Cisplatin/5-Fluorouracil Treatment of Recurrent Cervical Carcinoma: A Phase II Study with Long-Term Follow-up

Objective: To evaluate the response rate and corrected survival in patients with recurrent cervical carcinoma (RCC) treated with 100 mg/m²cisplatin (CDDP) iv on Day 1 and 1000 mg/m²5-fluorouracil (5-FU) iv on Days 1 to 5. Methods: A phase II study of CDDP/5-FU in RCC was initiated in 1986. Up to December 1991, a total of 72 patients were enrolled. Of these, 65 were evaluable for response. Results: The overall response rate was 49%. For 9 patients with complete remission, the median duration of response was 16 months, range 6 to 79+. The corresponding figures for 26 patients with partial remission were 10 months, range 3 to 80 months. By multivariate analysis, FIGO stage, disease-free interval, WHO performance status, and number of lesions at recurrence were independent prognostic variables. Twenty-two percent of the patients survived for more than 2 years and 9% for more than 5 years. Toxicity was tolerable. Leucopenia, ototoxicity, and neurotoxicity were the main problems. Conclusion: A high response rate (49%) was observed with CDDP/5-FU treatment in patients with RCC with 9% of the patients surviving for more than 5 years.     

Phosphorylation of EGFR measured with in situ proximity ligation assay: Relationship to EGFR protein level and gene dosage in cervical cancer

Purpose

We have applied the sensitive and specific in situ proximity ligation assay (PLA) to characterize Tyr1068 phosphorylation of the epidermal growth factor receptor (EGFR) in cervical cancer in relation to the protein level and gene dosage.

Materials and methods

Pretreatment tumor biopsies from 178 patients were analyzed. EGFR protein level was determined by immunohistochemistry, and Tyr1068 phosphorylation was detected with PLA in 97 EGFR positive tumors. EGFR gene dosage was derived from array comparative genomic hybridization of 86 cases.

Results

EGFR was expressed in most tumors, whereas phosphorylation was seen in about half of the EGFR positive ones. A correlation was found between the expression of EGFR and phosphorylated EGFR (p = 0.016, membrane; p = 0.012, cytoplasm). However, tumor regions with high protein level without phosphorylation were occasionally seen and the percentage of EGFR positive cells was higher than the phosphorylated percentage (p < 0.001). Moreover, an increase in the phosphorylation in both the membrane (p = 0.014) and cytoplasm (p = 0.002) was seen in 11 tumors with gain of EGFR. The protein level was not correlated with gene dosage.

Conclusion

In contrast to gain of the EGFR chromosomal region, high EGFR protein level may not necessarily indicate Tyr1068 phosphorylation and thereby receptor activation in cervical cancer.     

Improved sensitivity to fluorescence for cancer detection in wide-field image-guided neurosurgery

In glioma surgery, Protoporphyrin IX (PpIX) fluorescence may identify residual tumor that could be resected while minimizing damage to normal brain. We demonstrate that improved sensitivity for wide-field spectroscopic fluorescence imaging is achieved with minimal disruption to the neurosurgical workflow using an electron-multiplying charge-coupled device (EMCCD) relative to a state-of-the-art CMOS system. In phantom experiments the EMCCD system can detect at least two orders-of-magnitude lower PpIX. Ex vivo tissue imaging on a rat glioma model demonstrates improved fluorescence contrast compared with neurosurgical fluorescence microscope technology, and the fluorescence detection is confirmed with measurements from a clinically-validated spectroscopic probe. Greater PpIX sensitivity in wide-field fluorescence imaging may improve the residual tumor detection during surgery with consequent impact on survival.OCIS codes: (170.3890) Medical optics instrumentation, (170.6280) Spectroscopy, fluorescence and luminescence     

Oxygen Tension and Vascular Density in Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix

The prognosis of patients with carcinoma of the uterine cervix has been shown to depend on the oxygenation and vascularization status of the tumors. The purpose of the study reported here was to search for possible differences in oxygen tension and vascular density between adenocarcinomas and squamous cell carcinomas. Ten patients with adenocarcinoma and forty patients with squamous cell carcinoma were included in the study. Oxygen tension was measured polarographically using the Eppendorf pO₂ Histograph 6650. Vascular density was determined by histological examination of tumor biopsies. The adenocarcinomas were significantly better oxygenated than the squamous cell carcinomas. The squamous cell carcinomas and the adenocarcinomas did not differ significantly in vascular density. The difference in prognosis between patients with adenocarcinoma and patients with squamous cell carcinoma is probably not attributable to differences in tumor oxygenation or vascularization.     

Identification of eight candidate target genes of the recurrent 3p12–p14 loss in cervical cancer by integrative genomic profiling

The pathogenetic role, including its target genes, of the recurrent 3p12–p14 loss in cervical cancer has remained unclear. To determine the onset of the event during carcinogenesis, we used microarray techniques and found that the loss was the most frequent 3p event, occurring in 61% of 92 invasive carcinomas, in only 2% of 43 high‐grade intraepithelial lesions (CIN2/3), and in 33% of 6 CIN3 lesions adjacent to invasive carcinomas, suggesting a role in acquisition of invasiveness or early during the invasive phase. We performed an integrative DNA copy number and expression analysis of 77 invasive carcinomas, where all genes within the recurrent region were included. We selected eight genes, THOC7, PSMD6, SLC25A26, TMF1, RYBP, SHQ1, EBLN2, and GBE1, which were highly down‐regulated in cases with loss, as confirmed at the protein level for RYBP and TMF1 by immunohistochemistry. The eight genes were subjected to network analysis based on the expression profiles, revealing interaction partners of proteins encoded by the genes that were coordinately regulated in tumours with loss. Several partners were shared among the eight genes, indicating crosstalk in their signalling. Gene ontology analysis showed enrichment of biological processes such as apoptosis, proliferation, and stress response in the network and suggested a relationship between down‐regulation of the eight genes and activation of tumourigenic pathways. Survival analysis showed prognostic impact of the eight‐gene signature that was confirmed in a validation cohort of 74 patients and was independent of clinical parameters. These results support the role of the eight candidate genes as targets of the 3p12–p14 loss in cervical cancer and suggest that the strong selection advantage of the loss during carcinogenesis might be caused by a synergetic effect of several tumourigenic processes controlled by these targets. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Spatial frequency domain tomography of protoporphyrin IX fluorescence in preclinical glioma models

Multifrequency (0 to 0.3 mm(-1)), multiwavelength (633, 680, 720, 800, and 820 nm) spatial frequency domain imaging (SFDI) of 5-aminolevulinic acid-induced protoporphyrin IX (PpIX) was used to recover absorption, scattering, and fluorescence properties of glioblastoma multiforme spheroids in tissue-simulating phantoms and in vivo in a mouse model. Three-dimensional tomographic reconstructions of the frequency-dependent remitted light localized the depths of the spheroids within 500 μm, and the total amount of PpIX in the reconstructed images was constant to within 30% when spheroid depth was varied. In vivo tumor-to-normal contrast was greater than ～1.5 in reduced scattering coefficient for all wavelengths and was ～1.3 for the tissue concentration of deoxyhemoglobin (ctHb). The study demonstrates the feasibility of SFDI for providing enhanced image guidance during surgical resection of brain tumors.     

Metabolic mapping by use of high-resolution magic angle spinning <Superscript>1</Superscript>H MR spectroscopy for assessment of apoptosis in cervical carcinomas

Background  

High-resolution magic angle proton magnetic resonance spectroscopy (HR¹H MAS MRS) provides a broad metabolic mapping of intact tumor samples and allows for microscopy investigations of the samples after spectra acquisition. Experimental studies have suggested that the method can be used for detection of apoptosis, but this has not been investigated in a clinical setting so far. We have explored this hypothesis in cervical cancers by searching for metabolites associated with apoptosis that were not influenced by other histopathological parameters like tumor load and tumor cell density.