We thank Dr. Vordermark for addressing the important issue of hypoxia-inducible factor (HIF)-1α expression, tumor hypoxia, and radiosensitivity. It is well known that tissue hypoxia is associated with increased resistance to radiotherapy in human tumors,1 and that HIF-1α expression might be induced by hypoxia as well as by oncogenic activation.2 Due to the rarity of pure oligodendrogliomas, no data on intravital hypoxia within tumors measured by polarographic electrodes exist, as stated by Dr. Vordermark. Although we can not definitely rule out that HIF-1α expression is mainly induced by tissue hypoxia in our samples, the following arguments favor oncogenic activation: oligodendrogliomas are slowly growing tumors and show a relatively uniform pattern of dense neovascularization throughout the whole tumor. Although a dense vascular network does not automatically imply the lack of hypoxia,3 our thesis is further supported by the fact that necrotic areas, the strongest indicator of hypoxia, are generally not present within oligodendrogliomas, in contrast to glioblastoma, for example. As noted by Dr. Vordermark, we performed survival analysis only in the subgroups of patients who received adjuvant radiotherapy in oligodendrogliomas and in cervical carcinoma. There was no significant influence of HIF-1α expression (absent/low vs. moderate/high) on survival in the 33 patients with oligodendroglioma (P = 0.6841, log rank test) who received adjuvant radiotherapy, as we detailed previously.4 Nevertheless, statistical power in such small subgroups is low, and due to the long period of patient recruitment (25 years), radiotherapy protocols underwent changes, further hampering the analysis. Based on the histologic characteristics of oligodendrogliomas and statistical analysis results, we think that expression of HIF-1α is mainly induced by oncogenic stimuli in oligodendrogliomas and that the negative influence of HIF-1α on survival cannot be attributed to decreased radiosensitivity alone. Our group is currently investigating the mechanisms of angiogenesis and hypoxia in brain tumors in detail, and we anticipate that results will be reported in the near future. In patients with cervical carcinoma pT1b (International Union Against Cancer [UICC] classification) who received adjuvant radiotherapy in addition to radical hysterectomy (55 patients; patient and therapy details reported previously5), we found a significantly shorter disease free survival in patients with strong HIF-1α expression compared to patients with moderate to absent expression (P = 0.025, log rank test). In patients without adjuvant radiotherapy, HIF-1α overexpression was associated even stronger with disease free survival (P < 0.001, log rank test). In patients with strong HIF-1α expression, comparison of survival of patients with adjuvant radiotherapy to those without showed no significant differences (P > 0.05, log rank test). Altogether, our findings indicate that HIF-1α expression in cervical carcinoma influences the prognosis of patients independently of radiotherapy. Therefore, HIF-1α overexpression in cervical carcinoma cannot be attributed to hypoxia alone, since in that case a stronger influence of HIF-1α expression on survival in patients with adjuvant radiotherapy might be expected, as suggested by Dr. Vordermark. In addition, we also observed common expression of HIF-1α in Grade III cervical intraepithelial lesions5 and in ovarian tumors of low malignant potential,6 which are both quite unlikely to develop the significant tissue hypoxia which is necessary for hypoxic induction of HIF-1α expression. However, the role of HIF-1α expression with regard to radiotherapy response in our collective of cervical carcinomas has to be judged carefully, since only patients with advanced disease (positive lymph nodes or tumor infiltrating the outer third of the cervix) received adjuvant radiotherapy in addition to primary surgery. This could cause a considerable bias. These uncertainties could be solved in prospective trials comparing two groups of patients with identical stages of cervical carcinomas (UICC stage T1b N0 M0 would be ideal) treated by primary surgery without adjuvant irradiation or primary radiotherapy. It would also be of interest to correlate in cervical carcinoma intratumoral O2 levels measured by polarographic electrodes and HIF-1α protein expression in subsequent biopsies and response to radiotherapy. Such a study could identify cases where HIF-1α is overexpressed due to hypoxia or because of oncogenic stimuli. In conclusion, we strongly agree with Dr. Vordermark that additional research is needed on the subjects of hypoxia, HIF-1α expression, and responses to radiotherapy in human tumors. Peter Birner M.D.*, Brigitte Gatterbauer M.D. , Georg Oberhuber M.D. , Monika Schindl M.D. , Karl Rössler M.D. , Axel Prodinger M.D. , Herbert Budka M.D.§, Johannnes A. Hainfellner M.D.§, * Institute of Clinical Pathology, Institute of Neurology, University of Vienna, Vienna, Austria, Department of Neurosurgery, University of Vienna, Vienna, Austria, Institute of Clinical Pathology, University of Vienna, Vienna, Austria, § Institute of Neurology, University of Vienna, Vienna, Austria