Philip R. Debruyne

Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases.

Background:The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ).Methods:Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk.Results:Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates.Conclusion:Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.

Prognostic impact of baseline serum C‐reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib

To evaluate the impact of baseline serum C‐reactive protein (CRP) level on outcome in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib.

Bile acids initiate lineage-addicted gastroesophageal tumorigenesis by suppressing the EGF receptor-AKT axis.

While bile acids are a risk factor for tumorigenesis induced by reflux disease, the mechanisms by which they contribute to neoplasia remain undefined. Here, we reveal that in gastroesophageal junction (GEJ) cells bile acids activate a tissue‐specific developmental program defining the intestinal epithelial cell phenotype characterizing GEJ metaplasia. Deoxycholic acid (DCA) inhibited phosphorylation of EGF receptors (EGFRs) suppressing the proto‐oncogene AKT. Suppression of EGFRs and AKT by DCA actuated an intestine‐specific cascade in which NF‐κB transactivated the tissue‐specifi c transcription factor CDX2. In turn, CDX2 orchestrated a lineage‐specific differentiation program encompassing genes characterizing intestinal epithelial cells. Conversely, progression from metaplasia to invasive carcinoma in patients, universally associated with autonomous activation of EGFRs and/or AKT, was coupled with loss of this intestinal program. Thus, bile acids induce intestinal metaplasia at the GEJ by activating the lineage‐specifi c differentiation program involving suppression of EGFR and AKT, activating the NF‐κB‐CDX2 axis. Induction of this axis provides the context for lineage‐addicted tumorigenesis, in which autonomous activation of AKT corrupts adaptive intestinal NF‐κB signaling, amplifying tumorigenic programs.

A Belgian survey on geriatric assessment in oncology focusing on large-scale implementation and related barriers and facilitators

OBJECTIVES The aim of this study is to describe a large-scale, Belgian implementation project about geriatric assessment (=GA) in daily oncology practice and to identify barriers and facilitators for implementing GA in this setting. Design / setting / participants: The principal investigator of every participating hospital (n=22) was invited to complete a newly developed questionnaire with closed- and open-ended questions. The closed-ended questions surveyed how GA was implemented. The open-ended questions identified barriers and facilitators for the implementation of GA in daily oncology practice. Descriptive statistics and conventional content analysis were performed as appropriate. RESULTS Qualifying criteria (e.g. disease status and cancer type) for GA varied substantially between hospitals. Thirteen hospitals (59.1%) succeeded to screen more than half of eligible patients. Most hospitals reported that GA data and follow-up data had been collected in almost all screened patients. Implementing geriatric recommendations and formulating new geriatric recommendations at the time of follow-up are important opportunities for improvement. The majority of identified barriers were organizational, with high workload, lack of time or financial/staffing problems as most cited. The most cited facilitators were all related to collaboration. CONCLUSION Interventions to improve the implementation of GA in older patients with cancer need to address a wide range of factors, with organization and collaboration as key elements. All stakeholders, seeking to improve the implementation of GA in older patients with cancer, should consider and address the identified barriers and facilitators.

Pathological staging and therapy of oesophageal and gastric cancer

Oesophageal and gastric cancers are a significant cause of morbidity and mortality worldwide. Despite improvements in surgical techniques, radiation and chemotherapy, the prognosis of both cancers remains poor. Immunohistochemical and experimental studies indicate that the concept of micrometastasis is applicable to oesophageal and gastric cancer. New staging approaches, including immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) of various markers, have been proposed for a more accurate staging of oesophageal and gastric cancer. Preliminary results suggest that real-time RT-PCR of markers for intestinal differentiation, such as guanylyl cyclase C (GC-C), might be useful for both the detection of premalignant conditions, such as intestinal metaplasia and the detection of micrometastasis from adenocarcinoma of the upper intestinal tract. Standard curative treatment options for oesophageal cancer include surgery or chemoradiotherapy. Chemotherapy is an option for the treatment of advanced and recurrent oesophageal cancer. Standard curative treatment for gastro-oesophageal junction and gastric cancer includes surgery and adjuvant chemoradiotherapy. Chemotherapy is an option for the treatment of advanced and recurrent gastric cancer.

Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography After Concurrent Chemoradiotherapy in Locally Advanced Head-and-Neck Squamous Cell Cancer: The ECLYPS Study

Purpose To assess the standardized implementation and reporting of surveillance [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan of the neck in locoregionally advanced head-and-neck squamous cell carcinoma (LAHNSCC) after concurrent chemoradiotherapy (CCRT). Patients and Methods We performed a prospective multicenter study of FDG-PET/CT scanning 12 weeks after CCRT in newly diagnosed patients with LAHNSCC (stage IVa/b) that used standardized reconstruction and Hopkins reporting criteria. The reference standard was histology or > 12 months of clinical follow-up. The primary outcome measure was the negative predictive value (NPV) of FDG-PET/CT scans and other supporting diagnostic test characteristics, including time dependency with increasing follow-up time. Results Of 152 patients, 125 had adequate primary tumor control after CCRT and entered follow-up (median, 20.4 months). Twenty-three (18.4%) had residual neck disease. Overall, NPV was 92.1% (95% CI, 86.9% to 95.3%; null hypothesis: NPV = 85%; P = .012) with sensitivity of 65.2% (95% CI, 44.9% to 81.2%), specificity of 91.2% (95% CI, 84.1% to 95.3%), positive predictive value of 62.5% (95% CI, 45.5% to 76.9%), and accuracy of 86.4% (95% CI, 79.3% to 91.3%). Sensitivity was time dependent and high for residual disease manifesting up to 9 months after imaging but lower (59.7%) for disease detected up to 12 months after imaging. Standardized reporting criteria reduced the number of equivocal reports (95% CI for the difference, 2.6% to 15.0%; P = .003). Test characteristics were not improved with the addition of lymph node CT morphology criteria. Conclusion FDG-PET/CT surveillance using Hopkins criteria 12 weeks after CCRT is reliable in LAHNSCC except for late manifesting residual disease, which may require an additional surveillance scan at 1 year after CCRT to be detected.

891PWEEKLY G-CSF IMPROVES THE TOLERABILITY OF WEEKLY PACLITAXEL-CARBOPLATIN. A PHASE II STUDY OF THE BELGIAN GYNAECOLOGICAL ONCOLOGY GROUP (BGOG-OV5)

ABSTRACT Aim: Weekly paclitaxel (60mg/m2) and carboplatin (AUC 2.7) (TCw) has been shown to be an effective treatment in patients with recurrent or advanced gynaecological cancer (Vandenput Int J Gyn Cancer 2012; Torfs Eur J Cancer 2012; Cadron Gynecol Oncol, 2013). The main toxicity of the regimen has been neutropenia grade (G) 3-4 and or neutropenic fever. Methods: In this prospective study 108 patients were needed to detect a 15% reduction in the occurrence of G3-4 neutropenia (a: 0.05; b: 0.95) compared with the historical incidence of 84%, by using prophylactic filgrastim on day 5 of each of the 18 weekly planned courses. The main inclusion criteria were: measurable disease, platin-resistant or refractory epithelial ovarian carcinoma (OC), or recurrent or advanced endometrial (EC) or cervical cancer (CC), and no prior weekly or dose-dense TC. Results: 108 (3 cohorts of ovarian, endometrial and cervical cancer of each 36 patients) were included by 12 BGOG centers between February 20, 2012 and March 14, 2013. The median number of prior chemotherapy lines was 3 for OC, 2 for EC and 1 for CC, respectively. The percentage of G3-4 neutropenia was 34% (CI: 26%-44%; p Conclusions: TCw with G-CSF support is feasible with an acceptable toxicity in patients with platin-resistant or –refractory OC, and advanced or recurrent EC or CC. The incidence of G3-4neutropenia is lower with the addition of weekly G-CSF compared with earlier studies without the addition of prophylactic G-CSF. Disclosure: All authors have declared no conflicts of interest.

Bile acids (BA) induce heparin-binding EGF-LIKE growth factor (HB-EGF) expression in human gastroesophageal (GE) adenocarcinoma cells

HB‐EGF, a member of the EGF family associated with tumor growth, is induced in GE cancers. BAs associated with GE reflux is a principle etiologic factor driving intestinal metaplasia and adenocarcinoma at the GE junction (GEJ). Recent studies revealed that HB‐EGF is a target gene of Cdx2, a transcription factor central to the development of differentiated intestinal cells. Here, the ability of BAs to regulate HB‐EGF expression in OE19 GEJ adenocarcinoma cells was examined.

Bile acids stimulate expression of intestinal differentiation markers in gastroesophageal junction (GEJ) adenocarcinoma cells

Reflux of acid and bile acids, and the subsequent development of intestinal metaplasia of the esophagus (Barretts esophagus) or gastric cardia are risk factors for the development of adenocarcinoma at the GEJ. However, the molecular mechanisms translating reflux exposure to epithelial cell transformation in the upper gastrointestinal tract remain undefined. Here, quantitative RT‐PCR revealed increased expression of guanylyl cyclase C (GC‐C), the receptor for bacterial heat‐stable enterotoxins (STa) and a marker of differentiated enterocytes, in adenocarcinomas of the esophagus and stomach, but not in squamous carcinomas of the esophagus, gastrointestinal stromal tumors, or normal esophageal or gastric mucosae. Similarly, the human GEJ adenocarcinoma cell line OE19 expressed GC‐C mRNA and accumulated cyclic GMP in response to STa. Interestingly, exposure of OE19 to the bile acid deoxycholate (DCA) stimulated GC‐C promoter activity, mRNA expression, protein expression (Western blot), and function (STa‐induced cyclic GMP accumulation). Moreover, treatment with DCA increased expression of the homeodomain proteins Cdx‐2 (mRNA and protein) and Oct1 (protein), upstream transcription factors important in regulating intestine‐specific expression of GC‐C. Of significance, hydrophilic bile acids such as cholate, taurodeoxycholate and ursodeoxycholate were ineffective compared to the hydrophobic bile acids chenodeoxycholic acid and DCA in inducing GC‐C and Cdx‐2 mRNA expression. These observations suggest that transformation at the GEJ is initiated, in part, by induction of the transcriptional program mediating enterocyte differentiation, including Oct1, Cdx‐2, and GC‐C, upon exposure to specific bile acids. Further, they suggest that suppression of hydrophobic bile acid production, for example by treatment with ursodeoxycholate, which does not activate the intestinal transcription program in epithelial cells, might be effective chemoprevention for GEJ tumorigenesis.