Radiotherapy For Laryngeal Carcinoma Research Articles

UBR5 regulates proliferation and radiosensitivity in human laryngeal carcinoma via the p38/MAPK signaling pathway.

Laryngeal carcinoma (LCC) is a common malignant tumor with low radiosensitivity and generally poor response rates. The ubiquitin protein ligase E3 component n-recognin 5 (UBR5) has prognostic implications in several neoplasms; however, its role in LCC and radiotherapy sensitivity remains unknown. Immunohistochemistry and bioinformatics analyses were performed to measure UBR5 protein and mRNA expression in LCC and adjacent non-tumor tissues. The gene and protein expression of UBR5 in LCC and HuLa-PC cell lines were measured using quantitative PCR and western blot analyses. Following transfection with small interfering RNA or UBR5 overexpression plasmid in LCC cells, the proliferation, cell cycle distribution, invasion, migration and radiosensitivity of LCC cells were analyzed. UBR5-related lncRNA, targeted miRNA and protein-protein interaction networks were analyzed using bioinformatics. Finally, the expression of the p38/mitogen-activated protein kinase (MAPK) pathway was evaluated following UBR5 silencing in M2E cells treated with radiation. Increased UBR5 expression was observed in LCC tissues compared with adjacent non-tumor tissues, and it was correlated with poor overall survival of LCC patients. After overexpression or silencing of UBR5 in M2E and M4E LCC cells, cell proliferation and radiosensitivity were significantly increased or decreased, respectively, compared with the control groups. The percentage of S phase cells decreased in the UBR5 si-RNA group compared with that in the control group, while overexpression of UBR5 exerted no effect on the cell cycle. In addition, the expression of Bcl-2 and p38 was decreased in the si-UBR5 combined with radiation groups. The level of phosphorylated p38 expression was increased after combination of si-UBR5 with radiation. The small molecule inhibitor of p38/MAPK signaling, SB203580, decreased the viability of UBR5-overexpressing cells and the survival fraction when cells were exposed to radiation. These findings demonstrated that UBR5 may be involved in regulating cell proliferation and sensitivity to radiotherapy in LCC via the p38/MAPK pathway, thereby highlighting its possible value for the development of new therapeutic strategies and targets for the treatment of this disease.

Altered O-glycosylation is associated with inherent radioresistance and malignancy of human laryngeal carcinoma

Radioresistance (inherent or acquired) remains a major obstacle affecting the clinical outcome of radiotherapy for laryngeal carcinoma. Results from our laboratory and other groups suggest that aberrant glycosylation contributes to cancer acquired radioresistance. However, the role of glycosylation in inherent radioresistance of laryngeal carcinoma has not been fully uncovered. In this study, we investigated the glycan profiling of the inherent radioresistant (Hep-2max) and radiosensitive (Hep-2min) cell lines using lectin microarray analysis. The results revealed that the radioresistant cell line Hep-2max presented higher core 1-type O-glycans than the sensitive one. Further analysis of the O-glycan regulation by benzyl-α-GalNAc application in Hep-2max cells showed partial inhibition of the O-glycan biosynthesis and increased radiosensitivity. In addition, core 1 β1, 3-galactosyltransferase (C1GALT1) overexpression in Hep-2min cells enhanced cell migration, invasion, and radioresistance. Conversely, knockdown of C1GALT1 in Hep-2max cells was able to suppress these malignant phenotypes. Moreover, mechanistic investigations showed that C1GALT1 modified the O-glycans on integrin β1 and regulated its activity. The glycosylation-mediated radioresistance was further inhibited by anti-integrin β1 blocking antibody. Importantly, we also observed that core 1-type O-glycans expression was correlated with advanced tumor stage, metastasis, and poor survival of laryngeal carcinoma patients. These findings suggest that altered O-glycosylation can lead to the inherent radioresistance and progression, and therefore may be important for enhancing the efficacy of radiotherapy in laryngeal carcinoma.

Prognostic value of the proliferation marker Ki‐67 in laryngeal carcinoma: Results of the Accelerated Radiotherapy with Carbogen Breathing and Nicotinamide phase III randomized trial

The prognostic and predictive value of the proliferation marker Ki-67 was investigated in a randomized trial comparing accelerated radiotherapy with carbogen breathing and nicotinamide (ARCON) to accelerated radiotherapy in laryngeal carcinoma. Labeling index of Ki-67 (Li Ki-67) in immunohistochemically stained biopsies and the colocalization with carbonic anhydrase IX (CAIX) were related to tumor control and patient survival. On average, node-positive patients had a higher Li Ki-67 (median 14% vs 8%; p < .01). In patients with a high Li Ki-67, the 5-year regional control and metastases-free survival were 79% versus 96% (p < .01) and 71% versus 88% (p = .05) for accelerated radiotherapy and ARCON, respectively. The 5-year local control and disease-specific survival were not significantly different. Patients with low Ki-67 expression had an excellent outcome with accelerated radiotherapy alone. Patients with laryngeal carcinomas with high proliferative activity are at increased risk of regional and distant metastases formation. This risk can be reduced by treatment with ARCON.

Indications for postoperative radiotherapy in laryngeal carcinoma: A panel of tumor tissue markers for predicting locoregional recurrence in surgically treated carcinoma. A pilot study

Combining primary surgery with postoperative radiotherapy (RT) significantly reduces locoregional recurrence rates in selected patients with laryngeal squamous cell carcinoma (SCC). A prognostic model was used to see if associating laryngeal SCC tissue markers (mammary serine protease inhibitor [MASPIN], CD105, angiogenin [ANG], and nm23-H1) with conventional criteria could better discriminate higher-risk patients warranting postoperative RT. The study involved 76 consecutively operated patients with laryngeal SCC not recommended for postoperative RT, in accord with current guidelines. On multivariate statistical modeling, non-nuclear MASPIN expression (p = .022), a CD105 expression ≥ 5.28% in vascular endothelial cells (p = .003), an nm23-H1 nuclear expression in carcinoma cells ≤ 12.0% (p = .028), and an ANG expression ≥ 5.0% (p = .07, statistical trend) showed a negative prognostic significance. The discriminatory power for disease recurrence of the 4 considered biomarkers generated an area under the curve (AUC; receiver operating characteristic [ROC]) of 0.872. The Hosmer-Lemeshow scale indicated an excellent discriminatory power. This panel's ability to predict laryngeal SCC recurrence warrants further prospective, randomized studies to assess its use among the parameters routinely considered before recommending postoperative RT for patients with laryngeal SCC.

Anterograde–retrograde rendezvous approach for radiation-induced complete upper oesophageal sphincter stenosis: case report and literature review

Strictures of the hypopharynx and oesophagus are frequently observed following (chemo)radiation. Anterograde dilatation of a complete stenosis carries a high risk of perforation. An alternative is described: a combined anterograde-retrograde approach. A 75-year-old man developed complete stenosis of the oesophageal inlet after primary radiotherapy for laryngeal carcinoma and full percutaneous endoscopic gastrostomy feeding. To prevent creation of a false route into the mediastinum, a dilatation wire was introduced in a retrograde fashion into the oesophagus, through the gastrostomy opening. The wire was endoscopically identified from the proximal side and then passed through a perforation created by CO2 laser. Anterograde dilatation was safely performed, and the patient returned to a normal diet. There is consensus in the literature that blind anterograde dilatation carries a high risk of perforation; therefore, an anterograde-retrograde rendezvous technique is advisable. In cases of complete obstruction of the oesophageal inlet, anterograde-retrograde dilatation represents a safe technique with which to restore enteric continuity.

Silencing of signal transducer and activator of transcription 3 gene expression using RNAi enhances the efficacy of radiotherapy for laryngeal carcinoma in vivo

To study the inhibitory effect of signal transducer and activator of transcription 3 (STAT3) shRNA generated by vector pSilence in conjunction with radiotherapy on laryngeal squamous cell carcinoma of nude mice xenograft tumor. The animal models of xenotransplanted human laryngeal carcinoma cell line Hep-2 were set up in 28 nude mice which were divided into 4 groups at random: the negative plasmid control group, the group that received pshSTAT3 (pGPU6/GFP/NeoshSTAT3) transfection, the radiation group, and the group of pshSTAT3 transfection combined with irradiation. Tumor volume was determined regularly. On the fifteenth day after termination of radiation treatment, the mice were sacrificed, the tumor weight was measured in all the groups, the inhibition rate for tumor growth was calculated and tumor growth curve was plotted. Meanwhile, the expressions of p-STAT3, B cell lymphoma 2 (bcl-2), p53, vascular endothelial growth factor (VEGF) protein and intratumor microvessel density (MVD) were observed by immunohistochemistry. Computer-assisted image analysis was used to obtain the results. Flow cytometry was used to detect the cell apoptosis rate. There was a significant difference in tumor volume among the groups (P<0.01). The rate of tumor inhibition in the pshSTAT3 group, radiation group and pshSTAT3 plus radiation group was 19.68%, 34.76% and 67.70%, respectively. The p-STAT3 protein expression decreased significantly in the group of pshSTAT3 plus simple radiotherapy (P<0.01). The intratumoral MVD in the group of pshSTAT3 plus simple radiotherapy was significantly lower compared to the negative plasmid control group and the radiotherapy group (P<0.01), while the apoptosis rate was much higher (P<0.01). There was a positive correlation between the expressing of p-STAT3 and bcl-2, p53, VEGF and MVD (r value was 0.738, 0.727, 0.735, 0.691, all P<0.01), and there was a negative correlation concerning cell apoptosis rate. Moreover, a statistically positive association was present between MVD and p53, VEGF protein expression, respectively (r value was 0.784, 0.641, all P<0.01); and the correlation was negative between expression of bcl-2 and apoptosis rate (r=-0.883, P<0.01). Using pshSTAT3 in conjunction with radiotherapy can significantly inhibit the growth of laryngeal carcinoma.

Radiotherapy in laryngeal carcinoma: Can a panel of 13 markers predict response?

To find biomarkers associated with response to radiotherapy in laryngeal cancer that can be used together with clinical parameters to improve outcome prediction. In this study, 26 patients irradiated for laryngeal carcinomas with a local recurrence within two years (cases) and 33 patients without recurrence (controls) were included. All pretreatment biopsies were arrayed onto a tissue array. Immunohistochemistry was performed for 13 biomarkers that were selected from the literature as potential predictors for radioresponse in head and neck (HN) cancer: Bcl-2, Bcl-xL, p16, p21, p27, p53, cyclin D1, HIF-1alpha, CA9, COX-2, EGFR, ki-67, and pRB. Univariate logistic regression models showed borderline statistically significant increased relative risks, with positivity for CA9, COX-2, and p53. Goeman's global testing revealed an overall association between outcome and the 13 markers together with clinical variables. The most important markers were CA9 and COX-2. In laryngeal carcinoma, hypoxia and COX-2 overexpression provide a stronger contribution to an increased risk of local recurrence after radiotherapy compared with the well-known candidate markers p53, Bcl-2, and cyclin D1. However, no robust expression profile for the prediction of radioresistance was found.

Swallowing Outcomes After Radiotherapy for Laryngeal Carcinoma

Swallowing Outcomes After Radiotherapy for Laryngeal Carcinoma

Late laryngeal radionecrosis in severe arteriosclerosis

Laryngeal necrosis is a serious complication that usually occurs within the first year following completion of radiotherapy, although it is reported that cases can develop after a long period of latency. Factors such as dosage and irradiation technique employed, tumour invasion into the laryngeal cartilage, infection, continued smoking, trauma and general vascular condition of the patient have been considered to increase the rate and degree of development of radionecrosis. We report an unusual case of laryngeal radionecrosis in a patient with hypertension, hyperlipidaemia, diabetes and a history of cigarette smoking, which developed 25 years after radiotherapy for laryngeal carcinoma. His systemic illnesses and continued smoking were speculated to have contributed to the progress of the radionecrosis, suggesting that cessation of smoking and control of arteriosclerotic diseases should be considered to decrease its incidence.

Cervical dystonia mimicking dropped-head syndrome after radiotherapy for laryngeal carcinoma

We report a case of cervical dystonia mimicking dropped-head syndrome (DHS) in a 57-year-old man treated for laryngeal carcinoma by radiotherapy (74.4 Gy) 3 months before. Cervical computerized tomographic scan and magnetic resonance imaging (MRI) did not find any muscle fat changes but found a high-intensity signal on T2 weighted images in the cervical spinal cord. Clinical and electromyographic findings were consistent with cervical dystonia. A trapezius biopsy was normal. Spontaneous remission of the dystonia was observed for 1 month whereas the laryngeal carcinoma progressed. The link between cervical dystonia and radiotherapy might be acute radiation-induced damage to the cervical spinal cord.

Three weeks radiotherapy for T1 glottic cancer: the Christie and Royal Marsden Hospital Experience

Background and purpose: Radiotherapy for laryngeal carcinoma is conventionally given over a 6–7-week period. However, in a number of UK centres early lesions are treated over 3 weeks. We review recent results of this policy and discuss the reasons why short treatment times may be advantageous. Materials and methods: Two hundred patients (100 from each centre) with T1 glottic invasive squamous cell carcinoma treated with definitive radiotherapy between 1989 and 1997 were analysed. The median age was 68 years. All patients received once daily fractionation, 5 days a week to a total tumour dose of 50.0–52.5 Gy in 16 fractions over 21 days; the fraction size ranged from 3.12 to 3.28 Gy. The median follow-up period was 5 years and 10 months. Results: The 5-year local control rates with radiotherapy for the whole group was 93%; there were 14 recurrences of which seven were salvaged by laryngectomy giving an ultimate local control of 96%. The 5-year overall survival was 80% and cause specific survival at 5 years was 97%. Univariate analysis revealed that T1 substaging ( P=0.82) and anterior commissure involvement ( P=0.47) did not significantly influence local control. A severe late radiation complication was seen in only one patient who continued to smoke heavily after treatment. There were no severe acute complications. Conclusions: Once daily radiotherapy over 3 weeks gives excellent local control in patients with T1 glottic squamous-cell carcinoma and has a low rate of severe complications. The short overall treatment time and large fraction size may be advantageous in radiotherapy of these well-differentiated tumours.

Concurrent chemotherapy and radiotherapy as initial treatment for stage II supraglottic squamous cell carcinoma

Objective: To evaluate the efficacy and safety of concurrent carboplatin (CBDCA) and radiotherapy for laryngeal carcinoma, we investigated survival rates and laryngeal preservation rates in patients with this treatment modality and those with radiation therapy only. Methods: We underwent chemotherapy with CBDCA and conventional radiotherapy concurrently to 17 patients with untreated stage II (T2N0M0) supraglottic squamous cell carcinoma since November 1990. CBDCA (100 mg/m 2) was administered intravenously once a week concurrently with radiotherapy (2.5 Gy/fr, 4 times a week). At the dose of 40 Gy, the results were evaluated, and some of the patients underwent planned surgery and others continued the radiotherapy up to 65 Gy. Results: Overall 5-year survival rate by Kaplan–Meier method was 81.1%. Actual laryngeal preservation rate was 76.0%. Toxicity over grade III was noticed in two patients. Compared with 14 cases of historical controls, which were treated by radiation therapy alone between 1988 and 1990, the cases with concurrent radiotherapy and chemotherapy had statistically significant advantage in overall successful laryngeal preservation rate ( P<0.05), whereas the two groups were not significantly different in the overall 5-year survival rate.

誤えんの治療に苦慮した喉頭癌照射後の喉頭麻ひ症例

A 80-year-old man developed impairment in his laryngeal movement, vocal fold fixation and severe misdeglutition after radiotherapy for laryngeal carcinoma. Despite of several surgical treatments for aspiration pneumonia, the misdeglutition did not cease because of the stiffness in his larynx until a laryngectomy was finally performed. The resected larynx showed marked fibrosis, and it was considered as a late complication of radiotherapy. The treatment course in this difficult case is discussed.

Positron emission tomography in the detection of residual laryngeal carcinoma

Positron emission tomography measures the metabolic activity of tissue. Because metabolism rates are higher in tumors than in normal tissue, positron emission tomography can be used to identify abnormal tissue. Positron emission tomography has proved useful in detecting residual or recurrent tumor in the brain and gastrointestinal tract after definitive treatment. We selectively used positron emission tomography in a preliminary trial to examine patients with laryngeal cancer who had previously been treated with organ-preservation therapy with radiation therapy alone or in combination with induction chemotherapy. These patients are often difficult to examine both clinically and radiographically because of posttreatment edema and fibrosis. From 1991 to 1993 patients at our institution who were treated with either radiation therapy or a combination of induction chemotherapy and radiotherapy for laryngeal carcinoma were evaluated after treatment. If clinical examination was suspicious for residual tumor or recurrence, a computed tomography or magnetic resonance imaging scan was obtained. In 10 patients neither clinical examination nor conventional imaging could absolutely rule out residual/recurrent carcinoma. In these patients positron emission tomography with 2-fluoro-2-deoxy- D-glucose was used to detect disease. The results from positron emission tomography were compared with the results from subsequent biopsy (five patients) or clinical follow-up. Positron emission tomography had a sensitivity of 67% and a specificity of 57%. The positive predictive value of positron emission tomography was 67%. The negative predictive value of positron emission tomography was 80%. Positron emission tomography may offer the clinician a useful diagnostic tool for cancer surveillance in organ-sparing treatment protocols for patients with laryngeal cancer. (OTOLARYNGOL HEAD NECK SURG 1995;113:404-7.)

The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinoma

An association between a low Hb-content and a poor response on radiation therapy has been established in previous years, especially in patients with squamous cell carcinomas. Whether this is linked with hypoxic conditions of the tumour or associated with tumour volume, blood loss or other conditions, is not yet known for certain. Patients with small head and neck tumours seem to form an interesting group to study this issue because several factors can be ruled out. Therefore, a retrospective analysis of 306 patients with glottic or supraglottic carcinoma was performed, to identify whether the Hb-value was of prognostic importance and whether this was linked to other patient characteristics. All patients were treated with primary radiotherapy with doses ranging from 60 to 70 Gy in 6-7 weeks. It appeared that in glottic carcinoma, the disease-free survival was significantly worse in patients with a Hb-value below normal at the start or/and at the end of therapy (p = 0.09, p = 0.0012, respectively). In patients with supraglottic carcinoma, the above mentioned difference approved only for a Hb-value below normal at the end of treatment (p = 0.05). A decrease in Hb-level of greater than or equal to 0.5 mmol/l during therapy, regardless whether the Hb-values were within or beyond normal range, reduced the disease-free survival in patients with glottic carcinoma (p = 0.0125). In a multivariate analysis, the Hb-value at the end of treatment proved to be an independent prognostic factor after T- and N-classification. There was no relationship with nutritional condition of the patient, nor with the Karnofsky Performance scale.(ABSTRACT TRUNCATED AT 250 WORDS)