Sex-based survival differences in IDH-wildtype glioblastoma: Results from a retrospective cohort study.

A female survival benefit has been described for glioblastoma patients. Recent studies report that the effect of 06-methylguanine-DNA-methyltransferase gene promoter (MGMTp) methylation is only present in female patients. We retrospectively studied sex-based survival, including MGMTp-methylation, in a cohort of 159 uniformly treated isocitrate dehydrogenase wildtype (IDHwt) patients. All patients were treated with temozolomide-based chemoradiotherapy after surgery. Kaplan-Meier survival curves and Cox regression models were used to evaluate overall survival. The study included 59 female (37.1%) and 100 male patients (62.9%). There were no statistically significant differences between sexes concerning demographic, surgical or radiological characteristics. Female patients harbored MGMTp-methylated tumors in 45.8% of cases and males in 33% (P = 0.129). Median overall survival was 13.4 months for men and women alike. After adjustment of survival for age, Karnofsky Performance Score, extent of resection and MGMTp-methylation, sex did not have a significant survival impact. However, MGMTp-methylation proved to be an independent beneficial prognosticator for both sexes, contradicting earlier reports. Several sex-based molecular subtypes of glioblastoma with different response to current treatment may exist explaining conflicting survival results in different patient cohorts. Further research on sex-based differences in IDHwt glioblastoma patients is needed.

Central nervous system relapse in high-risk stage 4 neuroblastoma: The HR-NBL1/SIOPEN trial experience.

BACKGROUND: There is rising concern on the impact of new strategies, such as high-dose chemotherapy (HDC) and immunotherapy, on the pattern of relapse in high-risk neuroblastoma (HR-NBL). Our aim is to evaluate the incidence and identify risk factors for first recurrence in the central nervous system (CNS) in HR-NBL. PATIENTS AND METHODS: Data from patients with stage 4V HR-NBL included from February 2002 to June 2015 in the prospective HR-NBL trial of the European International Society of Pediatric Oncology Neuroblastoma Group were analysed. Characteristics at diagnosis, treatment and the pattern of first relapse were studied. CNS imaging at relapse was centrally reviewed. RESULTS: The 1977 included patients had a median age of 3 years (1 day-20 years); 1163 were boys. Among the 1161 first relapses, 53 were in the CNS, with an overall incidence of 2.7%, representing 6.2% of all metastatic relapses. One- and three-year post-relapse overall survival was 25 ± 6% and 8 ± 4%, respectively. Higher risk of CNS recurrence was associated with female sex (hazard ratio [HR] = 2.0 [95% confidence interval {CI}: 1.1-3.5]; P = 0.016), MYCN-amplification (HR = 2.4 [95% CI: 1.2-4.4]; P = 0.008), liver (HR = 2.5 [95% CI: 1.2-5.1]; P = 0.01) or >1 metastatic compartment involvement (HR = 7.1 [95% CI: 1.0-48.4]; P = 0.047) at diagnosis. Neither HDC nor immunotherapy was associated with higher risk of CNS recurrence. Stable incidence of CNS relapse was reported over time. CONCLUSIONS: The risk of CNS recurrence is linked to both patient and disease characteristics, with neither impact of HDC nor immunotherapy. These findings support the current treatment strategy and do not justify a CNS prophylactic treatment.

Subventricular zone contacting glioblastoma: tumor size, molecular biological factors and patient survival.

BACKGROUND: Several studies show that subventricular zone (SVZ) contact of glioblastoma at diagnosis is a negative prognosticator of survival. In this report, we study glioblastoma patient survival, molecular biological and MRI-based volumetric findings according to SVZ contact. PATIENTS AND METHODS: We conducted a retrospective study of adult patients diagnosed with supratentorial glioblastoma and uniformly treated with temozolomide-based chemoradiotherapy after surgery. The patient cohort was dichotomized according to tumor contact with the SVZ at diagnosis as determined on preoperative MR imaging. Tumor volume was measured using semi-automated segmentation technique. MGMT-gene promoter methylation and IDH mutation status were determined on stored tumor tissue. Kaplan-Meier survival curves were constructed. Cox regression analysis was used to adjust for known confounding factors of glioblastoma patient survival. RESULTS: A total of 214 patients were included in the study of whom 68% belonged to the SVZpos group. Median tumor volume was significantly larger in the SVZpos group (33,8 mL vs 15,6 mL; p < .001). MGMT-unmethylated glioblastoma was more frequent in the SVZpos group (61.4% vs 44.9%; p = .028). The overall survival and progression-free survival were 12.2 months and 5.9 months for the SVZpos patient group but 16.9 months and 10.3 months for the SVZneg group (log-rank p = .016 and .007 respectively). In multivariate Cox survival analysis, SVZ contact proved a negative prognostic parameter, independent from age, KPS, extent of resection, MGMT-methylation and IDH mutation status. CONCLUSIONS: This study confirms SVZ contact at diagnosis as an independent negative prognostic factor for glioblastoma patient survival. SVZpos glioblastoma had larger tumor size and a larger proportion of unmethylated tumors than SVZneg glioblastoma. Further research is needed to establish whether the observed differences are solely explained by a different molecular profile of SVZpos glioblastoma or by interaction of glioblastoma with the unique SVZ microenvironment.

Weak MGMT gene promoter methylation confers a clinically significant survival benefit in patients with newly diagnosed glioblastoma: a retrospective cohort study.

INTRODUCTION: Quantitative methylation specific PCR (qMSP) is a frequently used technique to assess MGMT gene promoter methylation in glioblastoma patients. The optimal technical cut-off value to distinguish methylated from unmethylated samples is nevertheless still undetermined. In literature, a "grey zone" of diagnostic uncertainty has been described. METHODS: We performed a retrospective analysis of newly diagnosed glioblastoma patients treated according to the Stupp protocol. Epidemiological data were gathered from the individual patient files. MGMT gene promoter methylation status was determined on stored tumour samples using qMSP. A strong, weak or absent promoter methylation was determined based on Cq values (quantification value) of the MGMT and ACTB primers as well as a positive control sample. RESULTS: In total, 181 patient files were reviewed and included for statistical analysis. MGMT promoter hypermethylation was detected in 38.7% of glioblastoma patients. The median overall survival of unmethylated and strongly methylated patients was 10.1 months and 19.7 months respectively. Furthermore, 11% of the total patient cohort had a weak MGMT gene promoter methylation. The median OS in this subgroup was 15.4 months, significantly better compared to the unmethylated cohort (P < 0.001). Multivariate Cox regression analysis showed weak MGMT promoter methylation as an independent prognostic parameter for overall survival. CONCLUSION: Glioblastoma patients with weak promoter methylation show a statistically significant longer overall survival when compared to clearly unmethylated patients. Patients with grey zone qMSP test results should receive additional molecular analysis in future to further direct individual therapy strategies.

The Evidence for External Beam Radiotherapy in High-Risk Neuroblastoma of Childhood: A Systematic Review.

AIMS: External beam radiotherapy is widely used in various ways in the management of neuroblastoma. Despite extensive clinical experience, the precise role of radiotherapy in neuroblastoma remains unclear. The purpose of this systematic review was to survey the published literature to identify, without bias, the evidence for the clinical effectiveness of external beam radiotherapy as part of the initial multimodality treatment of high-risk neuroblastoma. We considered four areas: treatment of the tumour bed and residual primary tumour, identification of any dose-response relationship, treatment of metastatic sites, identification of any technical advances that may be beneficial. We also aimed to define uncertainties, which may be clarified in future clinical trials. MATERIALS AND METHODS: Bibliographic databases were searched for neuroblastoma and radiotherapy. Reviewers assessed 1283 papers for inclusion by title and abstract, with consensus achieved through discussion. Data extraction on 57 included papers was carried out by one reviewer and checked by another. Studies were assessed for their level of evidence and risk of bias, and a descriptive analysis of data was carried out. RESULTS: Fifteen papers provided some evidence that radiotherapy to the tumour bed and residual tumour may possibly be of value. However, there is a significant risk of bias and no evidence that all subgroups will benefit. There is some suggestion from six papers that dose may be important, but no hard evidence. It remains unclear whether irradiation of metastatic sites is helpful. Technical advances may be of value in radiotherapy of high-risk neuroblastoma. CONCLUSIONS: There are data that show that radiotherapy is of some efficacy in the management of high-risk neuroblastoma, but there is no level one evidence that shows that it is being used in the best possible way. Prospective randomised trials are necessary to provide more evidence to guide development of optimal radiotherapy treatment schedules.

Effect of neoadjuvant radiation dose on surgical and oncological outcome in locally advanced esophageal cancer.

INTRODUCTION: Neoadjuvant chemoradiation (CRT) confers a survival benefit in locally advanced esophageal cancer. The optimal dose of radiotherapy remains undefined. METHODS: From a prospective database, we identified patients who received CRT followed by Ivor Lewis esophagectomy. Surgical complications, pathological response, and oncological outcome were compared between patients who received a radiotherapy (RT) dose of 36 Gy (group 1) versus a dose of > 40 Gy (group 2). RESULTS: 147 patients were evaluated : 109 received 36 Gy, while 38 received 41-50 Gy. Mean age was 61 ± 9 years (84% male). Median hospital stay was 16 days. Anastomotic leakage occurred in 4.0%. Pulmonary complications occurred in 41.8%, neither being influenced by RT dose. Complete resection (R0) was achieved in 95% (group 1) and 100% (group 2), P = 0.3. Pathological complete response (pCR) was observed in 19% (group 1) and 37% (group 2), P = 0.04. Local recurrence developed in 9% in group 1, and 3% in group 2 (P = 0.3), but regional recurrence developed significantly higher in the low dose group (28% vs 3%, P < 0.001). Metastatic recurrence occurred in 48% in group 1 and 13% in group 2 (P < 0.001). CONCLUSIONS: In patients with locally advanced esophageal cancer a higher RT dose does not affect surgical outcome, enhances pCR rate, and reduces the locoregional and metastatic recurrence risk.

Effect of Neoadjuvant Radiation Dose on Surgical and Oncological Outcome in Locally Advanced Esophageal Cancer.

INTRODUCTION: Neoadjuvant chemoradiation (CRT) confers a survival benefit in locally advanced esophageal cancer. The optimal dose of radiotherapy remains undefined. METHODS: From a prospective database, we identified patients who received CRT followed by Ivor Lewis esophagectomy. Surgical complications, pathological response, and oncological outcome were compared between patients who received a radiotherapy (RT) dose of 36 Gy (group1) versus a dose of > 40 Gy (group 1). RESULTS: 147 patients were evaluated: 109 received 36 Gy, while 38 received 41-50Gy. Mean age was 61 ± 9 years (84% male). Median hospital stay was 16 days. Anastomotic leakage occurred in 4.0%. Pulmonary complications occurred in 41.8%, neither being influenced by RT dose. Complete resection (R0) was achieved in 95% (group 1) and 100% (group 2), P = 0.3. Pathological complete response (pCR) was observed in 19% (group 1) and 37% (group 1), P = 0.04. Local recurrence developed in 9% in group 1, and 3% in group 2 (P = 0.3), but regional recurrence developed significantly higher in the low dose group (18% vs 3%, P < 0.001). Metastatic recurrence occurred in 48% in group 1 and 13% in group 1 (P < 0.001). CONCLUSIONS: In patients with locally advanced esophageal cancer a higher RT dose does not affect surgical outcome, enhances pCR rate, and reduces the locoregional and metastatic recurrence risk.

Serial comprehensive geriatric assessment in elderly head and neck cancer patients undergoing curative radiotherapy identifies evolution of multidimensional health problems and is indicative of quality of life.

Head and neck (H&N) cancer is mainly a cancer of the elderly; however, the implementation of comprehensive geriatric assessment (CGA) to quantify functional age in these patients has not yet been studied. We evaluated the diagnostic performance of screening tools [Vulnerable Elders Survey-13 (VES-13), G8 and the Combined Screening Tool 'VES-13 + (17-G8)' or CST], the feasibility of serial CGA, and correlations with health-related quality of life evolution [HRQOL; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ)-C30 and -HN35] during therapy in hundred patients, aged ≥65 years, with primary H&N cancer undergoing curative radio(chemo)therapy. Respectively 36.8%, 69.0%, 62.1% and 71.3% were defined vulnerable according to VES-13, G8, CST and CGA at week 0, mostly due to presence of severe grade co-morbidities, difficulties in community functioning and nutritional problems. At week 4, significantly more patients were identified vulnerable due to nutritional, functional and emotional deterioration. The CST did not achieve the predefined proportion necessary for validation. Vulnerable patients reported lower function and higher symptom HRQOL scores as compared with fit patients. A comparable deterioration in HRQOL was observed in both groups through therapy. In conclusion, G8 remains the screening tool of choice. Serial CGA identifies the evolution of multidimensional health problems and HRQOL conditions during therapy with potential to guide individualised supportive care.

Differentiation between peri-anastomotic inflammatory changes and local recurrence following neoadjuvant radiochemotherapy surgery for colorectal cancer using visual and semiquantitative analysis of PET-CT data.

AIM: The aim of this study was to evaluate the usefulness of visual and semiquantitative [¹8F]fluorodeoxy-glucose (FDG) positron emission tomography-computed tomography (PET-CT) data for the diagnosis of peri-anastomotic colorectal cancer recurrence, taking into account the time period between surgery and [¹8F]FDG PET-CT scanning. METHODS: The study population consisted of 70 patients who had prior preoperative radiochemotherapy and surgical resection of the primary tumor and who underwent whole body [¹8F]FDG PET-CT scanning for the detection of recurrent disease. Visual and semiquantitative (SUV(max)) analysis of [¹8F]FDG uptake at the peri-anastomosis was performed. The final diagnosis was based on pathological proof or clinical and/or imaging follow-up data. RESULTS: On visual reading, 27 patients exhibited increased [¹8F]FDG uptake at the peri-anastomosis. Of these, 11 (41%) patients had a local tumor recurrence and 16 (59%) had no recurrent tumor. Among the 43 patients without increased [¹8F]FDG uptake at the peri-anastomosis, none had local tumor recurrence. On semiquantitation, SUV(max) in patients with and without a local recurrence overlapped. However, when the time period between surgery and [¹8F]FDG PET-CT scanning was taken into account, overlap of SUV(max) was mainly observed within a postoperative period of ≤12 months; thereafter, a threshold SUV(max) of 3.2 discriminated between benign and malignant lesions in all but one patient. CONCLUSION: In our series, visually increased [¹8F]FDG uptake at the peri-anastomosis was 100% sensitive but non-specific (73% specificity) for the diagnosis of local tumor recurrence. On the other hand, normal [¹8F]FDG uptake at the peri-anastomosis precluded a local tumor recurrence (a negative predictive value of 100%). In addition, semiquantitative (SUV(max)) analysis of [¹8F]FDG uptake at the peri-anastomosis may increase specificity (up to 97%), while preserving maximum sensitivity, if the postoperative period is >12 months.

Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I-II study.

BACKGROUND: The prognosis of pancreaticobiliary tumors is poor. The aim was to assess the feasibility of radiotherapy (RT) and concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma. PATIENTS AND METHODS: Twenty-two patients with locally advanced pancreatic (n = 17) or biliary tract cancer (n = 5) were included. They received two cycles of gemcitabine/oxaliplatin followed by 5 weeks of RT in combination with a weekly fixed dose gemcitabine and an escalating dose of oxaliplatin from 40 up to 70 mg/m(2). National Cancer Institute-Common Toxicity Criteria 3.0 was used to score weekly the treatment-related toxicity. RESULTS: The patients treated at a dose of 40 mg/m(2) of oxaliplatin had no dose-limiting toxicity. At 50 mg/m(2), two patients developed grade 4 thrombocytopenia. Nine patients received 60 mg/m(2), one developed grade 4 thrombocytopenia. Grade 4 thrombocytopenia in two patients and grade 3 diarrhea in one patient were observed with 70 mg/m(2). Median time to progression was 8 months and median overall survival was 17 months. CONCLUSIONS: RT in combination with gemcitabine and oxaliplatin is feasible in patients with locally advanced pancreaticobiliary cancer. The reported time to progression underlines the potential activity of this regimen. The dose of 60 mg/m(2) of oxaliplatin can be considered as the recommended dose.

In vitro cytotoxicity of paclitaxel/beta-cyclodextrin complexes for HIPEC.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising strategy in the treatment of peritoneal carcinomatosis. To perform HIPEC, a tensioactive- and solvent-free paclitaxel formulation consisting of water-soluble paclitaxel/randomly methylated-beta-cyclodextrin (Pac/RAMEB) complexes was developed previously. Using MTT and SRB assays the cytotoxic activity of this formulation versus Taxol, was evaluated as well as the cytotoxicity of the different formulation excipients (RAMEB and Cremophor EL. The possible synergistic effect of heat and paclitaxel-based chemotherapy during HIPEC was also evaluated in vitro. The cytotoxicity assays revealed differences in viability between Cremophor EL and RAMEB treated cells of 40 and 50% for the CaCo-2 human and the CC531s rat colon cancer line, respectively, in favour of RAMEB. Despite the higher cytotoxicity of Cremophor EL, Pac/RAMEB complexes and Taxol were equipotent. Using the MTT and SRB assays the average difference in viability between both cell lines was below 10% and IC50 values showed no significant difference. Hyperthermia after drug administration (41 degrees C during 1h) had no effect on cell viability. These results indicated that it was possible to reformulate paclitaxel with a less cytotoxic vehicle while maintaining the cytotoxic activity of the formulation and that there is no synergism between paclitaxel and heat for in vitro cytotoxicity.

Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G(2) assay was used to measure chromosomal radiosensitivity. The results demonstrated that head and neck cancer patients had a statistically higher number of radiation-induced chromatid breaks than controls, with mean values of 1.23 and 1.10 breaks per cell, respectively (P<0.001). Using the 90th percentile of the G(2) scores of the healthy individuals as a cutoff value for chromosomal radiosensitivity, 26% of the cancer patients were radiosensitive compared with 9% of the healthy controls (P=0.008). The mean number of radiation-induced chromatid breaks and the proportion of radiosensitive individuals were highest for oral cavity cancer patients (1.26 breaks per cell, 38%) and pharynx cancer patients (1.27 breaks per cell, 35%). The difference between patients and controls was most pronounced in the lower age group (

Intraoperative high-dose-rate brachytherapy (IBT) for locally unresectable intraabdominal malignancy.

PURPOSE: Intraoperative high-dose-rate brachytherapy (IBT) has been successfully used in locally advanced unresectable intraabdominal malignancy. We retrospectively evaluated the safety, feasibility, and general outcome of IBT following cytoreductive surgery. PATIENTS AND METHODS: After radical resection, the target area to be treated by IBT was determined jointly by the surgeon and the radiation oncologist. A silicon template was used to position parallel hollow catheters spaced 1 cm apart against the area of interest. IBT doses were prescribed at 1 cm depth from the template surface and calculated using standard plans. Radiation was administered in a dedicated shielded room. RESULTS: Between August 2001 and February 2006, 10 patients (colorectal cancer n = 6, cervix cancer n = 1, extramedullar plasmocytoma n = 1, liposarcoma n = 1 and sacrococcygeal teratocarcinoma n = 1) were treated. The mean delivered IBT dose was 8 Gy (range 7.5-20). No postoperative mortality was seen, while major complications developed in one (10%) patient with a rectovaginal fistula and intraabdominal abscess. Five of the six colorectal cancer patients developed local recurrence while 3 also developed distant metastases. The mean disease-free and overall survival in this group was 8.5 months (range 4-15) and 25.5 months (range 10-48) respectively. Palliation of symptoms was observed in 89 % of cases. CONCLUSION: IBT combined with debulking surgery is feasible and can be safely performed. While cure is rarely achieved, IBT offers the potential to prolong local control and survival in locally unresectable intraabdominal cancer. Therefore, IBT can be considered as a valuable adjuvant in the therapeutic and palliative armamentarium in these selected patients.

Recombinant human erythropoietin alpha modulates the effects of radiotherapy on colorectal cancer microvessels.

Recent data suggest that recombinant human erythropoietin (rhEPO) modulates tumour growth and therapy response. The purpose of the present study was to examine the modulation of radiotherapy (RT) effects on tumour microvessels by rhEPO in a rat colorectal cancer model. Before and after 5 x 5 Gy of RT, dynamic contrast-enhanced -magnetic resonance imaging was performed and endothelial permeability surface product (PS), plasma flow (F), and blood volume (V) were modelled. Imaging was combined with pO(2) measurements, analysis of microvessel density, microvessel diameter, microvessel fractal dimension, and expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 alpha (HIF-1alpha), Bax, and Bcl-2. We found that RT significantly reduced PS and V in control rats, but not in rhEPO-treated rats, whereas F was unaffected by RT. Oxygenation was significantly better in rhEPO-treated animals, and RT induced a heterogeneous reoxygenation in both groups. Microvessel diameter was significantly larger in rhEPO animals, whereas VEGF expression was significantly lower in the rhEPO group. No differences were observed in HIF-1alpha, Bax, or Bcl-2 expression. We conclude that rhEPO results in spatially heterogeneous modulation of RT effects on tumour microvessels. Direct effects of rhEPO on neoplastic endothelium are likely to explain these findings in addition to indirect effects induced by increased oxygenation.

Pre-operative combined modality therapy in the management of locally advanced rectal cancer.

AIMS: To review the use of pre-operative combined modality therapy (CMT, chemotherapy with radiotherapy) in the management of resectable rectal cancer. METHODS: A systematic search was performed on pre-operative CMT and rectal cancer. Additional information was retrieved from hand searching the literature and from relevant congress proceedings. We addressed the following issues: Phase II studies of pre-operative CMT, pre-operative radiotherapy (RT) alone vs pre-operative CMT, pre-operative vs post-operative CMT, functional outcome and pathologic downstaging after CMT, prediction and importance of complete response to CMT. RESULTS: Pre-operative CMT results in an average pathological complete response (pCR) rate of 18.5% in Phase II studies. Compared with pre-operative RT alone, the addition of CT significantly improves tumour response but not overall survival while acute toxicity increases and the effect on sphincter preservation is at present unclear. Pre-operative CMT has been proven to be superior to post-operative CMT in a German multicenter randomized trial. The scarce available data suggest that the addition of CT might worsen anorectal function compared to pre-operative RT alone. Although a significant pathological response is prognostically favourable, the clinical and imaging tools available at present do not allow to accurately predict pCR in clinical complete responders confirming the indication for surgery in this subgroup. CONCLUSIONS: Pre-operative CMT enhances tumour response and could therefore, have a role in patients with possibly invaded resection margins or low lying cancers, although both acute toxicity and anorectal function are worse compared to RT alone. The final results of ongoing randomized trials will more accurately establish the role of pre-operative CMT in resectable rectal cancer patients.

Adjuvant gemcitabine and concurrent continuous radiation (45 Gy) for resected pancreatic head carcinoma: a multicenter Belgian Phase II study.

PURPOSE: To evaluate the feasibility and tolerance of a postoperative course of gemcitabine (GEM) combined with continuous radiation after curative resection of pancreatic adenocarcinoma. METHODS AND MATERIALS: Thirty patients (median age, 61 years; performance status, 0 to 1) with Stage II and III curatively resected pancreatic head adenocarcinoma were included. Gemcitabine 1000 mg/m2 (3 out of 4 weeks, two cycles) was given within 8 weeks of surgery and followed by GEM 300 mg/m2 weekly combined with continuous radiation (45 Gy in 25 fractions, 1.8 Gy per fraction). RESULTS: For GEM alone, all patients received the two courses with dose reductions in 14 of 30 patients (46%). All but 3 patients completed full chemoradiation; 1 stopped radiation because of subocclusion of a gastroenterostomy, and 2 did not start owing to disease progression. Reduction in GEM during radiation was necessary in 12 of 30 patients (40%). No toxic death was noted; World Health Organization Grade 3/4 hematologic and nonhematologic toxicities were seen in 10 of 30 patients (33%) and 3 of 30 patients (10%), respectively. After a median follow-up of 19 months, no late toxicity was reported. Eleven patients died from progressive disease; median disease-free survival and overall survival were 14.5 and 19 months, respectively. CONCLUSION: This adjuvant combination is well tolerated and can be safely administered after curative surgery for pancreatic cancer. Further evaluation of this regimen is ongoing.

8-Prenylnaringenin, the phytoestrogen in hops and beer, upregulates the function of the E-cadherin/catenin complex in human mammary carcinoma cells.

The E-cadherin/catenin complex is a powerful invasion suppressor in epithelial cells. It is expressed in the human MCF-7 breast cancer cell line family, but functionally defective in the invasive MCF-7/6 variant. Previous experiments have shown that IGF-I, tamoxifen, retinoic acid and tangeretin are able to upregulate the function of this complex in MCF-7/6 cells. We investigated the effect of 8-prenylnaringenin (8-PN), the phytoestrogen present in hops and beer, on aggregation, growth and invasion in MCF-7/6 cells. 8-PN was found to stimulate E-cadherin-dependent aggregation and growth of MCF-7/6 cells in suspension. These effects could be inhibited by the pure anti-estrogen ICI 182,780. 8-PN did not affect invasion of MCF-7/6 cells in the chick heart assay in vitro. In all these aspects 8-PN mimics the effects of 17beta-estradiol on MCF-7/6 cells.