Macroscopic and multiple metastases in sentinel lymph node biopsy are respectively associated with poor prognosis in early oral cancer.

BACKGROUND: A multicenter, randomized controlled phase III trial was conducted on sentinel lymph node biopsy (SLNB) and elective neck dissection for T1 (depth of invasion ≥ 4 mm)-T2N0M0 oral cavity squamous cell carcinoma. This study identified factors associated with poor prognosis in patients who underwent SLNB based on a subgroup analysis of this trial. METHODS: We analyzed 418 sentinel lymph nodes (SLNs) from 132 patients who underwent SLNB. The metastatic SLNs were classified into three categories based on size-isolated tumor cells: < 0.2 mm, micrometastasis: ≥ 0.2 mm and < 2 mm, and macrometastasis: ≥ 2 mm. Three groups were formed based on the number of metastatic SLNs: no metastasis, 1 metastatic node, and ≥ 2 metastatic nodes. The size and number of metastatic SLNs on survival were evaluated using Cox proportional hazard models. RESULTS: Patients with macrometastasis and ≥ 2 metastatic SLNs had worse overall survival (OS) and disease-free survival (DFS) after adjustment for potential confounders (HR for OS: macrometastasis, 4.85; 95% CI 1.34-17.60; ≥ 2 metastatic SLN, 3.63; 95% CI 1.02-12.89; HR for DFS: macrometastasis, 2.94; 95% CI 1.16-7.44; ≥ 2 metastatic SLN, 2.97; 95% CI 1.18-7.51). CONCLUSIONS: In patients who underwent SLNB, a poorer prognosis was associated with macrometastasis or having ≥ 2 metastatic SLNs.

A new combined index of SUVmax of lymph node in PET / CT by a weighting coefficient plus its maximum minor axis in CECT to evaluate occult lymph node metastasis in clinical N0 patients with tongue cancer.

To predict occult nodal metastasis in clinical N0 patients with tongue cancer, we developed combined index (CI) : SUVmax of the largest lymph node in PET / CT by weighting coefficient plus its maximum minor axis (< 10 mm) in contrast-enhanced CT (CECT). In this retrospective study, 57 clinical N0 patients with tongue cancer, who underwent elective supraomohyoid neck dissection at cervical levels of I-III were enrolled. The cutoff value of SUVmax of 2.0 obtained using receiver operating characteristic (ROC) analysis predicted the postoperative positive cervical levels containing metastatic lymph nodes from clinical N0 cervical levels in tongue cancer patients with a sensitivity of 54.5% and a specificity of 78.2%. The cutoff value of CI with weighting coefficient of 1.5 obtained using ROC analysis was 9.8 at the maximum area under the curve of 0.750. The cutoff value of 9.8 predicted the postoperative positive cervical levels containing metastatic lymph nodes from clinical N0 cervical levels in tongue cancer patients with a sensitivity of 68.2% and a specificity of 81.5%. These findings suggest that CI of functional PET / CT and morphological CECT components might improve the diagnostic performance of occult nodal metastasis to select clinical N0 patients with tongue cancer preferable for elective neck dissection. J. Med. Invest. 68 : 154-158, February, 2021.

Death unrelated to cancer and death from aspiration pneumonia after definitive radiotherapy for head and neck cancer.

BACKGROUND AND PURPOSE: The incidence of hypopharyngeal and supraglottic cancer (HSC) is high in Japan. This study aimed to retrospectively identify risk factors for death unrelated to cancer and death from aspiration pneumonia after definitive radiotherapy (RT) for HSC. MATERIALS AND METHODS: Overall, 391 patients who began definitive RT for HSC between 2006 and 2014 were identified from the Osaka International Cancer Institute electronic database. Among 391 patients, 33 had a history of surgery for esophageal cancer (EC) and 19 received simultaneous RT for synchronous EC. The cause of death was divided into 3 main categories: "cancer under study," "other malignancy," and "unrelated to cancer." Cox proportional hazard model was used to estimate the hazard ratio (HR). RESULTS: The median follow-up for survivors was 8 (range 3.6-14.1) years. At the last follow-up, 202 patients died. Death from "cancer under study," "other malignancy," and "unrelated to cancer" occurred in 92 (45.5%), 55 (27.2%), and 55 (27.2%) patients, respectively. Twelve patients died from aspiration pneumonia. In multivariate analysis for death unrelated to cancer and death from aspiration pneumonia, history of surgery for EC (HR: 3.87, p < 0.001; HR: 6.84, p = 0.007, respectively) and simultaneous RT for synchronous EC (HR: 3.74, p = 0.006; HR: 16.37, p < 0.001, respectively) were significant risk factors. CONCLUSION: The laryngeal preservation approach by RT for HSC patients with a history of surgery for EC and simultaneous RT for synchronous EC should be used with caution.

Trends in the Detail of the Stage and Survival Rate in Hypopharyngeal Cancer over 20 Years.

Background: Hypopharyngeal cancer frequently presents at an advanced stage and has one of the worst prognosis among the head and neck cancers. Recently, superficial hypopharyngeal cancers with a good prognosis have been detected with a novel endoscopic technique, such as narrow band imaging. Objectives: To evaluate trends in the detail of the stage and survival rate in hypopharyngeal cancer over 20 years. Patients and methods: Between 1993 and 2012, 722 patients with hypopharyngeal cancer treated at the Osaka Medical Center for Cancer and Cardiovascular Disease were studied retrospectively. The 20-year period was subdivided into 5-year periods; Period A (1993-1997, n=101), Period B (1998-2002, n=123), Period C (2003-2007, n=196) and Period D (2008-2012, n=302). The patients at Stage I-II were divided into superficial cancer as Stage I-IIs and invasive cancer as Stage I-IIi. In every period, a transition of the staging and overall survival rate were compared. Results: The 5-year overall survival in Period A, B, C and D were 34%, 39%, 54% and 60%, respectively. The patients at Stage III-IV in Period A, B, C and D comprised 32%, 36%, 47% and 54%, respectively. Both survival rates improved significantly from Period B to C. The ratio of Stage 0 and Stage I-IIs increased significantly from Period C to D. Whereas the 5-year overall survival rates of Stage 0 and Stage I-IIs were similar (80% vs 88%), the 5-year overall survival of Stage I-IIi was significantly poor. Excluding Stage 0 and Stage I-IIs, the 5-year overall survival had little change from Period C to D. Conclusion: The reason for the improvement in hypopharyngeal cancer prognosis was the prognostic improvement of advanced cancer from Period B to C, and an increase in superficial cancer from Period C to D.

[Videofluoroscopic Examination of Swallowing Using the AsR Score for Postoperative Swallowing Function in Oral Cancer Patients].

To evaluate the postoperative swallowing function in head and neck cancer patients, videofluoroscopic examination of swallowing (VF) proved useful as a qualitative evaluation, but was complex as a quantitative evaluation. We made use of the AsR score which consisted of a 10-point scale as a quantitative evaluation of VF. To identify the usefulness of the AsR score, 146 patients who had undergone extensive resection and reconstruction with free flaps or pedicle grafts were reviewed. The AsR score of VF for the first time after surgery was defined as "first score", and at the last time in the hospital was defined as "last score". The correlations between the first score and continuity of direct therapy, and between the last score and way of nutrition at the time of discharge were examined. Using the ROC (receiver operator characteristic) analysis and the AUC (area under the curve) the cut-off values of the AsR score were estimated. One hundred and thirty one patients could continue direct therapy after the first time of VF. The first score detected continuity of direct therapy with high accuracy (AUC = 0.946), furthermore using a cut-off of 5, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were about 96.2%, 86.6%, 98.4%, and 72.2%, respectively. At the time of discharge, 138 patients had no limitation of oral intake and 8 patients had a limitation e.g. PEG (n = 7) and a total laryngectomy for preventing aspiration (n = 1). The last score detected oral intake ability with no limitation with high accuracy (AUC = 0.925). Using a cut-off of 6, the sensitivity, specificity, PPV and NPV were about 82.6%, 87.5%, 99.1% and 22.6%, respectively. The AsR score is useful as a quantitative evaluation of postoperative swallowing function in oral cancer patients.

Endoscopic submucosal dissection as minimally invasive treatment for superficial pharyngeal cancer: a phase II study (with video).

BACKGROUND AND AIMS: Although endoscopic submucosal dissection (ESD) has been applied for superficial pharyngeal cancer, no prospective trials have been reported. To investigate the efficacy and safety of ESD for superficial pharyngeal cancer, we conducted a prospective phase II trial. METHODS: Fifty-four patients with 73 lesions were enrolled from September 2010 to August 2014, and ESD was performed. The primary endpoint was the complete resection rate. Secondary endpoints were safety, recurrence-free survival, overall survival, and incidence of metachronous pharyngeal cancer. RESULTS: Fifty-four patients had stage 0-III cancer: stage 0, n = 22; stage I, n = 14; stage II, n = 17; and stage III, n = 1. The en bloc resection rate was 100%, and the complete resection rate was 79.5% (58/73 lesions; 95% confidence interval, 68%-88%). No serious adverse events related to ESD were encountered. Four patients required nasogastric intubation and feeding. No patients required percutaneous endoscopic gastrostomy and tracheotomy. Swallowing, speech, and airway functions were preserved in all patients. One of the 54 patients died of an unrelated illness. Median follow-up was 27 months (range 6-55 months). Local cervical lymph node metastasis was observed in 1 patient, and the case was salvaged successfully with lymph node dissection. The 3-year overall and recurrence-free survival rates were 97.7% and 98.1%, respectively. Cumulative development of multiple cancers of the pharynx at 3 years was 18.4%. CONCLUSIONS: ESD appears to be a safe and effective minimally invasive treatment in patients with superficial pharyngeal cancer. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000003623.).

Treatment outcomes of external-beam radiotherapy for squamous cell carcinoma of the base of the tongue.

PURPOSE: To evaluate definitive external-beam radiotherapy (EBRT) for patients with base of the tongue (BOT) cancers. METHODS: We reviewed results for 26 patients with BOT cancers who were treated with EBRT. Clinical stages T1, T2, T3, and T4a were observed for 10, 7, 4, and 5 patients, respectively, and stages N0, N1, N2a, N2b, N2c, and N3 were observed for 4, 2, 5, 6, 8, and 1 patients, respectively. More than half of the patients (n = 19) were stage IVA. Standard total delivered doses were 70 Gy to primary tumors and cervical lymph node (CLN) metastases and 40-46 Gy to elective nodal regions. Eleven patients with advanced loco-regional disease received concurrent or neoadjuvant chemotherapy. Four T3 patients and one T2 patient received 2 or 3 cycles of concurrent intra-arterial cisplatin with EBRT (RADPLAT). RESULTS: Three-year overall survival was 69 % (95 % CI 47-83 %), with a median follow-up period of 33 months. Three-year local control was 100, 86, 100, and 20 % for T1, T2, T3, and T4 patients, respectively. Three-year regional control was 100 % for N0, N1, and N2a, 83 % for N2b, 75 % for N2c, and 0 % for N3 patients. Treatment failed for 7 patients. All 5 patients undergoing RADPLAT achieved complete responses and did not develop local recurrence. CONCLUSIONS: We achieved favorable outcomes for patients with T1-T3 BOT cancers by use of definitive EBRT with or without chemotherapy.

p53-Dependent suppression of genome instability in germ cells.

Radiation increases mutation frequencies at tandem repeat loci. Germline mutations in γ-ray-irradiated medaka fish (Oryzias latipes) were studied, focusing on the microsatellite loci. Mismatch-repair genes suppress microsatellite mutation by directly removing altered sequences at the nucleotide level, whereas the p53 gene suppresses genetic alterations by eliminating damaged cells. The contribution of these two defense mechanisms to radiation-induced microsatellite instability was addressed. The spontaneous mutation frequency was significantly higher in msh2(-/-) males than in wild-type fish, whereas there was no difference in the frequency of radiation-induced mutations between msh2(-/-) and wild-type fish. By contrast, irradiated p53(-/-) fish exhibited markedly increased mutation frequencies, whereas their spontaneous mutation frequency was the same as that of wild-type fish. In the spermatogonia of the testis, radiation induced a high level of apoptosis both in wild-type and msh2(-/-) fish, but negligible levels in p53(-/-) fish. The results demonstrate that the msh2 and p53 genes protect genome integrity against spontaneous and radiation-induced mutation by two different pathways: direct removal of mismatches and elimination of damaged cells.

High-resolution melting curve analysis for rapid detection of mutations in a Medaka TILLING library.

BACKGROUND: During the last two decades, DNA sequencing has led to the identification of numerous genes in key species; however, in most cases, their functions are still unknown. In this situation, reverse genetics is the most suitable method to assign function to a gene. TILLING (Targeting Induced Local Lesions IN Genomes) is a reverse-genetic strategy that combines random chemical mutagenesis with high-throughput discovery of the induced mutations in target genes. The method has been applied to a variety of plant and animal species. Screening of the induced mutations is the most important step in TILLING. Currently, direct sequencing or nuclease-mediated screening of heteroduplexes is widely used for detection of mutations in TILLING. Both methods are useful, but the costs are substantial and turnaround times are relatively long. Thus, there is a need for an alternative method that is of higher throughput and more cost effective. RESULTS: In this study, we developed a high resolution melting (HRM) assay and evaluated its effectiveness for screening ENU-induced mutations in a medaka TILLING library. We had previously screened mutations in the p53 gene by direct sequencing. Therefore, we first tested the efficiency of the HRM assay by screening mutations in p53, which indicated that the HRM assay is as useful as direct sequencing. Next, we screened mutations in the atr and atm genes with the HRM assay. Nonsense mutations were identified in each gene, and the phenotypes of these nonsense mutants confirmed their loss-of-function nature. CONCLUSIONS: These results demonstrate that the HRM assay is useful for screening mutations in TILLING. Furthermore, the phenotype of the obtained mutants indicates that medaka is an excellent animal model for investigating genome stability and gene function, especially when combined with TILLING.

[A clinical study of 104 patients with tongue cancer and the relationship between DNA ploidy and prognosis in 41 cases].

One-hundred and four patients with previously untreated tongue cancer seen in our department between 1986 and 1998 were enrolled in a clinical study. The DNA ploidy patterns observed in fresh frozen specimens obtained from 41 patients were analyzed, and prognostic factors were investigated. According to the TNM classification (UICC 1997), 43 patients had stage I tumors, 29 had stage II tumors, 17 had stage III tumors, and 15 had stage IV tumors. The 5-year cause-specific survival rates for each stage were 94.7%, 64.4%, 50.0% and 45.7%, respectively. The most frequent cause of death associated with the original disease was the recurrence of the disease in cervical lymph nodes (19/27, 70.4%). The occurrence of late cervical metastasis was high among patients with a T2N0 disease. Patients with stage II disease should undergo elective neck dissection or be carefully monitored using ultrasonography. Among the 41 cases in which the DNA ploidy pattern was analyzed, diploid patterns were found in 30 cases and aneuploid patterns were found in 11. The 5-year cause-specific survival rate and the 5-year locoregional control rate were significantly lower for the aneuploid cases (18.2%, 38.9%) than for the diploid cases (66.5%, 69.8%) (p = 0.0003, p = 0.0339). The incidence of distant metastasis was significantly higher among the aneuploid cases (6/11, 54.5%) than among the diploid cases (3/30, 10.0%) (p = 0.0058). The ploidy pattern, as determined by flow cytometric DNA analysis, may reflect the malignancy grade of tongue cancers.