The contribution of neck dissection for residual neck disease after chemoradiotherapy in advanced oropharyngeal and hypopharyngeal squamous cell carcinoma patients.

BACKGROUND: Planned neck dissection after chemoradiotherapy (CRT) has remained controversial in advanced oro- and hypopharyngeal squamous cell carcinoma (OHSCC) patients. We evaluated the survival contribution of neck dissection (ND) in OHSCC patients with residual nodal disease following CRT. METHODS: We retrospectively evaluated 84 OHSCC patients with N2-3 disease treated at Aichi Cancer Center Hospital between 1995 and 2006. ND after CRT was performed for residual neck disease in 36 patients, but not in 48 patients to achieve a complete response. These two groups were analyzed in terms of both overall survival (OS) and regional control (RC), and surgical complications were evaluated. RESULTS: The 5-year OS was 76.7 % [95 % confidence interval (CI) 58.8-87.6] for the ND group and 73.9 % (58.6-84.3) for the non-ND group (P = 0.883). The 5-year RC was 91.6 % (76.1-97.2) for the ND group and 81.1 % (65.4-90.2) for the non-ND group (P = 0.252). Stratified by primary tumor site, the 5-year RC was 96.3 % (76.5-99.5) for the ND group, and 78.6 % (58.0-89.9) for the non-ND group (P = 0.072) in oropharyngeal squamous cell carcinoma patients, and 77.8 % (36.5-93.9) for the ND group and 85.9 % (54.0-96.3) for the non-ND group (P = 0.541) in hypopharyngeal squamous cell carcinoma patients. In addition, the complications after ND were tolerable. CONCLUSIONS: We demonstrated that ND was feasible, safe, and correlated with clinical outcomes in OHSCC patients with residual nodal disease after CRT.

Follow-up after intraoperative sentinel node biopsy of N0 neck oral cancer patients.

The objective of the study was to evaluate the validity of sentinel node (SN) biopsy in early oral cancer patients focusing on the accuracy of intraoperative diagnoses of SN status, recurrences in follow-up and impact on patient survival. Previously untreated N0 oral cancer patients were candidates for the study. Using a radioisotope method, an intraoperative SN biopsy was performed. Patients with a positive frozen section of SN underwent immediate neck dissection as a single-stage procedure; they were followed in our outpatient clinic. Forty-five cT1-2N0 patients with squamous cell carcinoma were analyzed. There were seven patients with positive SN, five of whom were detected by intraoperative frozen section analysis. The sensitivity, specificity and accuracy of the intraoperative frozen section analysis of SN were 71.4, 100 and 95.6%, respectively. There were 13 recurrences in the course of all patients treated. Those with positive SN showed a tendency toward recurrence. Three patients with negative SN suffered from delayed ipsilateral neck recurrence. These were considered false negatives at a rate of 7.9%. The 5-year overall survival rate of all patients was 91.1%. SN-positive patient survival was significantly poorer than that of SN-negative patients. Positive SN had a negative impact on the survival. SN biopsy was shown to be a valuable method for determining the neck status of early oral cancer patients. The concordance rate of intraoperative multislice frozen section analysis of SN and patient neck status at the time of operation was 95.6%. SN-positive patients exhibited a tendency toward cancer recurrence. There were three cases of false negatives not conforming to the SN concept and their rate was 7.9%. Positive SN had a negative impact on patient survival.

Clinical evaluation of fully automated molecular diagnostic system "Simprova" for influenza virus, respiratory syncytial virus, and human metapneumovirus.

Influenza virus, respiratory syncytial virus, and human metapneumovirus commonly cause acute upper and lower respiratory tract infections, especially in children and the elderly. Although rapid antigen detection tests for detecting these infections have been introduced recently, these are less sensitive than nucleic acid amplification tests. More recently, highly sensitive point-of-care testings (POCTs) have been developed based on nucleic acid amplification tests, which are easy to use in clinical settings. In this study, loop-mediated isothermal amplification (LAMP)-based POCT "Simprova" to detect influenza A and B viruses, respiratory syncytial virus, and human metapneumovirus was developed. Simprova system is fully automated and does not require skilled personnel. In addition, positive results can be achieved faster than with PCR. In this study, the accuracy of the POCT was retrospectively analyzed using 241 frozen stocked specimens. Additionally, the usability of the Simprova at clinical sites was assessed in a prospective clinical study using 380 clinical specimens and compared to those of real-time PCR and rapid antigen detection test. The novel LAMP-based POCT demonstrated high sensitivity and specificity in characterizing clinical specimens from patients with influenza-like illnesses. The Simprova is a powerful tool for early diagnosis of respiratory viral infections in point-of-care settings.

Publisher Correction: Clinical evaluation of fully automated molecular diagnostic system "Simprova" for influenza virus, respiratory syncytial virus, and human metapneumovirus.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

[A Phase II study of docetaxel and cisplatin in patients with recurrent or unresectable squamous cell carcinoma of the head and neck].

A Phase I / II study of docetaxel (DOC) and cisplatin (CDDP) combination therapy was conducted. The respective recommended dose (RD) in a phase I study was DOC 60 mg/m(2) and CDDP 80 mg/m(2). We performed a multicenter phase II study to assess the antitumor activity and toxicity of this RD. Patients with recurrent or unresectable squamous cell carcinoma of the head and neck were eligible. For inclusion in this study, patients were required to be >or=20<70 years of age with a Performance Status of 0 to 2. Adequate bone marrow as well as adequate renal and liver function were required. We assessed 22 patients, 13 of whom were enrolled in the phase II study, and 9 patients in phase I were given the RD. Grade 3 or higher neutropenia occurred in 12 patients (55%). There was no episode of febrile neutropenia of more than 3 days or grade 4 neutropenia of more than 3 days receiving G-CSF. Nausea was the most frequent toxicity, but only one patient experienced vomiting of more than grade 3. Pneumonia (grade 3), thrombocytopenia (grade 4) and emphysema (grade 2) were observed. No one achieved a complete response (CR) and 5 achieved a partial response (PR), for an overall response rate of 22.7% (5/22). Stable disease (SD) was seen in 11 and progressive disease (PD) in 6. In 21 of 22 patients, a relapse occurred despite previous treatment. For this population, the response rate was 19.0% (4/21).

En bloc petrosectomy for malignant tumors involving the external auditory canal and middle ear: surgical methods and long-term outcome.

OBJECTIVES: The aim of this study was to describe a method for resecting malignant tumors originating in the external auditory canal or middle ear and requiring en bloc resection of the petrous bone. METHODS: Between 1995 and 2005, the authors performed en bloc petrosectomy for 18 malignant tumors in 9 male and 9 female patients, ranging in age from 15 to 74 years. Fourteen tumors originated in the external ear, 2 in the middle ear, and 2 in the parotid gland. The pathological entities included 15 squamous cell carcinomas, 2 adenoid cystic carcinomas, and 1 rhabdomyosarcoma. Through an L-shaped temporosuboccipital craniotomy, a medial osteotomy was created through the inner ear for tumors without extension into the inner ear (14 cases) and through the tip of the petrous bone for tumors reaching the inner ear (4 cases). Temporal dura mater in 3 patients and the base of the temporal lobe in 2 patients were included in the en bloc resection. RESULTS: Surgical complications occurred in 5 patients (28%) with no deaths. During a mean follow-up period of 45 months, 3 patients died of tumor recurrence. Overall, 2- and 5-year survival rates were 86 and 78%, respectively. Two of three patients with dural extension and 1 of 2 with brain invasion remain alive. Two of four patients with tumor extension into the inner ear died. CONCLUSIONS: En bloc petrosectomy is recommended for malignant tumors of the ear. It is safe and effective for lesions limited to the middle ear and may be the procedure of choice for tumors reaching the inner ear and those with dural or brain invasion.

Prediction of chemosensitivity using multigene analysis in head and neck squamous cell carcinoma.

AIMS: The main purpose of the current study was to find predictive biomarkers that can be routinely used for the response to chemotherapy in head and neck squamous cell carcinoma (HNSCC). METHODS: From this standpoint, we selected the histoculture drug response assay (HDRA) to assess in vitro chemosensitivity, and real-time reverse transcription polymerase chain reaction to investigate the gene expression profile of individual tumors as available predictive biomarkers. Using both surgery and biopsy specimens, we analyzed their gene expression profiles using the 18 markers that we thought were likely predictors of the response to anti-cancer agents. RESULTS: Statistically significant associations were found between 5-fluorouracil (5-FU) sensitivity in HDRA and HER-2 mRNA expression level (p = 0.0030). Moreover, HER-2 expression was significantly associated with cisplatin sensitivity (p = 0.0089). Cisplatin sensitivity in HDRA was also demonstrated to have a significant association with epidermal growth factor receptor (EGFR) expression in which the group with cisplatin resistance tended to have a higher expression level than the sensitive group (p = 0.0385). CONCLUSION: HER-2 and EGFR may be possible reliable predictive biomarkers for anti-cancer therapy, and might help in the decision-making process for individual patients with HNSCC.

Evaluation of optimal drug concentration in histoculture drug response assay in association with clinical efficacy for head and neck cancer.

Induction chemotherapy or concomitant chemoradiotherapy has been used increasingly to improve survival, organ preservation and function in patients with head and neck cancer (HNC). However, this regimen encounters significant side effects with potential adverse reactions causing many disadvantages for patients. Therefore, reliable chemosensitivity assays are needed to accurately predict the response to chemotherapy and guide the selection and treatment of patients with HNC. The main purpose of this study was to examine the optimal drug concentrations for evaluating in vitro chemosensitivity using the histoculture drug response assay (HDRA). The tested tumor specimens included 7 from oral cavities (14.3%), 12 from oropharynx (24.5%), 10 hypopharynx (20.4%), 3 larynx (6.1%), 5 sinonasal (10.2%), 2 salivary glands (4.1%), and 10 from metastatic lymph nodes (20.4%), respectively. Histopathologic types of all 49 specimens were squamous cell carcinoma. We investigated the optimal drug concentrations in HDRA searching at doses of 4-100 microg/ml for cisplatin and 60-1500 microg/ml for 5-FU. We considered the concentration of 20 microg/ml to be appropriate for evaluating cisplatin sensitivity in HNC among the tested dosages. As for cisplatin sensitivity in vitro, the 50% cut-off inhibition index (I.I.) was found to have a significant association with the clinical response to chemotherapy, with an accurate prediction rate of 77.8%. The HDRA shows a predictive value for chemosensitivity in HNC patients using the optimal drug concentration cut-off with this site specificity.

MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma.

PURPOSE: Mucoepidermoid carcinoma is the most common primary malignancy of the salivary gland. Mucoepidermoid carcinoma translocated gene 1-mastermind-like gene family (MECT1-MAML2) gene fusion was identified from a recurring t(11;19)(q21;p13) translocation, which is often the sole cytogenetic alteration in this disease. This fusion transcript has been frequently detected in mucoepidermoid carcinoma and shown to be involved in the transformation of epithelial cells. However, its clinicopathologic significance remains unclear. EXPERIMENTAL DESIGN: Seventy-one cases of mucoepidermoid carcinoma and 51 cases of nonmucoepidermoid carcinoma salivary gland tumors (including 26 Warthin tumor cases) were retrospectively analyzed. RNA was extracted from archival materials: histologic paraffin specimens in all cases and cytologic specimens in 10 mucoepidermoid carcinoma cases. The MECT1-MAML2 fusion transcript was detected by a reverse transcription-PCR assay, which can be applied to both histologic and cytologic specimens. The presence of the fusion transcript was correlated with relevant clinicopathologic and survival data of the mucoepidermoid carcinoma patients. RESULTS: The MECT1-MAML2 fusion transcript was detected in 27 of the 71 (38%) mucoepidermoid carcinoma cases but not in any case of nonmucoepidermoid carcinoma tumors. The reverse transcription-PCR results showed no difference between histologic and cytologic specimens. Detection of the MECT1-MAML2 fusion transcript was associated with a less advanced clinical stage and a low-grade tumor histology. The presence of the transcript was associated with longer disease-free and overall survivals on univariate analysis and emerged as an independent prognostic factor for longer overall survival on multivariate analysis. CONCLUSIONS: The MECT1-MAML2 fusion transcript may be specific to mucoepidermoid carcinoma and associated with a distinct mucoepidermoid carcinoma subset that exhibits favorable clinicopathologic features and an indolent clinical course.

Analysis of salvage operation in head and neck microsurgical reconstruction.

In this study, we examined salvage operations after reexploration in head and neck reconstruction and analyzed ways to solve problems. Free flap reconstruction of the head and neck lesion was carried out for 513 cases in our hospital over the past 12 years. Twenty-one cases of reexploration were caused by postoperative thrombosis (4.1%). We could only salvage seven cases (33.3%) of 21 cases from flap thrombosis. All seven cases were included in the category of venous thrombosis, and they were undertaken within 3 days postoperatively. Our results have shown that once thrombosis occurs, there is little possibility of flap salvage, particularly 3 days after operation and in infectious cases. When no flow phenomena are observed and no flap salvage is deemed possible, aggressive treatment such as a second free flap or next pedicle flap should be chosen as soon as possible to avoid any delay in postoperative treatment.

[Salvage surgery for radiation failure in oral, oropharyngeal, and hypopharyngeal squamous cell carcinoma].

Few reports have covered salvage surgery after radiotherapy, especially with chemotherapy for oral, oropharyngeal, and hypopharyngeal squamous cell carcinoma. The feasibility of salvage surgery is unclear. We analyzed postoperative complications and prognosis after salvage surgery for local recurrence after definitive radiotherapy. Subjects were 37 patients with oral, oropharyngeal, and hypopharyngeal squamous cell carcinoma treated from 1994 to 2003. Of these, 14 (37.8%) had postoperative complications. The complication rate was significantly high in the reconstructive operation group (p = 0.031) and the chemotherapy group (p = 0.049). The 5-year overall survival rate after salvage surgery was 70.7%. Although there was no significant improvement, the prognosis was good in early-stage groups with primary tumors. We found that salvage surgery after definitive radiotherapy was effective for recurrent oral, oropharyngeal, and hypopharyngeal squamous cell carcinoma. We stress the need to pay attention to postoperative complications in reconstructive operation and chemotherapy groups.

[Detection of FDG-PET and FDG-PET/CT in head and neck squamous cell carcinoma].

We evaluated the accuracy of staging in 159 patients with head and neck squamous cell carcinoma (HNSCC) scanned by FDG-PET and 116 patients with the same cancer scanned by FDG-PET/computed tomography (CT). The accuracy was measured by comparing the FDG-PET/FDG-PET/CT findings at the primary tumor site, cervical node sites and distant metastatic sites with the clinical diagnosis. Especially, accuracy at cervical sites was evaluated from the screening point of view. Both examinations yielded an accuracy rate of more than 80% for each site, and a negative predictive value of more than 90% for the cervical sites. For the cervical sites, the positive predictive value (PPV) of FDG-PET was 78% and of FDG-PET/CT was 82%. When one cervical lymph node metastasis was detected by FDG-PET, the PPV was 63%, which appears to be comparatively low. Both examinations showed high accuracy for staging of HNSCC. In the near future, excellent screening examination might become possible with the spread of FDG-PET/CT. However, both examinations do not yield the direct image of the carcinoma itself, but only the status of glucose metabolism in the carcinoma. Care must always be exercised in the interpretation, as there are not a few false negative and false positive cases.

Prognostic factors and outcomes for salvage surgery in patients with recurrent squamous cell carcinoma of the tongue.

AIM: Recurrence rates of oral cancer following primary treatment have been reported in the range of 25-48%. However, salvage therapy remains a critical challenge to improving outcomes. Here, we investigated prognostic factors and outcomes for salvage surgery in patients with recurrent oral tongue squamous cell carcinoma (OTSCC). METHODS: We retrospectively reviewed patients who were referred to Aichi Cancer Center, Japan, for the treatment of recurrent OTSCC. All patients included in the present study had undergone salvage surgery. Data to identify the predictive value of prognostic factors were available from 69 patients. Prognostic factors were assessed using Cox's proportional hazards regression analysis. Differences in overall survival between groups of patients were assessed by the log-rank test. RESULTS: In all, 36 patients (52%) developed second recurrence or died, of which 21 (58%) occurred within 12 months of salvage surgery. Univariate analysis indicated that survival was significantly worse in patients with recurrent stage III or IV tumors, two or more positive cervical lymph nodes, levels IV or V positive cervical lymph nodes, extracapsular spread (ECS) of positive cervical lymph nodes and a disease-free interval from initial treatment of less than 12 months. On multivariate analysis, ECS was an independent prognostic factor for overall survival after salvage surgery. CONCLUSION: Neck status at the time of salvage surgery, particularly ECS is a significant prognostic factor for surgical salvage. Survival was also influenced by the stage of the recurrent tumor and disease-free interval, suggesting that the biological features of recurrent tumors might impact on prognosis.

Loss of p21WAF1/CIP1 expression in invasive fronts of oral tongue squamous cell carcinomas is correlated with tumor progression and poor prognosis.

The clinicopathological significance of cell-cycle proteins has remained unclear in oral tongue squamous cell carcinomas (OTSCC). In the current study, we evaluated several cell-cycle proteins in relation to clinicopathological parameters and disease outcome for OTSCC. A total of 123 previously untreated patients with OTSCC, who underwent surgical treatment, were enrolled. Tumor specimens were examined for expression of p21, p27, p16, p53, and p63 using immunohistochemistry, with reference to clinicopathological factors and disease outcome. It is noteworthy that differences in p21 immunoreactivity were evident between the shallow region and invasive front of tumors within the same specimens. Loss of p21 expression in invasive fronts was found to be associated with clinicopathological factors of tumor progression and poor prognosis. p21 expression in invasive fronts is a significant indicator for impact on survival. Moreover, p21 is one of the important factors that regulate the progression of malignant cells in OTSCC.

Prognostic significance of late cervical metastasis and distant failure in patients with stage I and II oral tongue cancers.

Stage I and II oral tongue cancers (OTC) generally have a favorable prognosis, but there are some early OTC cases with a poor prognosis. OTC is known for its propensity for subclinical nodal metastasis and, moreover, we must devise a strategy that takes account of the possibility of recurrence and distant metastasis. In the current study, 90 previously untreated patients with stage I or II OTC who underwent surgical treatment were eligible for review. The authors investigated the associations of their clinico-pathologic factors with disease outcomes, and also examined the postoperative course for patients with a poor prognosis. The most common cause of death was distant metastasis and late cervical lymph node metastasis (LCM) was the significantly independent prognostic variable. Since LCM can be treated with salvage surgery, the central issue is to control patients with distant metastises who are free of disease in their loco-regional sites.

[A Phase I study of docetaxel and cisplatin for advanced squamous cell carcinoma of the head and neck].

A Phase I study of docetaxel (DOC) and cisplatin (CDDP) combination therapy was conducted as second-line treatment for advanced squamous cell carcinoma of the head and neck in order to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) of DOC, and the recommended dose (RD) for this combination therapy. Twenty patients with recurrence for whom failed first-line chemotherapy with CDDP and 5-FU proved in-effective (17 male, 3 female; age range 38-74 years; performance status 0=7, 1 =8, 2=5) were included in this study. DOC at dose level I (40 mg/m2), level II (50 mg/m2), level III (60 mg/m2) and level IV (70 mg/m2) was used, followed by CDDP administration at a fixed dose of 80 mg/m2. Originally, chemotherapy was repeated every 3 weeks. In level I, grade 4 hypokalemia occurred in one patient. No DLT occurred at level II. At level III, one patient experienced grade 4 vomiting. At level IV, grade 2 creatinine clearance decrease occurred in a total of two patients. The maximum tolerated dose in this combination therapy was DOC 70 mg/m2, and CDDP 80 mg/m2. The recommended dose for this combination therapy is DOC 60 mg/m2, and CDDP 80 mg/ m2. A multicenter cooperative phase II study in this RD is recommended.

[Investigation for cervical lymph node metastasis in unknown primary sites].

In patients with cervical adenopathy, especially, those of cervical lymph node metastasis with no detectable primary tumor, diagnosis and treatment planning can become confused. We evaluated 36 patients with cervical lymph node metastasis of unknown origin between 1985 and 2002. Primary sites were detected in 20 before treatment. The other 36 patients clearly had no primary lesions when treatment started. Primary sites were 5 cases of oropharynx, 2 of the parotid gland, and 1 each of larynx, nasopharynx, hypopharynx, and malignant lymphoma detected in 11 after treatment for cervical lymph nodes. No primary lesion was found in 28 patients. The neck LN stage was N1 in 11 patients, N2 in 29, N3 in 11, and unknown in 8. To detect the primary site, we conducted "random" biopsy, panendoscopy, and radiographic evaluation including FDG-PET. Biopsy sites were the nasopharynx, palatine and lingual tonsil, and piriform sinus. Some 35 patients (59.3%) underwent random biopsy, and primary sites were found this way in 5 patients (14.3%). The 36 who had no primary lesion were treated for cervical lymph nodes, of whom 24 underwent neck dissection. Chemotherapy and radiotherapy were the treatment of choice in many cases. We analyzed 31 patients for 5 year survival. Overall survival was 63.7%, disease-specific survival 69.2%, and disease-free survival 46.8%. In another analysis a statistically significant difference was seen in survival among patients who had neck surgery or not (85.7% vs. 38.9%, p = 0.029; log rank test). Analysis suggested that primary sites should be studied by CT, MRI, FDG-PET, and panendoscopy, including random biopsy. The primary site cannot be detected, treatment should initially involve cervical adenopathy with combined surgery, chemotherapy, and radiotherapy. After treatment, the patient should be followed up carefully to find the primary lesion.

[Oral cancer].

This paper reviews the Japanese literature regarding sentinel lymph node localization in head and neck surgery and relevant domestic and foreign articles from other fields of medicine, and reports our results. Even though we have less experience with it in Japan, we believe the sentinel node concept for the head and neck region will be established. Further investigation and practical application in clinical settings are anticipated in the future.

[Long-term outcomes and complications associated with the use of a Groningen voice prosthesis].

We have been using the Groningen voice prosthesis as a method of voice restoration after total laryngectomy for approximately five years. During this period, the Groningen voice prosthesis has been used in 19 patients and a total of 125 unit replacements have been performed. No serious complications have occurred to date. Upon examination of the voice restoration results, exchange frequency, and complications, we noted that 15 out of 19 patients (78.9%) were able to maintain a good voice quality, including cases with long-term observation periods. Voice restoration was difficult in the remaining 4 cases. The overall mean exchange period was 4.5 months, with 2.5 months being the shortest exchange interval in cases without complications. The mean exchange period for cases without complications was 6.1 months. No serious complications, such as a foreign body in the trachea, were encountered. However, several problems with water leakage occurred and were managed appropriately. Aspiration pneumonia from repeated water leakage did not occur, and no cases of TE shunt closure were encountered. These problems may occur with further aging. Thorough follow-ups will be continued in the future.