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Background: Locally advanced rectal cancer is customarily treated with neoadjuvant chemoradiotherapy (CRT) followed by a total mesorectal excision. During the course of CRT, previously non-detectable distant metastases can appear. Therefore, a restaging CT scan of the chest and abdomen was performed prior to surgery. The aim of this study was to determine the frequency of a change in treatment strategy after this restaging CT scan., Methods: Patients treated with neoadjuvant CRT for locally advanced rectal cancer between January 2003 and July 2013 were included retrospectively. To determine the value of the restaging CT scan, the surgical treatment as planned before CRT was compared with the treatment ultimately received., Results: A total of 153 patients (91 male) were eligible, and median age was 62 (32-82) years. The restaging CT scan revealed the presence of distant metastases in 19 patients (12.4, 95 % confidence interval [CI] 7.0-17.8). In 17 patients (11.1, 95 % CI 6.1-16.1), a change in treatment strategy occurred due to the detection of metastases with a restaging CT scan., Conclusion: A restaging CT scan after completion of neoadjuvant CRT may detect newly developed metastases and consequently alter the initial treatment strategy. This study demonstrated the added value of the restaging CT scan prior to surgery.

Background: Neoadjuvant chemoradiotherapy (CRT) improves locoregional control and overall survival in esophageal cancer patients. Although adverse events are relatively low during neoadjuvant CRT, severe postoperative adverse effects may occur, leading to morbidity and even mortality. We investigated the impact of a more frequently used neoadjuvant CRT regimen of 41.4 Gy/5 weeks radiotherapy with concurrent carboplatin and paclitaxel (CROSS schedule) on the postoperative course., Methods: Between 2006 and 2012, a total of 96 esophageal cancer patients (staged cT1N+/T2-4a/N0-3 and M0) were treated according to the above neoadjuvant scheme. To reduce bias in this single-center study, we performed a propensity score-matched analysis with patients who underwent surgery alone (n = 230) from a prospectively maintained database (n = 326)., Results: Baseline characteristics between both groups were equally distributed in the matched cohort. In the neoadjuvant treated group, significantly more patients were diagnosed with pneumonia (27.1 vs. 51.0%; p = 0.001), pleural effusion (12.5 vs. 24.0%; p = 0.040), and arrhythmia (20.4 vs. 34.4%; p = 0.008). In addition, in the multivariate analysis, neoadjuvant CRT was significantly associated with an increased risk of pneumonia (p = 0.001, odds ratio 2.896), pleural effusion (p = 0.041, odds ratio 2.268), and arrhythmia (p = 0.023, odds ratio 2.215). Despite these outcomes, no differences were detected in duration of intensive care unit or hospital stay. Short-term mortality did not differ between both groups., Conclusions: We observed an increase of cardiopulmonary complications in the neoadjuvant CRT group, without any effect on hospital or intensive care unit stay and mortality. Further research is warranted on the limitation of chemoradiation-induced cardiopulmonary toxicity.

Purpose: To evaluate the rate and pattern of recurrences after neoadjuvant chemoradiotherapy (CRT) in esophageal cancer patients., Methods: We described survival and differences in recurrences from a single center between neoadjuvant CRT (carboplatin/paclitaxel and 41.4 Gy) and surgery alone for the period 2000-2011. To reduce bias, we performed a propensity score matched analysis., Results: A total of 204 patients were analyzed, 75 treated with neoadjuvant CRT and 129 with surgery alone. The pathologic response to neoadjuvant CRT was 69% with a complete response rate of 25%. After matching, baseline characteristics between the groups (both n = 75) were equally distributed. The 3- and 5-year disease-free survival was 53 and 42% in the neoadjuvant CRT group compared with 24 and 18% in the surgery-alone group (P = 0.011). After 3 and 5 years' CRT, patients had an estimated locoregional recurrence-free survival of 83 and 73% compared with 52 and 49% in the surgery-alone group (P = 0.015). The distant recurrence-free survival was comparable in both groups. Locoregional recurrences were located less in the paraesophageal lymph nodes in the CRT group than in the surgery-alone group, 9 versus 21%, respectively (P = 0.041). With respect to differences in distant recurrences, we observed more skeletal recurrences in the surgery-alone group compared to CRT, 12 versus 1% (P = 0.009)., Conclusions: The neoadjuvant CRT regimen we used offers a significant improvement in outcome, with a different recurrence pattern compared with surgery alone. This effect is probably due to both the pathologic complete response and eradication of micrometastases in CRT group.

Background: Definitive (chemo)radiotherapy is employed in esophageal cancer patients as an alternative for patients considered medically unfit for surgery or having unresectable tumors. We evaluated a population-based cohort to improve the selection for intensified nonsurgical strategies and to identify prognostic factors., Methods: Patients who had squamous cell carcinoma (SCC) or adenocarcinoma (AC) were treated in four referral centers in the north-east Netherlands with definitive chemoradiotherapy (dCRT) or radiotherapy (dRT) between 1996 and 2008., Results: Of the 287 included patients, 110 were treated with dCRT and 177 with dRT. Median overall survival (OS) was 11 months (95 % confidence interval: 10-12 months), with OS of 22 and 8 % and disease-free survival (DFS) of 16 and 5 % at 2 and 5 years, respectively. DFS at 2 and 5 years was 24 and 9 % for SCC versus 10 and 2 % for AC patients (P = 0.006). OS after 2 and 5 years was 29 and 14 % for SCC patients versus 17 and 3 % for AC patients (P = 0.044). On multivariate Cox regression, SCC was an independent prognostic factor for DFS [P = 0.020, hazard ratio (HR) = 0.71] and OS (P = 0.047, HR = 0.76). On matched cohort analysis, DFS was higher in the dCRT group compared with dRT patients (P = 0.016). The locoregional failure rate was lower in the dCRT group and in SCC patients (P = 0.001 and 0.046)., Conclusions: Long-term results and the local control rate in SCC patients were better after definitive (chemo)radiotherapy compared with in AC patients. SCC was an independent prognostic factor for survival. Definitive chemoradiotherapy leads to improved local control rate and DFS.

Aim: To investigate the feasibility of using bevacizumab to improve the survival of American Joint Committee on Cancer (AJCC) stage III melanoma patients, we investigated how a single bevacizumab treatment affected nodal disease and a panel of biomarkers in clinically fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT)-staged, stage III melanoma patients, prior to therapeutic lymph node dissection (TLND)., Methods: Four weeks before TLND, nine patients (median age 50, range 28.8-62.1 years; two male, seven female) with palpable lymph node metastases received 7.5 mg/kg bevacizumab. Before and after this treatment, all patients were assessed by measurements of the maximum standardized uptake value (SUVmax) by FDG-PET scan, and serum S-100B and lactate dehydrogenase (LDH). After TLND, the dissection specimen was analyzed for number of removed lymph nodes, number of metastatic lymph nodes, and tumor necrosis., Results: Median follow-up was 15.5 (2.2-32.9) months. Histopathological analysis revealed tumor necrosis in six patients, of whom five had an S-100B decline and one had an unchanged S-100B level after bevacizumab. The other three patients showed an S-100B increase and no necrosis. Tumor necrosis was correlated with S-100B decrease (P = 0.048). No association was found between necrosis and the markers SUVmax and LDH. No wound healing disturbances were encountered., Conclusion: Tumor necrosis in dissection specimens was associated with declining S-100B levels, while elevated S-100B was only found in cases with no necrosis. Bevacizumab might be useful in treating AJCC stage III melanoma patients prior to TLND, and S100-B appears to be a useful marker for assessment of treatment effects.

Worldwide, gastric cancer is one of the most common and fatal cancers. The majority of patients present with an advanced stage of disease. Even with use of palliative chemotherapy most patients die within 1 year after diagnosis. Medical psychological attention after a diagnosis of incurable cancer is focused on end of life support. This paper presents the care of a patient treated with palliative intent with chemotherapy for an irresectable histologically confirmed gastric cancer. When, unexpectedly prolonged symptom free survival followed, the reaction of the patient came as a surprise to the attending medical team. In this case history we urge those who care for incurable cancer patients, that the rare patient who survives against all odds may require special psychological care.

Background: We studied the maximum tolerated dose (MTD) and efficacy of oxaliplatin added to capecitabine and radiotherapy (Capox-RT) as neoadjuvant therapy for rectal cancer., Methods: T3-4 rectal cancer patients received escalating doses of oxaliplatin (day 1 and 29) with a fixed dose of capecitabine of 1000 mg/m(2) twice daily (days 1-14, 25-38) added to RT with 50.4 Gy and surgery after 6-8 weeks. The MTD, determined during phase I, was used in the subsequent phase II, in which R0 resection rate (a negative circumferential resection margin) was the primary end point., Results: Twenty-one patients were evaluable. In the phase I part, oxaliplatin at 85 mg/m(2) was established as MTD. In phase II, the main toxicity was grade III diarrhea (18%). All patients underwent surgery, and 20 patients had a resectable tumor. An R0 was achieved in 17/21 patients, downstaging to T0-2 in 7/21 and a pCR in 2/21., Conclusion: Combination of Capox-RT has an acceptable acute toxicity profile and a high R0 resection rate of 81% in locally advanced rectal cancer. However the pCR rate was low.

To improve current angiogenic gene therapy with a vascular endothelial growth factor (VEGF)-encoding plasmid (Baumgartner et al. Circulation 1998; 97: 1114-23 [1]; Kusumanto et al. Fifth Annual Meeting of the American Society of Gene Therapy, Boston, 2002, Abstr. 621 [2]), we have generated a combination plasmid, encoding the VEGF gene and the thymidine phosphorylase (TP, also known as platelet-derived endothelial growth factor (PD-ECGF) or gliostatin (GLS)) gene: phVEGF165-TP.MB. Upon transfection in COS-7 cells both gene products were expressed and functional as shown by Western blots, ELISAs and bioassays. Culture supernatants of COS-7 cells transfected with this plasmid were able to induce endothelial proliferation. In an in vitro angiogenesis assay with recombinant proteins, TP was able to increase VEGF-induced tube formation. The phVEGF165-TP.MB plasmid is therefore a promising candidate for in vivo angiogenesis studies.

The measurement of circulating vascular endothelial growth factor (VEGF) levels as a prognostic factor will gain increasing relevance in the diagnosis and evaluation of treatment in cancer patients. Angiogenesis is an absolute requirement in tumour growth and metastatic disease. In the present study data are presented which indicate that circulating VEGF mainly resides in peripheral blood cells. In 15 healthy volunteers we demonstrated that approximately 34% of the circulating VEGF resides in platelets and approximately 11% in patients with cancer ( n = 4). An important part namely 58% in healthy volunteers and 69% in patients with cancer of the total circulating VEGF is contained in granulocytes, particular in the neutrophils, as confirmed by fluorescence-activated cell sorting (FACS). Also an increased VEGF level per granulocyte is found in patients with cancer (77 microg VEGF/l) compared with the healthy volunteers (164 microg VEGF/l). In contrast only 2% was present in plasma. The biological significance of platelet- or granulocyte-derived VEGF is not yet known. Liberation of VEGF from these compartments could well be of importance for tumour angiogenesis. Therefore, future studies on the clinical value of circulating VEGF as a prognostic factor in cancer patients should include measurements of VEGF in peripheral blood cells.

Endothelial cells (EC) are currently used as in vitro model systems for various physiological and pathological processes, especially in angiogenesis research. Primary EC have a limited lifespan and display characteristics that differ from batch to batch due to their multidonor origin. In recent years many groups have established EC lines. This Review gives an overview of the advantages and disadvantages of currently available vascular EC lines. Its aim is to help the investigator to decide which cell line matches his or her research goal best. Truly immortalized cell lines are generally better characterized and more stable in their endothelial traits than EC that were given an extended life span. Presently the best characterized macro- and micro-vascular EC lines are EA.hy926 and HMEC-1, respectively.

Specific inhibition of mammalian genes is possible through the use of antisense oligonucleotides (AS ODNs) or ribozymes. These strategies have led to a better understanding of several cellular and molecular mechanisms, among which cancer development. Recently, these strategies have been applied also for therapeutical purposes in diseases such as AIDS and cancer. In some of these therapeutical trials the antisense strategy is combined with gene transfer technology: the AS ODN or the ribozyme are expressed within the cell by the use of adenoviral or retroviral vectors. However, many difficulties have still to be overcome before ODNs and ribozymes can be used routinely in the clinic.