Mandible handling in the surgical treatment of oral squamous cell carcinoma: lessons from clinical results after marginal and segmental mandibulectomy.

OBJECTIVE: The aim of this retrospective, single-center study was to analyze long-term results after marginal and segmental mandibulectomies in patients with oral squamous cell carcinoma (OSCC). STUDY DESIGN: The study included 259 patients treated for OSCC with mandibulectomy between 1996 and 2010. Data acquisition consisted of analysis of operation reports, re-evaluation of histologic bone specimens, and collection of clinical follow-up data. RESULTS: Of the included patients, 86.5% had received segmental and 13.5% marginal mandibulectomies. Patients who received segmental mandibulectomy generally displayed a higher TNM (tumor-node-metastasis) stage; 47% of patients who received segmental mandibulectomy and 14% of those receiving marginal mandibulectomy showed bone infiltration (pT4 a). Of all patients with bone infiltration, 49% showed an invasive histologic infiltration pattern, and 35% showed an erosive histologic infiltration pattern. We found healthy residual crestal bone height in 43% of all segmental mandibulectomies. Only 8% of all patients were prosthodontically rehabilitated. With regard to prognostic parameters, there was no significant difference between patients receiving marginal mandibulectomy and those receiving segmental mandibulectomy. CONCLUSIONS: Because healthy residual crestal bone height was found in 43% of all patients who had received segmental mandibulectomies, it is conceivable that a significant number of patients would profit from marginal mandibulectomy, at least in cases of absent or erosive bone infiltration pattern, because the residual crestal bone is functionally stable.

BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma.

To determine the role of BRAFV600E mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAFV600E mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAFV600E mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAFV600E mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAFV600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAFV600E mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAFV600E mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAFV600E positive NEC xenografts. High frequencies of BRAFV600E mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs.

New model for gastroenteropancreatic large-cell neuroendocrine carcinoma: establishment of two clinically relevant cell lines.

Recently, a novel WHO-classification has been introduced that divided gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) according to their proliferation index into G1- or G2-neuroendocrine tumors (NET) and poorly differentiated small-cell or large-cell G3-neuroendocrine carcinomas (NEC). Our knowledge on primary NECs of the GEP-system is limited due to the rarity of these tumors and chemotherapeutic concepts of highly aggressive NEC do not provide convincing results. The aim of this study was to establish a reliable cell line model for NEC that could be helpful in identifying novel druggable molecular targets. Cell lines were established from liver (NEC-DUE1) or lymph node metastases (NEC-DUE2) from large cell NECs of the gastroesophageal junction and the large intestine, respectively. Morphological characteristics and expression of neuroendocrine markers were extensively analyzed. Chromosomal aberrations were mapped by array comparative genomic hybridization and DNA profiling was analyzed by DNA fingerprinting. In vitro and in vivo tumorigenicity was evaluated and the sensitivity against chemotherapeutic agents assessed. Both cell lines exhibited typical morphological and molecular features of large cell NEC. In vitro and in vivo experiments demonstrated that both cell lines retained their malignant properties. Whereas NEC-DUE1 and -DUE2 were resistant to chemotherapeutic drugs such as cisplatin, etoposide and oxaliplatin, a high sensitivity to 5-fluorouracil was observed for the NEC-DUE1 cell line. Taken together, we established and characterized the first GEP large-cell NEC cell lines that might serve as a helpful tool not only to understand the biology of these tumors, but also to establish novel targeted therapies in a preclinical setup.

Diagnostic accuracy of ultrasound, ¹8F-FDG-PET/CT, and fused ¹8F-FDG-PET-MR images with DWI for the detection of cervical lymph node metastases of HNSCC.

OBJECTIVE: This study aimed to compare (18)F-fluorodesoxyglucose positron emission tomography/MRI ((18)F-FDG-PET-MRI) fusion images, including diffusion-weighted imaging (DWI), (18)F-FDG-PET/CT, and ultrasound (US) regarding their performance in nodal staging of patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Eighteen patients prospectively underwent ultrasound examination, (18)F-FDG- PET/CT, and MRI before oral tumor resection and bilateral neck dissection. PET data sets were fused with contrast-enhanced T1-weighted MR images. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for nodal detection were calculated for all the imaging modalities. Furthermore, the accuracy of the correct N-staging was calculated for all methods. Detailed histopathology served as the standard of reference. RESULTS: The sensitivity, specificity, PPV, NPV, and accuracy for detection of lymph node metastases were 63, 99, 86, 96, and 95 % for ultrasound; 30, 97, 56, 92, and 90 % for (18)F-FDG-PET/CT; 52, 96, 59, 94, and 91 % for (18)F-FDG-PET-MRI; and 53, 97, 67, 95, and 92 % for (18)F-FDG-PET-MRI plus DWI, respectively. There was no significant difference in the diagnostic accuracy for lymph node metastasis detection between (18)F-FDG-PET-MRI and (18)F-FDG-PET/CT (p = 0.839) and between (18)F-FDG-PET-MRI plus DWI and (18)F-FDG-PET/CT (p = 0.286), respectively. US was significantly more accurate than (18)F-FDG-PET/CT (p = 0.009), whereas no significant difference was seen between (18)F-FDG-PET-MRI and US (p = 0.223) or (18)F-FDG-PET-MRI plus DWI and US (p = 0.115). The nodal stage was correctly rated by (18)F-FDG-PET-MRI in eight patients, (18)F-FDG-PET-MRI plus DWI in nine patients, US in 12 patients, and (18)F-FDG-PET/CT in five out of 18 patients. CONCLUSION: Software-based fusion of (18)F-FDG-PET-MRI and (18)F-FDG-PET-MRI plus DWI may not increase nodal detection and N-staging performance in patients with oral malignancies compared to US and (18)F-FDG-PET/CT. CLINICAL RELEVANCE: Surgical staging of cervical lymph nodes will not be replaced even by advanced imaging modalities in the near future.

CT-scan is a valuable tool to detect mandibular involvement in oral cancer patients.

In patients with oral squamous cell carcinomas (OSSC) it is desirable to avoid unnecessary bone resection without neglecting the overall surgical treatment goal of tumor-free margins. Whereas computed tomography (CT) is most commonly used to detect mandibular invasion, there are conflicting reports regarding the accuracy of CT. Therefore, the aim of this study was to reinvestigate the accuracy of CT in predicting mandibular involvement by OSSC. One hundred and seven patients with OSSC who received a mandibulectomy were included. Before treatment all patients underwent a contrast-enhanced multi-detector CT. Axial 3 or 1.25 mm thick images were reconstructed for evaluation in overlapping technique and displayed in a bone (1400/400 HU) and a soft tissue window (350/50 HU). CT scans were examined by three investigators and compared with the histological findings. The radiological examination showed a high interrater reliability (Cronbachs alpha 0.982). Comparing the radiological findings with the histological results the CT showed 8 false-positive results and 8 false-negative patients. The quality criteria for detecting bone involvement of OSSC by CT were calculated as follows: sensitivity 82.6%; specificity 86.9%; positive predictive value 82.6%; negative predictive value 86.9%. However, in all false-positive patients a sagittal bone defect of 15.1mm could be found presumably caused by pressure of the tumor, but no histologically detectable bone infiltration. Modern CT (1-2 mm sections) is a valuable tool for surgical treatment planning. If bone invasion is detected, a mandibulectomy seems always reasonable. In radiologically negative cases histological assessment is necessary to detect mandibular involvement.

Identification of an MSI-H tumor-specific cytotoxic T cell epitope generated by the (-1) frame of U79260(FTO).

Microsatellite instability (MSI-H) induced by defects of the DNA mismatch repair system results in insertion or deletion of single nucleotides at short repetitive DNA sequences. About 15% of sporadic and approximately 90% of hereditary nonpolyposis colorectal cancers display MSI-H. When affecting coding regions, MSI-H results in frameshift mutations and expression of corresponding frameshift peptides (FSPs). Functional tumor promoting relevance has been demonstrated for a growing number of genes frequently hit by MSI-H. Contrary, immune reactions against FSPs are involved in the immune surveillance of MSI-H cancers. Here, we provide conclusive data that the (-1) frame of U79260(FTO) encodes an HLA-A0201-restricted cytotoxic T cell epitope (FSP11; TLSPGWSAV). T cells specific for FSP11 efficiently recognized HLA-A0201((pos)) tumor cells harboring the mutated reading frame. Considering the exceptionally high mutation rate of U79260(FTO) in MSI-H colorectal carcinoma (81.8%), this recommends that FSP11 be a component of future vaccines.