A rare case of Ewing sarcoma metastasis to the oral cavity.

Ewing sarcoma in the head and neck is rare, and metastasis from other bones to the mandible accounts for 0.7% of cases. This report presents a case of oral metastasis in a 24-year-old male patient diagnosed with Ewing sarcoma of the femur (p53 gene mutation and EWSR1-ERG fusion). The chief complaint was numbness in the mandible and pain for 1 month and a hardened, ulcerated exophytic lesion in the right retromolar region. Imaging exams revealed an unspecified thinning of the cortical bone of the inferior alveolar canal in the right mandibular ramus, associated with erosion of the alveolar bone. Histopathological analysis confirmed metastasis of Ewing sarcoma. The patient presented an aggressive disease progression and died 1 month after the oral diagnosis. It is important to recognize the signs and symptoms compatible with rare clinical outcomes, leading to an early diagnosis that can improve patients' quality of life and survival.

Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial.

IMPORTANCE: Locoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC. OBJECTIVE: To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population. INTERVENTIONS: Patients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life. RESULTS: A total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P = .48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group). CONCLUSIONS AND RELEVANCE: This study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01345669.

Uso do PET-SCAN como preditor de eficácia para controle locoregional e sobrevida em carcinoma de cabeça e pescoço / Use of PET-SCAN as a predictor of efficacy for locoregional control and survival in head and neck carcinoma

Introdução: A avaliação da resposta à quimioterapia de indução (QI) com regimes triplos, incluindo taxane, cisplatina e 5 fluorouracil (TPF) em carcinoma de células escamosas de cabeça e pescoço localmente avançado (CECCPLA) é geralmente realizada após 2 ciclos de quimioterapia usando critérios morfológicos. Preocupações em relação ao perfil de toxicidade do TPF sugerem um benefício potencial de uma abordagem de avaliação de resposta precoce. Objetivo: o objetivo deste estudo é avaliar a utilidade de se avaliar precocemente a resposta tumoral por método funcional e morfológico com uso do PET-SCAN em pacientes portadores de CECCPLA tratados com QI seguido de radioteapia após o primeiro ciclo de QI. Métodos: Pacientes com CECCPLA que se submeteram ao QI com TPF foram avaliados prospectivamente. Os procedimentos de estadiamento incluíram imagem locorregional e de tórax, exame endoscópico e PET-SCAN. Pacientes foram avaliados para resposta tumoral após o segundo ciclo da QI e ao término do tratamento, conforme conduta estabelecida para a prática clínica. No dia 14 do primeiro ciclo, um segundo PET- SCAN foi realizado e os médicos e pacientes foram cegados para os seus resultados. Todos os pacientes assinaram consentimento para participação do estudo. Resultados: Entre fevereiro de 2010 e julho de 2013, 49 pacientes portadores de CECCPLA estádio III / IVA-B CECCPLA foram recrutados. Após um seguimento mediano de 44,3 meses, pacientes cujos achados de PET-SCAN não registraram aumento no Stardard Uptake Value (SUV) máximo dos linfonodos regionais apresentaram melhor sobrevida livre de recidiva (HR = 0,18; IC95% 0,056-0,585; p = 0,004) e sobrevida global (HR = 0,14, IC 95% 0,040-0,498; p = 0,002) e foram considerados respondedores. Neste subgrupo, os pacientes que atingiram pelo menos 45% de redução no SUV máximo do tumor primário apresentaram melhor sobrevida livre de progressão tumoral (HR = 0,23, IC 95% 0,062-0,854; p = 0,028) e sobrevida global (HR = 0,11, IC 95% 0,013 -0,96; p = 0,046). Conclusão: Estes resultados sugerem um potencial papel da avaliação da resposta tumoral precoce com PET-SCAN em pacientes com CECCPLA submetidos a QI. Aumento no SUV máximo do linfonodo regional e diminuição insuficiente na captação do tumor primário predizem pior evolução clínica (AU)

Introduction: Evaluation of induction chemotherapy (IC) response with triplet taxane, cisplatin and 5 fluorouracil containing regimen (TPF) in locally advanced head and neck squamous cell carcinoma (LASCCHN) is usually performed after 2 cycles of chemotherapy using morphological criteria. Concerns regarding the TPF toxicity profile suggest a potential benefit of an early tumor response assessment approach. Objective: The objective of this study is to evaluate the usefulness of early evaluation of tumor response by functional and morphological method using PET-SCAN patients with LASCCHN treated with IC followed by radiotherapy after the first IC cycle. Methods: Patients with LASCCHN who underwent IC with TPF were prospectively evaluated. Staging procedures included standard primary neck tumor and chest imaging, endoscopic examination and PET-SCAN. Patients were evaluated for tumor response after the second cycle of IC and at the end of treatment, according to established practice guidelines. On day 14 of the first cycle, a second PET-SCAN was performed and physicians and patients were blinded to their exam findings. Results: Between February 2010 and July 2013, 49 patients staged AJCC III / IVA-B LASCCHN were recruited. After a median follow-up of 44.3 months, patients with no increase in the regional maximum lymph node SUV had better relapse-free survival (HR = 0.18, 95% CI 0.056-0.585, p = 0.004) and overall survival (HR = 0.14, 95% CI 0.040-0.498, p = 0.002) and were considered responders. Among cases considered responders, patients who achieved at least 45% reduction of SUV in the primary tumor presented improvement in progression-free (HR = 0.23, 95% CI 0.062-0.854, p = 0.028) and overall survival (HR = 0.11, 95% CI 0.013 -0.96, p = 0.046). All patients provided informed consent for study participation. Conclusion: These results suggest an important role of the evaluation of the early response with PET-SCAN in patients with LASCCHN undergoing IC. Increase in the regional SUV maximum and insufficient decrease in primary tumor uptake predict worse clinical outcome (AU)

The roles of PTEN, cMET, and p16 in resistance to cetuximab in head and neck squamous cell carcinoma.

There is no established biomarker for cetuximab efficacy in recurrent head and neck squamous cell carcinoma (HNSCC). The aim of the present study was to evaluate the prognostic and predictive impact of PTEN, cMET, and p16 expression in recurrent HNSCC. In this retrospective study, 112 patients with recurrent HNSCC received chemotherapy (CT) alone (n = 37) or chemotherapy with cetuximab (n = 75). PTEN, cMET, and p16 protein expression were evaluated by immunohistochemistry. The median overall survival (mOS) for the patients treated with cetuximab + CT versus CT alone was 11.4 months and 7.0 months, (p = 0.949). The median progression-free survival (mPFS) was 6.2 months versus 3.0 months (p = 0.154). Patients with PTEN loss exhibited a mOS of 5.8 months versus 10.5 months (p = 0.002) and a mPFS of 3.2 months versus 4.7 months (p = 0.019). A multivariate analysis identified an independent association between PTEN loss and OS (HR 2.27; 95% confidence 95% CI 1.27-4.08; p = 0.006) and with PFS (HR 1.85; 95% CI 1.09-2.99; p = 0.022). A negative prognostic impact of PTEN loss was observed in the patients treated with cetuximab + CT, and not in the CT only group. Expression of cMET and p16 showed no impact on OS or PFS. The present findings confirm that PTEN is a prognostic factor for metastatic HNSCC and they support further studies of PTEN expression to evaluate its predictive value to cetuximab response.

Early metabolic 18F-FDG PET/CT response of locally advanced squamous-cell carcinoma of head and neck to induction chemotherapy: A prospective pilot study.

OBJECTIVE: The objective of this study was to assess the clinical value of 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) after the first cycle of induction chemotherapy (IC) in locally advanced squamous cell carcinoma of the head and neck (LASCCHN). METHODS AND FINDINGS: A prospective, single-arm, single center study was performed, with patients enrolled between February 2010 and July 2013.Patients (n = 49) with stage III/IVA-B LASCCHN who underwent IC with taxanes, cisplatin, and fluorouracil were recruited. Staging procedures included loco-regional and chest imaging, endoscopic examination, and PET/CT scan. On day 14 of the first cycle, a second PET/CT scan was performed. Patients with no early increase in regional lymph node maximum 18F-FDG standard uptake value (SUV), detected using 18F-FDG PET/CT after first IC had better progression-free survival (hazard ratio (HR) = 0.18, 95%, confidence interval (CI) 0.056-0.585; p = 0.004) and overall survival (HR = 0.14, 95% CI 0.040-0.498; p = 0.002), and were considered responders. In this subgroup, patients who achieved a reduction of ≥ 45% maximum primary tumor SUV experienced improved progression-free (HR = 0.23, 95% CI 0.062-0.854; p = 0.028) and overall (HR = 0.11, 95% CI 0.013-0.96; p = 0.046) survival. CONCLUSIONS: These results suggest a potential role for early response evaluation with PET/CT examination in patients with LASCCHN undergoing IC. Increased regional lymph node maximum SUV and insufficient decrease in primary tumor uptake predict poorer outcomes.

EGFR expression in circulating tumor cells from high-grade metastatic soft tissue sarcomas.

INTRODUCTION: Soft tissue Sarcomas (STS) are rare malignances, with high mortality rates. Half of patients develop metastasis. The presence of isolated Circulating Tumor Cells (CTCs) and Circulating Tumor Microemboli (CTM) in the blood may be early markers of tumor invasion. Epidermal Growth Factor (EGF) family receptors can also influence this process. OBJECTIVES: to quantify CTCs and identify CTM as well as the EGF Receptor (EGFR) protein expression in these cells and correlate with clinical outcome in metastatic STS. MATERIALS AND METHODS: Approximately 8mL of blood was prospectively collected from patients with different types of high-grade STS, before the beginning of chemotherapy. The samples were processed and filtered by ISET (Rarecells, France) for the isolation and quantification of CTCs and CTMs. EGFR expression was analyzed by immunocytochemistry (ICC) on CTCs/ CTMs. RESULTS: We analyzed 18 patients with median age of 49 years (18-77 y). The positivity for EGFR protein expression in CTCs was observed in 93.75% of the patients. This result shows that targeting EGFR positive CTCs from STS origen can be translated in clinical benefit for some patients. In addition, if target therapy is chosen, the EGFR expression in CTCs can be used in follow-up to measure treatment effectiveness. CONCLUSIONS: This is the first study to demonstrate the expression of EGFR protein in CTCs from sarcoma patients. It may open an area for future investigations. The next step is to characterize CTCs in a larger cohort of patients to better understand the role of EGFR in sustaining tumor metastasis in sarcomas.

Evaluation of incidence, significance, and prognostic role of circulating tumor microemboli and transforming growth factor-ß receptor I in head and neck cancer.

BACKGROUND: Circulating tumor microemboli (CTM) are clusters of circulating tumor cells (CTCs), involved in metastasis, as also transforming growth factor-ß (TGF-ß). The purpose of this study was to verify their role in progression-free survival (PFS). METHODS: Blood from patients with locally advanced head and neck squamous cell carcinoma (HNSCC; n = 53) was analyzed in 2 moments. TGF-ß receptor I (TGF-ßRI) expression was evaluated by immunocytochemistry. RESULTS: Comparing CTM1 (baseline) with CTM2 (first follow-up), patients with CTM1-positive disease who became CTM2-negative were classified as favorable (PFS 20 months). Patients with unfavorable evolution (CTM1-negative/CTM2-positive), had PFS of 17.5 months. Patients always CTM-negative showed PFS of 22.4 months, those always positive, 4.7 months (P < .001). The TGF-ßRI expression in the first follow-up correlated with poor PFS (12 × 26 months; P = .007), being an independent prognostic factor (hazard ratio [HR] = 6.088; P = .033). CONCLUSION: CTM1/2, TGF-ßRI expression, and unfavorable CTM kinetics may represent poor prognosis in locally advanced HNSCC.

Is early response by (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography a predictor of long-term outcome in patients with metastatic colorectal cancer?

BACKGROUND: Identify in advance responder patients to chemotherapy in metastatic colorectal cancer (CRC) would allow prompt interruption of ineffective therapies in non-responder patients. Hence, predictive markers are sought in numerous trials to detect responder patients, including tumor shrinkage measured by imaging methods. Usually, Response Evaluation Criteria in Solid Tumors (RECIST) is used to evaluate tumor response in metastatic CRC, but these criteria are questionable with use of biological agents associated to chemotherapy. Our aim was correlate early metabolic response by (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography ((18)FDG-PET-CT) with long-term outcome in metastatic CRC in first-line therapy. METHODS: We prospectively evaluated 36 patients with metastatic CRC in first-line treatment with 5-fluorouracil, leucovorin (folinic acid), oxaliplatin (FOLFOX) or 5-fluorouracil, leucovorin (folinic acid), irinotecan (FOLFIRI) associated with cetuximab or bevacizumab. (18)FDG-PET-CT was performed at baseline and after two cycles of chemotherapy. The early metabolic response [standardized uptake value (SUV)] was measured to identify responder and non-responder patients and correlated with overall survival (OS) and progression-free survival (PFS). RESULTS: Median age was 58.5 years (range, 41-74 years). PFS was 15.5 months for responder and 13.3 months for non-responder (P=0.42), OS was 55.7 months for responder and not reached for non-responder. There was no correlation between delta-SUV and clinical and pathological variables analyzed. In the subgroup of patients who did not undergo resection of metastasis (45%), PFS was higher for responders (15.3×6.8 months, P=0.02). CONCLUSIONS: According to our findings, early response by (18)FDG-PET-CT was not a predictor of long-term outcome for patients with metastatic CRC treated in the first-line chemotherapy with a monoclonal antibody.

Diffusion-Weighted MRI in the Assessment of Early Treatment Response in Patients with Squamous-Cell Carcinoma of the Head and Neck: Comparison with Morphological and PET/CT Findings.

OBJECTIVE: To evaluate changes in apparent diffusion coefficients (ADC) as measured by magnetic resonance imaging (MRI) before and after the treatment of primary tumors and cervical metastases in patients with squamous-cell carcinoma (SCC) of the head and neck, and to compare these values to the results of widely used morphological criteria and [18F]-FDG PET/CT findings. MATERIAL AND METHOD: This was a longitudinal, prospective, single-center nonrandomized trial involving patients with head and neck SCC treated with chemotherapy alone or in combination with radiotherapy. Imaging examinations ([18F]-FDG PET/CT and diffusion-weighted MRI) were performed on the same day, up to one day prior to the beginning of the first treatment cycle, and on the 14th day of the first chemotherapy cycle. Treatment response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) morphological criteria, as well as PET Response Criteria in Solid Tumors (PERCIST) metabolic criteria. RESULTS: Seventy-five lesions were examined in 23 patients. Pre- and post-treatment comparisons of data pertaining to all target lesions revealed reductions in tumor size and SUV, as well as increases in ADC values, all of which were statistically significant. The increase in ADC following treatment was significantly higher in patients classified as complete responders by both morphological criteria than that observed in any of the other patient groups of response. Patients with a complete metabolic response also showed greater increases in ADC values as compared to the remaining groups. CONCLUSION: The assessment of tumor response based on diffusion-weighted MRI showed an increase in the ADC of cervical lesions following treatment, which was corroborated by morphological and metabolic findings. Associations between changes in ADC values and treatment response categories using morphologic criteria and [18F]-FDG PET/CT were only identified in complete responders.

Oral metastasis of metaplastic breast carcinoma in a patient with neurofibromatosis 1.

Neurofibromatosis type 1 (NF1) has been associated with an increased risk for development of malignancy, especially malignant peripheral nerve sheath tumors. In addition, recently, literature has demonstrated an increased risk of breast cancer in women with NF1. The present paper shows a 53-year-old woman with NF1 who presented with metaplastic breast carcinoma and developed multiple metastases, including mandible. Furthermore, we reviewed the English literature, found 63 cases showing the association between NF1 and breast cancer, and added one more case. The present study demonstrated an important association between NF1 and breast cancer. Until the present time, there has been only one case of metaplastic breast carcinoma associated with NF1. Curiously, in our case the oral metastasis corresponded to sarcomatous component of metaplastic breast carcinoma.