Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe.

Genomic patterns of nasopharyngeal carcinomas (NPCs) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemoradiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating-lymphocyte-rich (TILs) samples were available in 19 and paired tumor-germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n = 27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n = 21); and of intermediate stability (1-7 singly mutated genes, n = 78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients (p < 0.001). No pathogenic germline mutations were identified. NPC exhibited APOBEC3A/B and nucleotide-excision-repair-related mutational signatures. As compared to TC, TILs demonstrated few shared and a higher number of low frequency private mutations (p < 0.001). In multivariate analysis models for progression-free survival, EBV positivity was a favorable prognosticator in stable tumors; BRCA1 mutations were unfavorable only in tumors of intermediate stability. In conclusion, other than described for SEA NPC, somatic BRCA1 mutations were common in SEE NPC; these were shared between TC and TILs, and appeared to affect patient outcome according to tumor genomic stability status. Along with the identified mutational signatures, these novel data may be helpful for designing new treatments for locally advanced NPC.

Expression profiling of 21 biomolecules in locally advanced nasopharyngeal carcinomas of Caucasian patients.

BACKGROUND: Since scarce data exist on the pathogenesis of nasopharyngeal carcinoma in Caucasian patients, we attempted to elucidate the responsible molecular pathways in this patient population. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples from 107 patients, diagnosed with locally-advanced nasopharyngeal carcinoma and treated with chemotherapy or chemo-radiotherapy, were analyzed by immunohistochemistry for the expression of the following proteins: E-cadherin, P-cadherin, Fascin-1, Cyclin D1, COX-2, EGFR, VEGF-A, VEGF-C, VEGFR-2, VEGFR-3, ERCC1, p53, p63, Ki67, MAPT, phospho-p44/42MAPK, PTEN, phospho-AKT, phospho-mTOR, and phospho-GSK-3ß. EBER status was assessed by in situ hybridization. The majority of the cases were included in tissue microarray. All stains were performed and assessed centrally by two pathologists. The median follow-up time was 76.8 (42.3 - 99.2) months. RESULTS: Biomolecules expressed in >90% of cases were: p53, COX-2, P-cadherin, EBER, phospho-GSK-3ß, and Fascin-1. WHO II+III tumors were more frequently EBER & PTEN positive and VEGF-A negative. Advanced age was significantly associated with positive phospho-GSK-3ß and ERCC1 expression; male gender with positive phospho-AKT and phospho-p44/42MAPK; and worse performance status (1 or 2) with negative Ki67, ERCC1, PTEN, and phospho-mTOR expression. Earlier disease stage was closely associated with p63, MAPT, PTEN, and Cyclin D1 positivity. Univariate Cox regression analysis highlighted Cyclin D1 as a negative prognostic factor for disease-free survival (p=0.034) and EBER as a positive one for overall survival (p=0.048). In multivariate analysis, advanced age and stage, poor performance status, and positive ERCC1 emerged as predictors of worse disease-free and overall survival, as opposed to positive phospho-mTOR. Clustering analysis defined two protein-expression groups being predictive of better overall survival (p=0.043). CONCLUSIONS: Our study is the first to examine the activation and interaction of established biomolecules and signaling pathways in Caucasian NPC patients in an effort to reveal new therapeutic targets.

Acoustic Radiation Force Impulse quantitative elastography: a new noninvasive technique for the evaluation of parotid glands. A preliminary study in controls and in patients with irradiated nasopharyngeal carcinoma.

AIM: We aim to define the values of the shear wave velocity (SWV) in the normal parotid glands (PG) and to identify the modifications of tissue stiffness in patients with irradiated nasopharyngeal carcinoma. MATERIAL AND METHODS: Sixty normal parotid glands pertaining to 30 healthy volunteers and 40 pathological parotid glands pertaining to 20 patients who had had underwent radiation therapy for nasopharyngeal carcinoma were included in this study. The patients underwent a B mode ultrasonography examination and the volume of the parotid gland was determined. A subsequent Acoustic Radiation Forde Impulse Imaging (ARFI) examination was performed and the SWV were determined for the central and the periphery of the glandular parenchyma. RESULTS: The mean volume of the gland in the volunteers' group (12.02+/-0.6 ml) was significantly higher than in the group of patients who underwent radiation therapy (10.3+/-0.74 ml) (p<0.0001). The SWV values in the normal group were lower compared to the patients group (1.54+/-0.6 m/s vs. 1.76+/-0.73 m/s, p<0.0001). CONCLUSION: Elastography using the ARFI technique constitutes an objective method used for the evaluation of glandular stiffness in both normal and post radiotherapy glands. The SWV values determined in patients who underwent head and neck radiotherapy are increased, indicating a greater tissue stiffness thereby implying a structural transformation of the glandular parenchyma.

Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer: a Hellenic Cooperative Oncology Group Phase III Study.

The primary objective of the present randomized phase III trial was to compare the 3-yr survival rate of patients treated with standard fractionated radiotherapy (RT) alone or with the same RT concomitantly with cisplatin (DDP) or carboplatin (Cb). From January 1995 until July 1999, 124 patients with histologically proven locally advanced non-nasopharyngeal head and neck cancer (HNC) were randomized to receive either RT monotherapy (70 Gy, Group A) or the same RT concomitantly with DDP (100 mg/m2 on d 2, 22, 42, Group B) or Cb (7 AUC on d 2, 22, 42, Group C). There were no significant differences in complete response rates between patients treated with RT alone or combined chemoradiotherapy. However, median time to progression (TTP) and overall survival (OS) were significantly longer in patients treated with concomitant chemoradiotherapy. Thus, median TTP was 6.3, 45.2, and 17.7 mo in groups A, B, and C respectively (p = 0.0002). Similarly, median OS was 12.2, 48.6, and 24.5 mo, respectively (p = 0.0003). At 3 yr follow-up, 17.5% of patients in group A were alive compared to 52% in group B and 42% in group C (p < 0.001). Patients treated with concomitant chemoradiotherapy experienced more frequently severe hematological toxicity. Also, severe nausea/vomiting was more pronounced in group B, as expected. The present study clearly demonstrated that concomitant chemoradiotherapy with platinum analogs significantly prolongs 3-yr survival and median OS in patients with locally advanced HNC compared to conventional RT alone.

Extraosseous Ewing sarcoma and peripheral primitive neuroectodermal tumor of the thyroid gland: Case report and review.

The Ewing family of tumors and peripheral primitive neuroectodermal tumor (pPNET) represent different manifestations of the same entity. Immunohistochemical and cytogenetic studies suggest that these tumors have a common origin. Ewing sarcoma is more common in bone, while pPNET is more common in soft tissues. Extraosseous Ewing sarcoma (EoES) is rare. We present the case of a 48-year-old man who presented with acute obstructive respiratory failure secondary to a large thyroid swelling. The patient was initially diagnosed with giant B-cell non-Hodgkin lymphoma and treated with chemotherapy. However, subsequent immunohistochemical staining of biopsy specimens revealed that the patient actually had EoES/pPNET of the thyroid gland. We performed a nearly complete surgical resection of the tumor plus a total laryngectomy and resection of five tracheal rings. However, the patient died of a cerebral metastasis 1 month later after he had completed one cycle of postoperative chemotherapy.

ARFI quantitative elastography of the submandibular glands. Normal measurements and the diagnosis value of the method in radiation submaxillitis.

OBJECTIVES: Evaluation of Acoustic Radiation Force Impulse Imaging (ARFI) elastography performance in predicting the elasticity of the submandibular glands in normal situations and after radiation therapy. MATERIAL AND METHOD: A number of 54 normal submandibular glands from 27 voluntary subjects and 33 pathological submandibular glands (radiation submaxillities) from 18 patients who had undergone radiation therapy for various cervical and facial oncological conditions were included in study. All the patients had undergone a B mode ultrasonography (Tissue Harmonic Imaging, 8-14 MHz) while the submandibular volume was determined and subsequently an ARFI examination while the shear wave velocity (SWV) was measured (in the central, peripheral and subcapsular areas, with the results expressed in m/s). RESULTS: In the volunteers' group the mean value of the SWV of the left submandibular gland was 1.68 ± 0.46 m/s, determined in the centre of the gland, 1.88 ± 0.4 m/s in the periphery (corresponding to the subcapsular parenchyma) and the SWV of the right submandibular gland was 1.74 ± 0.35 m/s (centrally) and 1.84 ± 0.43 m/s in the periphery. The mean value of all measurements was 1.82 ± 0.41 m/s. The mean volume of the glands was 7.97 ± 2.63 cm3. In the group of patients who had underwent radiation therapy (at least 35Gy), the mean value of the SWV was 2.24 ± 0.49 m/s centrally and 2.1 ± 0.58 m/s in the periphery on the left and 1.99 ± 0.5 m/s centrally and 2.21 ± 0.52 m/s in the periphery on the right. The mean value of all the measurements was 2.13 ± 0.52 m/s and the mean volume of the gland was 5.95 ± 4.16 cm3. CONCLUSIONS: Elastography using ARFI technique is a valid examination in the evaluation of the normal and pathological submandibular gland stiffness. The values of the shear wave velocities that correspond to a normal stiffness, determined through the ARFI technique, are similar in the two glands. After cervical and facial radiation therapy the values of the SWV are increased, indicating a change in the consistency of the gland thus implying a structural transformation. The ARFI technique can be used in the evaluation of the salivary glands pathology.