Radiotherapy modulates expression of EGFR, ERCC1 and p53 in cervical cancer

Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.

Radiotherapy modulates expression of EGFR, ERCC1 and p53 in cervical cancer.

Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.

Exploiting HPV-Induced Carcinogenesis for a Rational Drug Development in Cervical Cancer.

Cervical carcinomas are almost universally associated with high-risk human papillomavirus (HPV) infections, and are a leading cause of cancer death in women worldwide. Since the late 1990s, when a spate of studies reported the benefit of cisplatin-based chemotherapy, there had been a dearth of clinical trials in cervical cancer (CC). More effective therapies in locally advanced and recurrent or metastatic CC are an urgent clinical need. In the era of molecular oncology one should look beyond conventional chemoradiation and chemotherapy for locally advanced and advanced CC. The fact that the initiating oncogenic insult, infection with a high-risk HPV and viral oncoprotein expression is common to almost all CC offers unique opportunities for disease control. Diverse biologic pathways with an implication in the development and progression of CC are being explored. For the first time, increase in overall survival has recently been obtained for advanced CC patients with a target drug, the antiangiogenic agent bevacizumab, and durable complete responses after HPV-targeted adoptive T cell therapy in metastatic CC patients were achieved. In this review, we will summarize molecular aspects of HPV infection focusing on potential targets to stop the carcinogenic process, present updated drug development data, and discuss challenges and prospects for the future.

Delineación tumoral basada en 18F-FDG-PET en el cáncer cervical: delimitación del contorno umbral y volúmenes de la lesión / 18F-FDG-PET-based tumor delineation in cervical cancer: Threshold contouring and lesion volumes

Evaluar el algoritmo de segmentación tumoral de la imagen PET semiautomatizada para delinear el volumen tumoral grueso (GTV) en pacientes con cáncer cervical localmente avanzado. Material y métodos. Se evaluó retrospectivamente a 32 pacientes con cáncer cervical localmente avanzado. Se utilizó la delineación GTV basada en imagen PET semiautomatizada, utilizando un algoritmo previamente establecido (GTV2SD) y 2 métodos basados en umbrales fijos (GTV40% y GTV50%). Se calculó GTV2SD, como el píxel con el valor medio más 2 desviaciones estándar de la intensidad del hígado, y GTV40% y GTV50% con el 40% y el 50% de intensidad tumoral máxima (Tmáx), respectivamente. A continuación se compararon los volúmenes derivados con los GTV generados manualmente, utilizando RM (GTVMR). Resultados. El valor medio de GTV2SD, GTV40% y GTV50% fue de 85,3 cc; 16,2 cc y 24,1 cc, respectivamente. Se halló una buena concordancia entre GTV2SD y GTVMR (rho=0,88). GTV40% y GTV50% mostraron una menor correlación con GTVMR (rho=0,68 y rho=0,71, respectivamente). Conclusiones. Este estudio prueba de modo preliminar que la delimitación del volumen tumoral metabólico es posible utilizando las mediciones generadas informáticamente en las imágenes de 18F-FDG PET. La generación de los volúmenes tumorales basados en PET se ve afectada por la elección del nivel de umbral utilizado. El grueso del tumor metabólico calculado utilizando el píxel con el valor medio más 2 desviaciones de la intensidad del hígado (GTV2SD) guarda una mejor correlación con los volúmenes tumorales derivados de RM. El método constituye un enfoque simple y clínicamente aplicable para generar el GTV derivado del PET, para la planificación de la terapia de radiación del cáncer cervical(AU)

Objective. To evaluate a semi-automated PET-image tumor segmentation algorithm for gross tumor volume (GTV) delineation in patients with locally advanced cervical cancer. Material and methods. Thirty-two patients with locally advanced cervical cancer were retrospectively evaluated. Semi-automated PET-image-based GTV delineation was applied using a previous established algorithm (GTV2SD) and 2 fixed threshold-based methods (GTV40% and GTV50%). GTV2SD was determined as the pixel with the mean value plus 2-standard deviation of the liver intensity, and GTV40% and GTV50% with 40% and 50% of the maximum tumor intensity (Tmax), respectively. The derived volumes were then compared with the GTVs generated manually using MR (GTVMR). Results. The mean value of GTV2SD, GTV40% and GTV50% was 85.3cc, 16.2cc and 24.1cc, respectively. Good agreement was noticed between GTV2SD and GTVMR (rho=0.88). GTV40% and GTV50% showed weaker correlation with GTVMR (rho=0.68 and rho=0.71, respectively). Conclusions. This study provides preliminary evidence that metabolic tumor volume delineation is feasible using computer-generated measurements in 18F-FDG PET images. Generation of PET-based tumor volumes is affected by the choice of threshold level used. Metabolic tumor bulk calculated using the pixel with the mean value plus 2-standard deviations of the liver intensity (GTV2SD) correlates better with the MR-derived tumor volumes. The method is a simple and clinically applicable approach to generate PET-derived GTV for radiation therapy planning of cervical cancer(AU)

18F-FDG-PET-based tumor delineation in cervical cancer: threshold contouring and lesion volumes.

OBJECTIVE: To evaluate a semi-automated PET-image tumor segmentation algorithm for gross tumor volume (GTV) delineation in patients with locally advanced cervical cancer. MATERIAL AND METHODS: Thirty-two patients with locally advanced cervical cancer were retrospectively evaluated. Semi-automated PET-image-based GTV delineation was applied using a previous established algorithm (GTV2SD) and 2 fixed threshold-based methods (GTV40% and GTV50%). GTV2SD was determined as the pixel with the mean value plus 2-standard deviation of the liver intensity, and GTV40% and GTV50% with 40% and 50% of the maximum tumor intensity (Tmax), respectively. The derived volumes were then compared with the GTVs generated manually using MR (GTVMR). RESULTS: The mean value of GTV2SD, GTV40% and GTV50% was 85.3cc, 16.2cc and 24.1cc, respectively. Good agreement was noticed between GTV2SD and GTVMR (ρ=0.88). GTV40% and GTV50% showed weaker correlation with GTVMR (ρ=0.68 and ρ=0.71, respectively). CONCLUSIONS: This study provides preliminary evidence that metabolic tumor volume delineation is feasible using computer-generated measurements in (18)F-FDG PET images. Generation of PET-based tumor volumes is affected by the choice of threshold level used. Metabolic tumor bulk calculated using the pixel with the mean value plus 2-standard deviations of the liver intensity (GTV2SD) correlates better with the MR-derived tumor volumes. The method is a simple and clinically applicable approach to generate PET-derived GTV for radiation therapy planning of cervical cancer.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life.

PURPOSE: This systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies. METHODS: The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. Two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results and conclusions for each article. RESULTS: The inclusion criteria were met by 184 articles covering salivary gland hypofunction and xerostomia induced by conventional, 3D conformal radiotherapy or intensity-modulated radiotherapy in head and neck cancer patients, cancer chemotherapy, total body irradiation/hematopoietic stem cell transplantation, radioactive iodine treatment, and immunotherapy. CONCLUSIONS: Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly submandibular and minor salivary glands, as these glands are major contributors to moistening of oral tissues. Other cancer treatments also induce salivary gland hypofunction, although to a lesser severity, and in the case of chemotherapy and immunotherapy, the adverse effect is temporary. Fields of sparse literature included pediatric cancer populations, cancer chemotherapy, radioactive iodine treatment, total body irradiation/hematopoietic stem cell transplantation, and immunotherapy.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact.

PURPOSE: This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations. METHODS: The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. For each article, two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results, and conclusions. RESULTS: Seventy-two interventional studies met the inclusion criteria. In addition, 49 intensity-modulated radiation therapy (IMRT) studies were included as a management strategy aiming for less salivary gland damage. Management guideline recommendations were drawn up for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. CONCLUSIONS: There is evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized to some degree, depending on the type of cancer treatment. Management guideline recommendations are provided for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. Fields of sparse literature identified included effects of gustatory and masticatory stimulation, specific oral mucosal lubricant formulas, submandibular gland transfer, acupuncture, hyperbaric oxygen treatment, management strategies in pediatric cancer populations, and the economic consequences of salivary gland hypofunction and xerostomia.