizutaii and emended descriptions of Sphingobacterium mizutaii as indole-production-positive and of the genus Sphingobacterium as variable for indole production.

Analysis of gyrB gene sequences, (GTG)5-primed PCR fingerprinting and biochemical characteristics determined in the Biolog GEN III microtest system were used to differentiate an unnamed Kerstersia species from Kerstersia gyiorum , the type and only named species in this genus. The inability to oxidize d-galacturonic and d-glucuronic acids and the ability to oxidize d-serine, along with gyrB gene sequence analysis and (GTG)5-PCR fingerprints, readily differentiated the unnamed taxon from the type species. Therefore, we propose to formally classify this unnamed taxon as Kerstersia similis sp. nov. with strain LMG 5890T ( = CCUG 46999T), isolated from a leg wound in the USA in 1983, as the type strain.

Objective. Hepatocellular carcinoma (HCC) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis. We assessed the safety, efficacy, and potential biomarkers of activity of bevacizumab in patients with advanced HCC. Methods. In this phase II trial, eligible patients received bevacizumab, 5 mg/kg or 10 mg/kg every 2 weeks. The disease-control rate at 16 weeks (16W-DCR) was the primary endpoint. Circulating endothelial cells (CECs) and plasma cytokines and angiogenic factors (CAFs) were measured at baseline and throughout treatment. Results. The 16W-DCR was 42% (95% confidence interval, 27%–57%). Six of the 43 patients who received bevacizumab achieved a partial response (objective response rate [ORR], 14%). Grade 3–4 asthenia, hemorrhage, and aminotransferase elevation occurred in five (12%), three (7%), and three (7%) patients, respectively. During treatment, placental growth factor markedly increased, whereas vascular endothelial growth factor (VEGF)-A dramatically decreased (p < .0001); soluble VEGF receptor-2 (p < .0001) and CECs (p = .03) transiently increased on day 3. High and increased CEC counts at day 15 were associated with the ORR (p = .04) and the 16W-DCR (p = .02), respectively. Lower interleukin (IL)-8 levels at baseline (p = .01) and throughout treatment (p ≤ .04) were associated with the 16W-DCR. High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times (p ≤ .04). Conclusion. Bevacizumab is active and well tolerated in patients with advanced HCC. The clinical value of CECs, IL-6, and IL-8 warrants further investigation.

We report a case of fulminant endocarditis on a prosthetic homograft aortic valve caused by Bordetella holmesii, which was successfully managed by surgical valve replacement and antibiotic treatment. B. holmesii, a strictly aerobic, small, Gram-negative coccobacillus, has been implicated as an infrequent cause of a pertussis-like syndrome and other respiratory illnesses. However, B. holmesii is also a rare cause of septicaemia and infective endocarditis, mostly in immunocompromised patients. To our knowledge, this is the first report of B. holmesii endocarditis on a prosthetic aortic valve. Routine laboratory testing initially misidentified the strain as Acinetobacter sp. Correct identification was achieved by 16S rRNA gene and outer-membrane protein A (ompA) gene sequencing. Interestingly, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry also produced an accurate species-level identification. Subsequent susceptibility testing and review of the literature revealed ceftazidime, cefepime, carbapenems, aminoglycosides, fluoroquinolones, piperacillin/tazobactam, tigecycline and colistin as possible candidates to treat infections caused by B. holmesii.

The purpose of this study was to study the pharmacokinetics of irinotecan injected intravenously, intra-arterially, or loaded onto a delivery platform.Fifty-four New Zealand White rabbits with VX2 liver tumor, divided in 3 groups of 17 rabbits, each received irinotecan either by intravenous (IV) route, intra-arterial hepatic (IA) route, or loaded on drug-eluting beads (DEBIRI). Animals were killed at 1, 6, and 24 h. Irinotecan and SN-38 concentrations were measured at different time points in serum, tumor, and normal liver.Twelve milligrams of irinotecan were injected IV and IA, whereas 6-16.5 mg were injected loaded onto DEBIRI. Normalized serum irinotecan reached a peak of 333 ng/ml (range 198.8-502.5) for IV, 327.1 ng/ml (range 277.1-495.6) for IA, and 189.7 ng/ml (range 111.1-261.9) for DEBIRI (P 0.001) delivery. The area-under-the-curve value from 10 to 60 min of serum irinotecan concentration was significantly lower for DEBIRI (P = 0.0009). Tumor irinotecan levels for IV, IA, and DEBIRI (in ng/200 mg of tissue followed by ranges in parentheses) were, respectively, 23.6 (0.3-24.9), 36.5 (7.7-1914.1), and 20.2 (2.9-319) at 1 h; 4.2 (1-27.9), 99.3 (46.6-159.5), and 42.1 (11.3-189) at 6 h; and 2.7 (2.5-6.9), 18.3 (1.5-369.1), and 174.4 (3.4-5147.3) at 24 h (P = 0.02). At 24 h, tumor necrosis was 25% (10-30), 60% (40-91.25), and 95% (76.25-95) for IV, IA, and DEBIRI, respectively (P = 0.03).Compared with IV or IA, DEBIRI induces lower early serum levels of irinotecan, a high and prolonged intratumoral level of irinotecan, and a greater rate of tumor necrosis at 24 h. Further evaluation of the clinical benefit of DEBIRI is warranted.

Purpose To assess the efficacy of isolated pelvic perfusion (IPP) with tumor necrosis factor (TNF)-α and melphalan in patients with locally advanced cancers in the pelvic and groin area requiring mutilating surgery. Methods A total of 27 patients were enrolled (carcinoma, n = 17; sarcoma/melanoma, n = 4; and endocrine tumor, n = 6). They were candidates for exarticulation (n = 3) or exenteration (n = 11) or were judged unresectable (n = 13). In installing IPP, tourniquets were positioned around both thighs, and an inflated pressure suit was placed at a subthoracic position. Tumor necrosis factor-α (300 μg) was injected in the perfusate, followed 5 minutes later by melphalan at 1.5 mg/kg. After 30 minutes, the remaining drugs were washed out. Leakage was assessed with technetium Tc 99m radiolabeled human serum albumin, and a pharmacokinetic study was performed. Efficacy was based on the complete response rate observed on magnetic resonance imaging. Results Pelvic/systemic ratios of melphalan/TNF/technetium Tc 99m were 14.2/7/3.6. Responses on magnetic resonance imaging were as follows: 30% complete, 30% partial, 19% no change, and 15% progression. Two patients were not evaluable because they did not receive the treatment. Pre-IPP/post-IPP median percentage of necrosis on magnetic resonance imaging was 10%/70%. Median follow-up was 43 months. Median overall survival was 17 months. Twelve-month survival rate, disease-free survival, and local and metastatic recurrence rates were 67%, 30%, 57%, and 26%, respectively. Conclusions Isolated pelvic perfusion with TNF-α compares favorably with historical data, as it was observed in limb perfusion and could provide a chance to translate its successful combination with chemotherapy into treatment of locally advanced pelvic cancers.

An Asian study showed that gamma glutamyl transpeptidase (GGT) can predict survival after transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). This study was designed to validate in a European population this biomarker as an independent predictor of outcome after TACE of HCC and to determine a threshold value for clinical use.In 88 consecutive patients treated by TACE for HCC, the optimal threshold for GGT serum level was determined by a ROC analysis. Endpoints were time-to-treatment failure (TTTF) and overall survival (OS). All multivariate models were internally validated using bootstrapping (90 replications).Median follow-up lasted 373 days, and median overall survival was 748 days. The optimal threshold for GGT was 165 U/L (sensitivity: 89.3%; specificity: 56.7%; area under the ROC curve: 0.7515). Median TTTF was shorter when GGT was ≥165 U/L (281 days vs. 850 days; P0.001). GGT ≥165 U/L (hazard ratio (HR) = 2.06; P = 0.02), WHO PS of 2 (HR = 5.4; P = 0.002), and tumor size (HR = 1.12; P = 0.014) were independently associated with shorter TTTF. Median OS was shorter when GGT was ≥165 U/L (508 days vs. not reached; P0.001). GGT ≥ 165 U/L (HR = 3.05; P = 0.029), WHO PS of 2 (HR = 12.95; P0.001), alfa-fetoprotein (HR = 2.9; P = 0.01), and tumor size (HR = 1.096; P = 0.013) were independently associated with shorter OS. The results were confirmed by bootstrapping.Our results provide in a European population the external validation of GGT as an independent predictor of outcome after TACE of HCC. A serum level of GGT ≥ 165 U/L is independently associated with both shorter TTTF and OS.

International audience; From 2006 to December 2009, 45 out of the 513 strains isolated from patients with invasive meningococcal disease in Belgium, were identified as Neisseria meningitidis serogroup B, non-serotypeable, subtype P1.14 (B:NT:P1.14). Most cases were geographically clustered in the northern part of the country. Multilocus Sequence Typing and antigen gene sequencing combined with Pulsed-Field Gel electrophoresis were used to investigate this cluster. Molecular typing showed that 39 out of these 45 N. meningitidis strains belonged to the clonal complex cc-269. The presence of the same PorA Variable Regions (VR1-VR2: 22, 14), the FetA allele (F5-1) and the highly similar Pulsed-Field Gel Electrophoresis profiles, supported genetic relatedness for 38 out of these 39 isolates. Retrospective analysis of B:NT:P1.22,14 isolates from 1999 onwards suggested that these strains belonging to the cc-269 complex, first emerged in the Belgian province of West-Flanders in 2004. This study showed that the combination of molecular tools with classical methods enabled reliable outbreak detection as well as a cluster identification.

340 Background: Hafnium oxide nanoparticles, NBXTR3, were developed to increase the tumor-localized high energy deposit once activated by ionizing radiation such as stereotactic body radiotherapy (SBRT) and thus to increase tumor cell death compared to the same dose of radiation. NBTXR3 is characterized by a single intratumor/intralesional (IL) administration and fits into standard RT schedule with no change in patient’s flow, treatment protocol or equipment. Herein the preliminary results of a phase I/II clinical trial evaluating this combination in patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets). Methods: HCC and liver mets patients were treated with an IL injection of NBTXR3 followed by SBRT (15 Gy∗3 fractions). The phase I part of the trial follows a 3+3 dose escalation design at dose levels of NBTXR3 corresponding to 10%, 15%, 22%, 33% of the baseline tumor volume. This study aims primarily to identify the Recommended Dose and the incidence of early Dose Limiting Toxicities (DLTs) of NBTXR3 activated by SBRT. Secondary endpoints include assessment of global safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST 1.1). Results: Enrollment is at the last dose level, 33%, and completed at 10% (6 pts), 15% (4 pts) and 22% (4 pts). So far, no early DLTs nor severe adverse events related to NBTXR3 were observed. Both CPS and APRI did not reveal important variations in accordance to NBTXR3 low toxicity. The best observed target lesions responses, among 7 evaluable HCC pts for response (mRECIST), were: 3 complete responses, 3 partial responses (PR) and 1 stable disease (SD) and among 5 evaluable liver mets pts: 1 PR, 3 SD and 1 progressive disease (RECIST 1.1). Conclusions: NBTXR3 is well tolerated at the 22% dose level with an overall positive safety profile. This innovative approach might constitute a valuable solution for pts with liver tumors beyond standard treatment lines. NBTXR3 was successful in a phase II/III in soft tissue sarcoma [NCT02379845] and is currently evaluated in head and neck [NCT01946867; NCT02901483], prostate [NCT02805894] and rectum cancers. Clinical trial information: NCT02721056.

To compare fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with computed tomography (PET/CT) and chest CT in the evaluation of the effectiveness of lung radiofrequency (RF) ablation.Institutional review board approved the study, and all patients gave written informed consent. Thirty-four patients (22 men and 12 women; mean age, 64 years) planned to undergo lung RF ablation were prospectively included and underwent FDG PET/CT and chest CT before (pre-RF ablation PET) and 24 hours, 1 month, and 3 months after RF ablation. Persistent equivocal findings up to 3 months were followed up.Pre-RF ablation PET led to changes in the treatment strategy in nine patients (26%) by depicting unexpected metastases. Two patients without FDG uptake in lesions to be treated were excluded. Overall, 28 patients (46 lesions: five primary cancer, 41 metastases) were treated and followed up. Within 3 months after RF ablation, incomplete treatment was diagnosed in four of 28 patients (14%, three at 1 month and one at 3 months). Findings of FDG PET/CT were true-positive in four, false-positive in one, and true-negative in 23 patients. Findings of chest CT were true-positive in one, false-positive in one, false-negative in three, and true-negative in 23 patients. Inflammatory FDG uptake in mediastinal lymph nodes and at the needle path puncture site used for RF ablation was observed in 15%, 21%, and 15% of patients and in 19%, 11%, and 15% of patients at 24 hours, 1 month, and 3 months, respectively.FDG PET/CT can be used for the evaluation of the effectiveness of lung RF ablation. Inflammatory FDG uptake in mediastinal lymph nodes or at the needle path site used for RF ablation may occur.

e16194Background: Hepatocellular carcinoma (HCC) is the most widespread primary liver cancer. Liver metastasis (mets) are even more common with a wide range of malignancies. Management of both live...

e23512Background: Imatinib (IM) treatment should be continued indefinitely in advanced GIST since treatment interruption is generally followed by rapid tumor progression in almost all cases, even w...

A transcriptional signature of the pan–cyclin-dependent kinase (Cdk) inhibitor PHA-793887 was evaluated as a potential pharmacodynamic and/or response biomarker in tumor and skin biopsies from patients treated in a phase I clinical study. We first analyzed the expression of a number of known E2F-dependent genes that were predicted to be modulated after Cdk2 and Cdk4 inhibition in xenograft tumor and skin samples of mice treated with the compound. This panel of 58 selected genes was then analyzed in biopsies from seven patients treated with PHA-793887 in a phase I dose escalation clinical trial in solid tumors. Quantitative real-time PCR or microarray analyses were done in paired skin and tumor biopsies obtained at baseline and at cycle 1. Analysis by quantitative real-time PCR of the signature in skin biopsies of patients treated at three different doses showed significant transcriptional downregulation with a dose-response correlation. These data show that PHA-793887 modulates genes involved in cell cycle regulation and proliferation in a clinical setting. The observed changes are consistent with its mechanism of action and correlate with target modulation in skin and with clinical benefit in tumors. Mol Cancer Ther; 9(5); 1265–73. ©2010 AACR.

During the summer of 2005, an increase in reports of human cases of Salmonella enterica serovar Ohio infection was observed in Belgium. During 11 weeks, between 1 July and 13 September, 60 cases of laboratory-confirmed Salmonella Ohio infection were reported to the National Reference Centre for Salmonella, with a peak onset of symptoms in the third week of July. All clinical isolates caused self-limiting gastroenteritis; both genders (32 males and 28 females) and all age groups (three children5 years of age, three children 5 to 14 years of age, 32 adults 15 to 64 years of age, and 22 adults65 years of age) were affected. The isolates were distributed throughout Belgium but a cluster of several cases was observed around Brussels. At the same time, an increase in the incidence of this serovar was observed in the Salmonella isolates originating from the official surveillance campaign conducted by the Federal Agency for the Safety of the Food Chain, which identified pork as a likely source of the outbreak strain. Pulsed-field gel electrophoresis typing confirmed the clonal relationship between the human isolates, the isolates from samples collected in the cutting plants, and the isolates from pork meat in distribution. Further epidemiological investigations indicated that one particular slaughterhouse was involved. In that slaughterhouse, the carcasses were contaminated during the evisceration process because of contaminated equipment and uncontrolled environmental conditions. This study highlights the importance of a centralized surveillance laboratory in the management of outbreaks and the need of strict implementation of hygienic rules to avoid this type of outbreak.

Background: The Mongolian gerbil model is often used to investigate the interactions between different gastric Helicobacter species and the gastric tissue. A preliminary screening of a gerbil population intended for use in Helicobacter suis infection studies revealed a natural yeast infection in the stomach of these animals. After identification, we have investigated the effect of the gastric yeast infection on the outcome of an experimental H. suis infection in Mongolian gerbils. Materials and methods: Yeast cells were isolated from the stomachs of Mongolian gerbils. Identification was done by Internally Transcribed rRNA Spacer 2 Region (ITS2) PCR fragment length analysis. To investigate a possible pathologic role of this yeast, Mongolian gerbils were infected experimentally with this yeast. Co-infection with the newly isolated Helicobacter suis was performed to investigate possible interactions between both micro-organisms. Results: Kazachstania heterogenica was found colonizing the stomach of Mongolian gerbils, mainly in the antrum. Few pathologic changes were seen in the stomachs of infected animals. Experimental co-infection of gerbils with this yeast and the newly isolated Helicobacter suis showed a significant increase in inflammation in animals infected with both micro-organisms compared to animals infected only with Helicobacter suis. Conclusions: Kazachstania heterogenica colonizes the stomach of Mongolian gerbils in exactly the same regions as gastric Helicobacter species. The uncontrolled presence of this yeast in the gerbil stomach can lead to an overestimation of the inflammation caused by Helicobacter in this animal model.

A collection of eight strains, NF 1366(T), NF 450, NF 1101, NF 1107, NF 1123, NF 1413, CCUG 15260 and CCUG 15624, from various clinical origins, were characterized biochemically as similar to Kaistella koreensis and Chryseobacterium haifense. They differed from K. koreensis, which is unable to alkalinize acetate, and from C. haifense, which is ONPG-positive (beta-galactosidase) and acidifies sucrose, fructose and lactose. Based on 16S rRNA gene sequence comparisons, this collection of strains was most closely related to the type strains of K. koreensis (97.3-97.5 %) and C. haifense (99.1 %). Representative strain NF 1366(T) showed only 41.8 % DNA-DNA relatedness with K. koreensis DSM 12107(T) and only 51.9 % with C. haifense DSM 19056(T). DNA-DNA hybridization of strains NF 450 and CCUG 15624 to strain NF 1366(T) was 41.7 and 74.6 %, respectively, and relatedness of these strains with C. haifense DSM 19056(T) was 72.6 and 70.2 %. With the present information, these two strains must be classified as intermediate between C. haifense and strain NF 1366(T). The fatty acid composition and polar lipid profile of strain NF 1366(T) were similar to those reported for other Chryseobacterium species. Like other chryseobacteria, strain NF 1366(T) exhibited a polyamine pattern with the predominant compound sym-homospermidine and a quinone system consisting of menaquinone MK-6 only. For this collection of clinical strains, the name Chryseobacterium anthropi sp. nov. is proposed, with NF 1366(T) (=CCUG 52764(T) =CIP 109762(T)) as the type strain. K. koreensis was shown to be very similar genotypically and phenotypically to Chryseobacterium. Its polar lipid profile exhibited the major characteristics shown for recently described Chryseobacterium species and the fatty acid profile of K. koreensis was also very similar to those of the Chryseobacterium species. Hence, no striking genotypic or phenotypic differences could be found that could justify the classification of this species into a separate genus, and we therefore propose to reclassify Kaistella koreensis in the genus Chryseobacterium as Chryseobacterium koreense comb. nov. (type strain Chj707(T) =IAM 15050(T) =JCM 21512(T) =KCTC 12107(T) =NBRC 103027(T)). An emended description of the genus Chryseobacterium is also proposed.

The name 'Acinetobacter venetianus' has been used previously to designate three marine hydrocarbon-degrading Acinetobacter strains, of which strain RAG-1 (=ATCC 31012) has industrial applications for the production of the bioemulsifier emulsan. However, to date, the name of this taxon has not been validly published. In this study, five strains were examined to corroborate the delineation of this taxon by means of phenotypic characterization, DNA-DNA hybridization, selective restriction fragment amplification (AFLP), amplified rDNA restriction analysis (ARDRA), rpoB gene sequence analysis and tRNA intergenic spacer length polymorphism analysis (tDNA-PCR) and to emend the description of 'Acinetobacter venetianus' (ex Di Cello et al. 1997). AFLP analysis showed that the five strains formed a tight cluster at 56.8 +/- 5.0% genomic relatedness that was separated from strains of other haemolytic species of the genus Acinetobacter and from the type and reference strains of other Acinetobacter species at

To prospectively evaluate the technical feasibility, effectiveness, and complications of percutaneous radiofrequency (RF) ablation for hepatic malignancies during temporary percutaneous balloon occlusion (PBO) of a large hepatic or portal vein.During a 4-year period, RF ablation was performed in 201 patients (106 men, 95 women; age range, 41-88 years) with 233 liver tumors. Institutional review board approval was obtained to attempt RF ablation during PBO for 18 tumors that were larger than 35 mm (mean, 43 mm +/- 7.6 [standard deviation]; range, 36-60 mm) and did not abut a portal or hepatic vein 4 mm in diameter or larger (group 1), 58 tumors 35 mm or smaller (mean, 23 mm +/- 7.3; range, 12-35 mm) that abutted a large vessel (group 2), and 20 tumors that were both larger than 35 mm (mean, 42 mm +/- 5.7; range, 38-50 mm) and abutted a large vessel (group 3). RF ablation without PBO was performed for 137 tumors 35 mm or smaller (mean, 22 mm +/- 6.8; range, 9-35 mm) and remote from large vessels (group 4). Rate of local tumor progression was estimated with the Kaplan-Meier method, and tumor progression-free rates were compared between the four groups with the log-rank test. Complications were compared by using the Fisher exact test between the four groups and between the two RF devices used.PBO was achieved in 94 of 96 attempts (98%), including 64 of 64 hepatic veins and 30 of 32 portal branches. After a mean follow-up of 18 months +/- 9, 10 tumors in eight patients were lost to follow-up. Local tumor progression was observed in six (40%) of 15 tumors in group 1, in six (11%) of 56 tumors in group 2, in eight (40%) of 20 tumors in group 3, and in 12 (9%) of 130 tumors in group 4. Combined analysis of tumor size and the use of PBO showed that size was the only prognostic factor for tumor progression, with a hazard ratio of 4.9 (95% confidence interval: 2.4, 9.9) (P.001). There were no differences between groups 2 and 4. Asymptomatic, transient postprocedure venous thrombosis was seen in nine of 94 RF ablations with PBO, while occlusion of one permanent portal branch induced segmental liver atrophy. There were no differences in rates of complications (5% and 6% for RF ablation with and that without PBO, respectively).RF ablation with PBO provides tumor control for tumors smaller than 35 mm in diameter that abut vessels 4 mm or larger, equivalent to tumor control of the same-size tumors away from vessels. PBO does not seem to affect the results of RF ablation for tumors 35 mm or larger.

The oncological landscape is constantly changing with the development of new curatively intended therapeutic strategies. More and more, liver metastases are amenable to resection following the progress achieved as a result of new oncological concepts (i.e., treat detectable disease with surgery and ablative therapies and treat the remaining nondetectable disease with efficient chemotherapy) as well as improved chemotherapeutic and ablation techniques. One of the major limitations to extending the indications for liver resection is the volume of the future remnant liver (FRL). To overcome these limitations, portal vein embolization (PVE) has played a key role in obtaining preoperative hypertrophy of the FRL and thus has reduced postoperative morbidity and mortality. Interestingly, thermal ablation of multiple bilateral liver metastases makes it difficult to predict the volume of parenchyma scheduled for ablation. Furthermore, prolonged chemotherapy impairs liver parenchyma function, which has a negative impact on liver hypertrophy. In the future, both volumetric and functional assessment of the FRL will be used to determine whether PVE is necessary before hepatectomy in individual patients and new strategies (e.g., PVE used alone or combined with other treatments; timing of PVE may vary) will be based on these principles. This article presents various current strategies for the use of PVE in patients with metastatic liver cancer.

To evaluate the diagnostic performance of lung biopsies performed immediately after radiofrequency ablation (RFA). Twenty consecutive patients were treated with lung RFA. A biopsy was performed immediately after RFA, through the cannula used to insert the RFA probe to avoid hampering the RFA probe placement. Biopsies were analysed for diagnostic of malignancy and tumour morphological characteristics. Recurrence of RFA and procedure-related complications are reported. Mean tumour size was 17.3 mm (±6.2 mm). Ninety per cent (18/20) of biopsies were able to help diagnose malignancy. Cancer subtype and origin were determined in 70 % (14/20) of tumours, including 12 metastases and two primary lung cancers. During a median follow-up of 24 months, one tumour demonstrated local progression (5 %). The overall survival, lung disease-free survival and progression-free survival rates at 12 months were 100 %, 75 % and 65 %, respectively. Adverse events of the procedure including RFA and biopsy were five pneumothoraces requiring chest tube placement (25 %), seven minor pneumothoraces (35 %) and one subsegmental intrapulmonary haemorrhage (5 %) not requiring any treatment. A biopsy performed immediately after lung RFA allowed diagnosis of malignancy in 90 % of cases. This diagnosis is obtained without the need for additional puncture and does not hamper the accuracy of the initial RF probe placement. • Treatment and biopsy are feasible during the same procedure, avoiding multiple punctures. • The best puncture path can be preserved to treat the lung tumour. • Malignancy can be determined on a post-RFA biopsy in 90 % of cases. • Cancer classification can be assessed in 70 % of cases after lung RFA.

MOSCATO-01 is a molecular triage trial based on on-purpose tumour biopsies to perform molecular portraits. We aimed at identifying factors associated with high tumour cellularity.Tumour cellularity (percentage of tumour cells in samples defined at pathology) was evaluated according to patient characteristics, target lesion characteristics, operators' experience and biopsy approach.Among 460 patients enrolled between November, 2011 and March, 2014, 334 patients (73%) had an image-guided needle biopsy of the primary tumour (N = 38) or a metastatic lesion (N = 296). Biopsies were performed on liver (N = 127), lung (N = 72), lymph nodes (N = 71), bone (N = 11), or another tumour site (N = 53). Eighteen patients (5%) experienced a complication: pneumothorax in 10 patients treated medically, and haemorrhage in 8, requiring embolisation in 3 cases. Median tumour cellularity was 50% (interquartile range, 30-70%). The molecular analysis was successful in 291/334 cases (87%). On-going chemotherapy, tumour origin (primary versus metastatic), lesion size, tumour growth rate, presence of necrosis on imaging, standardised uptake value, and needle size were not statistically associated with cellularity. Compared to liver or lung biopsies, cellularity was significantly lower in bone and higher in other sites (P 0.0001). Cellularity significantly increased with the number of collected samples (P 0.0001) and was higher in contrast-enhanced ultrasound-guided biopsies (P 0.02). In paired samples, cellularity in central samples was lower than in peripheral samples in 85, equal in 68 and higher in 89 of the cases.Image-guided biopsy is feasible and safe in cancer patients for molecular screening. Imaging modality, multiple sampling of the lesion, and the organ chosen for biopsy were associated with higher tumour cellularity.

A collection of eight clinical strains from Belgian hospitals and three clinical strains of the CCUG collection were characterized biochemically as being similar to CDC groups II-h and II-c; the latter differs from group II-h only by positivity for sucrose acidification. These 11 strains were found to cluster according to 16S rRNA gene sequence similarity at a level of ≥99.5 %, and on the basis of their tDNA-PCR profile. Based on 16S rRNA gene sequence analysis, this collection of strains was related most closely to Chryseobacterium hispanicum (97.2 %), but they differed from the type strain of this species by the following phenotypic characteristics: growth at 37 °C, negativity for xylose acidification, positivity for acetate assimilation–alkalinization on Simmons’ agar base and absence of flexirubin pigments, and by their tDNA-PCR profile. Strain NF802T showed only 57.8 % DNA–DNA relatedness to the type strain of C. hispanicum. Fatty acid composition did not enable differentiation from C. hispanicum. The DNA G+C content of strain NF802T is 36.5 mol%. The name Chryseobacterium hominis sp. nov. is proposed for this taxon, with type strain NF802T (=CCUG 52711T=CIP 109415T).

Purpose: To prospectively compare single- and multisection computed tomographic (CT) perfusion for tumor blood flow determination in an animal model. Materials and Methods: All animal protocols and experiments were approved by the institutional animal care and use committee before the study was initiated. R3230 mammary adenocarcinoma was implanted in 11 rats. Tumors (18–20 mm) were scanned with dynamic 16-section CT at baseline and after administration of arsenic trioxide, which is known to cause acute reduction in blood flow. The concentration of arsenic was titrated (0–6 mg of arsenic per kilogram of body weight) to achieve a defined blood flow reduction (0%–75%) from baseline levels at 60 minutes, as determined with correlative laser Doppler flowmetry. The mean blood flow was calculated for each of four 5-mm sections that covered the entire tumor, as well as for the entire tumor after multiple sections were processed. Measurements obtained with both methods were correlated with laser Doppler flowmetry ...

BACKGROUND New systemic therapies are needed to improve the prognosis of patients with advanced-stage hepatocellular carcinoma (HCC). In a Phase II trial involving previously untreated patients with advanced HCC, the more favorable schedule from a previous pilot study was evaluated. METHODS Thirty-four patients with previously untreated advanced-stage HCC were prospectively enrolled. The GEMOX regimen consisted of gemcitabine 1000 mg/m2 on Day 1 and oxaliplatin 100 mg/m2 on Day 2. The treatment was repeated every 2 weeks until disease progression or limiting toxicity. RESULTS Thirty-two patients were assessable for efficacy and 33 for toxicity. In all, 323 treatment cycles were administered. No toxic deaths occurred. Hematological grade 3-4 toxicity consisted of thrombocytopenia (27% of patients) and neutropenia (24%), including 2 febrile neutropenia and anemia (9%). Grade 3 oxaliplatin-induced neurotoxicity was observed in 3 (9%) patients. The overall response rate was 18% (95% confidence interval [CI]: 8-34) and disease stabilization was observed in 58% of patients (including 5 minor responses), giving a disease control rate of 76%. Median progression-free and overall survival times were, respectively, 6.3 months (95% CI: 4.3-10.1 months) and 11.5 months (95% CI: 8.5-14.3 months). Treatment was significantly more effective in patients with nonalcoholic cirrhosis than in those with alcoholic cirrhosis. CONCLUSIONS The GEMOX regimen seems to be well tolerated and active in advanced HCC, especially in patients with underlying nonalcoholic liver disease. A Phase II study of the GEMOX regimen plus cetuximab is ongoing. Cancer 2007. © 2007 American Cancer Society.