Epigenetic disruption of cadherin-11 in human cancer metastasis.

Little is known about the molecular events occurring in the metastases of human tumours. Epigenetic alterations are dynamic lesions that change over the natural course of the disease, and so they might play a role in the biology of cancer cells that have departed from the primary tumour. Herein, we have adopted an epigenomic approach to identify some of these changes. Using a DNA methylation microarray platform to compare paired primary tumour and lymph node metastatic cell lines from the same patient, we observed cadherin-11 promoter CpG island hypermethylation as a likely target of the process. We found that CDH11 DNA methylation-associated transcriptional silencing occurred in the corresponding lymph node metastases of melanoma and head and neck cancer cells but not in the primary tumours. Using in vitro and in vivo cellular and mouse models for depleted or enhanced CDH11 activity, we also demonstrated that CDH11 acts as an inhibitor of tumour growth, motility and dissemination. Most importantly, the study of CDH11 5'-CpG island hypermethylation in primary tumours and lymph node metastases of cancer patients showed this epigenetic alteration to be significantly confined to the disseminated cells. Overall, these results indicate the existence of metastasis-specific epigenetic events that might contribute to the progression of the disease.

Endoscopic type 3 tympanoplasty: Functional outcomes in chronic otitis media.

BACKGROUND: Type 3 tympanoplasty is the surgery of choice for middle ear reconstruction in cases where an integral stapes suprastructure and mobile footplate are present. OBJECTIVE: The objective of this study was to obtain functional results after endoscopic type 3 tympanoplasty in chronic otitis media. MATERIALS AND METHODS: Prospective study including 24 patients who underwent endoscopic type 3 tympanoplasty, using PORP for ossicular chain reconstruction (OCR) and cartilage graft for tympanic membrane reconstruction. Audiograms were made preoperatively, and 6 months after surgery. RESULTS: Dry, closed, self-cleaning ears were obtained in 91.7% of the cases. Mean preoperative air-bone gap (ABG) was 30.4dB, mean postoperative ABG was 16.7dB, dB gain of 13.6dB. ABG closure rate to 20dB or less of 79.2%, and to 10dB or less of 29.2%. CONCLUSION AND SIGNIFICANCE: Endoscopic tympanoplasty and OCR is a valid option for surgeons who are comfortable with the use of endoscopes for middle ear surgery as it allows improved visualization of the prosthesis and graft placement during middle ear reconstruction.

Hyperfractionated radiotherapy: improvement of survival in locally advanced nasopharyngeal carcinoma.

OBJECTIVES: Standard treatment with concomitant chemotherapy (CT) and radiotherapy (RT) for nasopharyngeal cancer has shown rates of locoregional control of 80% and has improved the rate of 5-year survival to 67% to 84%. Hyperfractionated radiotherapy (HFRT) may increase locoregional control of tumors of the head and neck, but the addition of concomitant CT involves an unacceptable level of toxicity. Adding induction CT may control distant metastasis. Here we compare the results of our protocol with induction CT followed by HFRT alone with the results obtained with concomitant treatments. METHODS: Between October 1994 and May 2002, 46 patients with nasopharyngeal carcinoma were treated with HFRT. The patients with N+ or T4 lesions also received cisplatin-based induction CT (55%). RESULTS: The patients received a mean of 3 CT cycles (range, 2 to 5). At 5 years, the rate of progression-free survival was 66% (range, 51.3% to 82.1%), and the global survival rate was 75.7% (range, 61.9% to 89.5%). CONCLUSIONS: The use of HFRT in association with induction CT in patients with the greatest risk of metastasis may be as effective as concomitant CT-RT for treatment of nasopharyngeal cancer. Efforts should now concentrate on minimizing the acute and chronic toxicities.

Hearing results after type III tympanoplasty: incus transposition versus PORP. A systematic review.

OBJECTIVE: The objective of this study is to compare hearing improvements in the air-bone gap (ABG) after type III tympanoplasties, comparing between incus transposition (IT) and partial ossicular replacement prosthesis (PORP). MATERIALS AND METHODS: Publications in English were searched in PUBMED database and were systematically reviewed. A total of 14 articles were included, obtaining 1055 patients, 614 for the IT group and 441 for the PORP group. Preoperative ABG, postoperative ABG, dB gain and ABG closure rate were compared. RESULTS: IT group: preoperative ABG of 31.74 dB (SD 10.51); postoperative ABG of 18.97 dB (SD 10.6); dB gain of 12.76 dB (SD 14.97); and ABG closure rate of 64.48%. PORP group: preoperative ABG of 28.02 dB (SD 10.47); postoperative ABG of 16.27 dB (SD 10.45); dB gain of 11.75 (SD 15.02); and ABG closure rate of 71.32%. No significant statistical difference was found in dB mean gain between groups (p > .05), although a difference was found in the ABG closure rate between groups favouring PORP series (p < .05). CONCLUSION: An improvement in hearing results was observed within both groups after type III tympanoplasty. There is no difference in decibels gained between both ossiculoplasty materials, but a better closure rate (%) was observed in the PORP group.

Importance of neoadjuvant chemotherapy in olfactory neuroblastoma treatment: Series report and literature review.

INTRODUCTION AND OBJECTIVES: Olfactory neuroblastoma (ONB) is a rare entity that constitutes less than 5% of nasosinusal malignancies. Mainstream treatment consists in surgical resection+/-adjuvant radiotherapy. By exposing results observed with apparition of new therapeutic options as neoadjuvant chemotherapy, the objective is to evaluate a series and a review of the current literature. METHODS: A retrospective review was conducted including patients diagnosed and followed-up for ONB from 2008 to 2015 in our institution. RESULTS: 9 patients were included. Mean follow-up of 52.5 months (range 10-107). Kadish stage: A, 1 patient (11.1%) treated with endoscopic surgery; B, 2 patients (22.2%) treated with endoscopic surgery (one of them received adjuvant radiotherapy); C, 6 patients (66.7%), 4 patients presented intracranial extension and were treated with neoadjuvant chemotherapy followed by surgery and radiotherapy. The other 2 patients presented isolated orbital extension, treated with radical surgery (endoscopic or craniofacial resection) plus radiotherapy. The 5-year disease free and overall survival observed was 88.9%. CONCLUSION: Neoadjuvant chemotherapy could be an effective treatment for tumor reduction, improving surgical resection and reducing its complications.

Salvage surgery after head and neck squamous cell carcinoma treated with bioradiotherapy.

BACKGROUND: The purpose of this study was to describe the results and complications of primary site salvage surgery after head and neck squamous cell carcinoma (HNSCC) treated with bioradiotherapy. METHODS: We conducted a retrospective chart review of 268 patients treated with bioradiotherapy between March 2006 and December 2013 at the Hospital Universitari de Bellvitge-ICO. RESULTS: Fifty-nine patients developed local recurrence or had residual disease with a 1-year and 3-year overall survival of 47% and 15.4%, respectively. Salvage surgery was feasible in 22 patients (37.3%). There were 16 complications in these 22 patients (72.7%), 11 (50%) of which were major. Bilateral neck dissection was identified as a risk factor for complications. CONCLUSION: Salvage surgery after bioradiotherapy is associated with a high rate of complications. Neck dissection seems to be related to an increased rate of complications with no survival improvement. © 2016 Wiley Periodicals, Inc. Head Neck 39: 116-121, 2017.

Could the Addition of Cetuximab to Conventional Radiation Therapy Improve Organ Preservation in Those Patients With Locally Advanced Larynx Cancer Who Respond to Induction Chemotherapy? An Organ Preservation Spanish Head and Neck Cancer Cooperative Group Phase 2 Study.

PURPOSE: To evaluate the efficacy and safety of induction chemotherapy (IC) followed by bioradiotherapy (BRT) to achieve functional larynx preservation in the setting of locally advanced head and neck tumors. METHODS AND MATERIALS: This was a phase 2, open-label, multicenter study of patients with stage III and IVA laryngeal carcinoma who were candidates for total laryngectomy. The primary endpoint was the rate of survival with functional larynx (SFL) at 3 years, with a critical value to consider the study positive of SFL >59%. Patients received 3 cycles of IC with TPF (docetaxel, cisplatin, and 5-fluorouracil), and those who responded received conventional BRT with cetuximab. In patients with residual nodal disease after BRT, neck dissection was planned 2 months after BRT. Patients who did not respond to IC underwent total laryngectomy plus neck dissection and radiation therapy. RESULTS: A total of 93 patients started TPF. Responses to IC on larynx target lesion were as follows: 37 patients (40%) showed a complete response; 38 patients (41%) showed a partial response; 8 patients (9%) showed stabilization; 2 patients (2%) showed progressive disease, and 8 patients (9%) were not evaluated (2 deaths, 5 adverse events, and 1 lost to follow-up). Seventy-three patients (78%) received BRT: 72 as per protocol, but 1 with only stable disease. Median follow-up was 53.7 months. Three-year actuarial rates were as follows: SFL: 70% (95% confidence interval [CI] 60%-79%); laryngectomy-free survival: 72% (95% CI 61%-81%); overall survival: 78% (95% CI: 63%-82%). The acute toxicity observed during both IC and BRT was as expected, with only 1 toxicity-related death (local bleeding) during BRT. CONCLUSIONS: According to this protocol, the SFL rate was clearly higher than the critical value, with acceptable levels of toxicity. The use of cetuximab added to radiation therapy in patients with stage III and IVA laryngeal cancer who respond to TPF could improve functional larynx preservation. A phase 3 trial is warranted.

Does induction chemotherapy still have a role in larynx preservation strategies? The experience of Institut Catala d'Oncologia in stage III larynx carcinoma.

BACKGROUND: Radiotherapy with concurrent cisplatin is the standard alternative to total laryngectomy for patients with locally advanced laryngeal cancer. The value of induction chemotherapy in larynx-preservation therapies remains unknown. Hyperfractionation radiotherapy might improve disease-free survival. METHODS: From August 1993 to August 2004, 71 patients with T3N0-1 larynx tumors and eligible for total laryngectomy received induction chemotherapy with three cycles of cisplatin plus fluorouracil. Clinical tumor response was assessed by indirect laryngoscopy and computed tomography scan. Patients with complete response received hyperfractionation radiotherapy, whereas those without complete response were proposed for total laryngectomy. RESULTS: A total of 71 consecutive patients were included. Thirty-three patients achieved complete response to induction chemotherapy (46.5%), four of them presented a tumor relapse, and all underwent salvage surgery. Seventy-six percent of surviving patients preserved a functional larynx. Despite not achieving complete response, 15 patients refused total laryngectomy and received hyperfractionation radiotherapy. Seven patients presented a tumor relapse and salvage surgery was performed in three of them. Fifty percent of surviving patients preserved a functional larynx. Twenty-two patients without complete response underwent total laryngectomy; three of them presented a tumor relapse but none could be rescued. With a median follow up of 68 months, 5 five-year overall survival, 5-year disease-free survival, and 5-year larynx function preservation survival rates were 68% (confidence interval [CI], 57-80), 75% (CI, 64-87), and 42% (CI, 29-54), respectively. No differences in overall survival were observed between groups. Five-year disease-free survival of patients without complete response who received hyperfractionation radiotherapy was significantly lower than that of the other two groups (P < .02). Ten patients with larynx preservation and no tumor relapse had chronic toxicity that caused the loss of larynx function: seven patients required permanent tracheotomy, two died from pneumonia, and one patient died as a result of a laryngeal necrosis. CONCLUSIONS: Patients with complete response to induction chemotherapy in laryngeal carcinoma have a high probability of cure after hyperfractionation radiotherapy. However, hyperfractionation radiotherapy induces a high degree of toxicity that reduces the laryngeal function preservation rate and may jeopardize overall survival.

A Phase 2 Open Label, Single-Arm Trial to Evaluate the Combination of Cetuximab Plus Taxotere, Cisplatin, and 5-Flurouracil as an Induction Regimen in Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: Despite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN. METHODS AND MATERIALS: A single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 years of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m(2) day 1; cisplatin, 75 mg/m(2) day 1; 5-fluorouracil [5-FU], 750 mg/m(2) day 1-5) and cetuximab, 250 mg/m(2) weekly (loading dose of 400 mg/m(2)). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF. RESULTS: Fifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval [CI]: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%). CONCLUSIONS: C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose.

Late toxicity after radical treatment for locally advanced head and neck cancer.

BACKGROUND: Multimodal treatment for locally advanced head and neck carcinomas (LAHNC) has been reported to improve survival. However, it is less clear to what extent this survival gain is given at the expense of an impact on the quality of life of our patients. Our aim is to analyze the ongoing late toxic effects among long survivors, to determine how much these impairments affect their QoL, and if there is any factor that clearly impacts on this toxicity. METHODS: 152 Patients diagnosed with LAHNC were treated radically in our clinical practice, either with concomitant chemoradiotherapy or bioradiotherapy, with or without induction chemotherapy. We prospectively assessed these patients' treatment-related late toxicities according to the Radiation Therapy Oncology Group scoring system, and patients answered a QoL question to subjectively evaluate the degree of impact caused by these sequelae in their daily life. Multivariate logistic regressions were performed to detect factors that could influence in toxicity. RESULTS: 21.9% Patients experienced grade 3-4 toxicity. Concomitant chemoradiation with cisplatin was found to be a risk factor of moderate and severe late toxicity compared to concomitant cetuximab in the adjusted analysis by RT fractionation. OR for moderate toxicity 0.292 (CI: 0.125-0.680, p=0.004); OR for severe toxicity: 0.299 (CI: 0.0909-0.999, p=0.05). Induction chemotherapy was found to be a protective factor for moderate late toxicity compared to concomitant treatment alone. CONCLUSION: Patients treated with concomitant chemoradiation with cisplatin have significantly more late toxicity compared to bioradiotherapy, whereas induction chemotherapy prevents from developing moderate late toxicity.

A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study).

BACKGROUND: Non-nucleoside reverse transcriptase inhibitor-containing regimens may be a valid alternative to protease inhibitor-containing regimens for initial antiretroviral therapy, but to date few studies comparing these two strategies have been performed. OBJECTIVE: To evaluate the efficacy and safety of nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients. DESIGN: Randomized, open-label, multicentre trial. SETTING: Twelve centres in Spain (9) and Argentina (3). PATIENTS: One hundred and forty-two HIV-infected naive patients without AIDS. INTERVENTIONS: Patients received combivir (zidovudine 300 mg/lamivudine 150 mg, twice-daily) plus either nelfinavir (1250 mg) twice-daily (zidovudine/lamivudine/nelfinavir, n=70) or nevirapine (200 mg) twice-daily (zidovudine/lamivudine/nevirapine, n=72), and were followed for 12 months. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA (pVL) of less than 200 copies/ml by PCR at 12 months. pVL of less than 20 copies/ml (PCR), changes in CD4 counts, clinical progression and adverse events were also evaluated. Efficacy was assessed using intent-to-treat (ITT) (missing=failure) and on-treatment analysis. RESULTS: At 12 months in the ITT analysis the proportion of patients with pVL below 200 copies/ml was 60% (95% CI 48.5-71.5) in the zidovudine/lamivudine/nelfinavir arm and 75% (95% CI 65-85) in the zidovudine/lamivudine/nevirapine arm (P=0.06), and the proportion below 20 copies/ml was 50% (95% CI 38.3-61.7) and 65% (95% CI 54.2-76.2), respectively (P=0.06). No differences were found when comparing the subgroup of patients with baseline pVL of more than 100,000 copies/ml. A gain of +173 and +162 CD4 cells/mm3, respectively, was observed. Zidovudine/lamivudine/nelfinavir was discontinued in 21% of patients, and zidovudine/lamivudine/nevirapine in 25%, due to toxicity (P>0.2). CONCLUSIONS: Our results suggest that zidovudine/lamivudine/nevirapine is at least as effective as zidovudine/lamivudine/nelfinavir as first-line therapy for HIV disease.

Importance of neoadjuvant chemotherapy in olfactory neuroblastoma treatment: Series report and literature review / Importancia de la quimioterapia neoadyuvante en el tratamiento del neuroblastoma olfatorio: serie de casos y revisión de la literatura

INTRODUCTION AND OBJECTIVES: Olfactory neuroblastoma (ONB) is a rare entity that constitutes less than 5% of nasosinusal malignancies. Mainstream treatment consists in surgical resection+/-adjuvant radiotherapy. By exposing results observed with apparition of new therapeutic options as neoadjuvant chemotherapy, the objective is to evaluate a series and a review of the current literature. METHODS: A retrospective review was conducted including patients diagnosed and followed-up for ONB from 2008 to 2015 in our institution. RESULTS: 9 patients were included. Mean follow-up of 52.5 months (range 10-107). Kadish stage: A, 1 patient (11.1%) treated with endoscopic surgery; B, 2 patients (22.2%) treated with endoscopic surgery (one of them received adjuvant radiotherapy); C, 6 patients (66.7%), 4 patients presented intracranial extension and were treated with neoadjuvant chemotherapy followed by surgery and radiotherapy. The other 2 patients presented isolated orbital extension, treated with radical surgery (endoscopic or craniofacial resection) plus radiotherapy. The 5-year disease free and overall survival observed was 88.9%. CONCLUSION: Neoadjuvant chemotherapy could be an effective treatment for tumor reduction, improving surgical resection and reducing its complications

INTRODUCCIÓN Y OBJETIVOS: Elneuroblastoma olfatorio es una entidad rara que se corresponde con menos del 5% de las neoplasias nasosinusales. El tratamiento principal consiste en la resección quirúrgica ± radioterapia adyuvante. El objetivo es evaluar la sobrevida en una serie de casos y la literatura actual, mostrando resultados observados con la aparición de nuevas opciones terapéuticas como la quimioterapia neoadyuvante. MÉTODOS: Se realizó un estudio retrospectivo incluyendo pacientes tratados y seguidos en nuestro centro desde 2008 a 2015. RESULTADOS: Dentro del estudio fueron incluidos 9 pacientes. El seguimiento medio fue de 52,5 meses (rango 10-107). Estadio Kadish: A) un paciente (11,1%) fue tratado con resección endoscópica; B) 2 pacientes (22,2%) tratados con resección endoscópica (uno de ellos recibió radioterapia adyuvante); C) 6 pacientes (66,7%), de los cuales 4 presentaron extensión intracraneal y fueron tratados con quimioterapia neoadyuvante, cirugía y radioterapia adyuvante. Los otros 2 pacientes presentaron invasión intraorbitaria aislada, tratados con cirugía radical y radioterapia adyuvante. La sobrevida y periodo libre de enfermedad a 5 años fue del 88,9%. CONCLUSIÓN: La quimioterapia neoadyuvante puede ser un tratamiento efectivo para la reducción del tamaño tumoral, mejorando la resección quirúrgica y reduciendo sus complicaciones

Endoscopic type 3 tympanoplasty: Functional outcomes in chronic otitis media / Timpanoplastia endoscópica tipo 3: resultados funcionales en la otitis media crónica

BACKGROUND: Type 3 tympanoplasty is the surgery of choice for middle ear reconstruction in cases where an integral stapes suprastructure and mobile footplate are present. OBJECTIVE: The objective of this study was to obtain functional results after endoscopic type 3 tympanoplasty in chronic otitis media. MATERIALS AND METHODS: Prospective study including 24 patients who underwent endoscopic type 3 tympanoplasty, using PORP for ossicular chain reconstruction (OCR) and cartilage graft for tympanic membrane reconstruction. Audiograms were made preoperatively, and 6 months after surgery. RESULTS: Dry, closed, self-cleaning ears were obtained in 91.7% of the cases. Mean preoperative air-bone gap (ABG) was 30.4dB, mean postoperative ABG was 16.7 dB, dB gain of 13.6dB. ABG closure rate to 20 dB or less of 79.2%, and to 10 dB or less of 29.2%. CONCLUSION AND SIGNIFICANCE: Endoscopic tympanoplasty and OCR is a valid option for surgeons who are comfortable with the use of endoscopes for middle ear surgery as it allows improved visualization of the prosthesis and graft placement during middle ear reconstruction. BACKGROUND: Type 3 tympanoplasty is the surgery of choice for middle ear reconstruction in cases where an integral stapes suprastructure and mobile footplate are present. OBJECTIVE: The objective of this study was to obtain functional results after endoscopic type 3 tympanoplasty in chronic otitis media. MATERIALS AND METHODS: Prospective study including 24 patients who underwent endoscopic type 3 tympanoplasty, using PORP for ossicular chain reconstruction (OCR) and cartilage graft for tympanic membrane reconstruction. Audiograms were made preoperatively, and 6 months after surgery. RESULTS: Dry, closed, self-cleaning ears were obtained in 91.7% of the cases. Mean preoperative air-bone gap (ABG) was 30.4dB, mean postoperative ABG was 16.7dB, dB gain of 13.6dB. ABG closure rate to 20dB or less of 79.2%, and to 10dB or less of 29.2%. CONCLUSION AND SIGNIFICANCE: Endoscopic tympanoplasty and OCR is a valid option for surgeons who are comfortable with the use of endoscopes for middle ear surgery as it allows improved visualization of the prosthesis and graft placement during middle ear reconstruction

INTRODUCCIÓN: La timpanoplastia tipo 3 es la cirugía de elección para la reconstrucción del oído medio en casos donde se encuentra íntegra la supraestructura del estapedio, y hay una platina móvil. OBJETIVOS: El objetivo de este estudio es obtener resultados funcionales tras timpanoplastias tipo 3 con abordaje endoscópico. MATERIALES Y MÉTODOS: Estudio prospectivo incluyendo 24 pacientes quienes fueron operados de timpanoplastia tipo 3 endoscópicas, usando una PORP como material de osiculoplastia, y cartílago como injerto de reconstrucción de membrana timpánica. Audiometrías tonales fueron hechas previas a la cirugía y 6 meses posterior a ella. RESULTADOS: Oídos cerrados, secos y autolimpiantes fueron obtenidos en el 91,7% de los casos. El GAP aéreo-óseo preoperatoria medio fue de 30,4 dB, la misma diferencia media postoperatoria fue de 16,7 dB. La reducción de GAP postoperatoria fue de 13,6 dB. La tasa de cierre de GAP a menos de 20dB o menos fue del 79,2% y a menos de 10 dB del 29,2%. CONCLUSIONES: La timpanoplastia y reconstrucción osicular con abordaje endoscópico es una técnica válida y segura cuando es usada por cirujanos que están cómodos con el uso de endoscopios en la cirugía de oído medio, como permite mejor visualización de la colocación de prótesis e injertos durante la cirugía