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Background: Our previous research showed that a high rate of secondary carcinogenesis is observed during follow-up after transoral surgery in patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal cancers. We speculate that the contributing factors are alcohol drinking, smoking, and aging; however, we could not provide clear evidence. In this study, we aimed to identify the risk factors for secondary carcinogenesis in patients with these cancers, particularly factors associated with drinking and/or smoking. Methods: The medical records of all-stage laryngeal, oropharyngeal, and hypopharyngeal cancer patients who had undergone definitive treatment were retrospectively analyzed. Assessments included visual and endoscopic observations of the primary site, enhanced cervical CT or US of the primary site and regional lymph nodes, PET-CT, and enhanced whole-body CT. Clinical characteristics were compared in patients with and without secondary carcinogenesis and in patients with hypopharyngeal cancer and patients with other cancers. Results: Hypopharyngeal cancer was an independent risk factor for secondary cancer. The 5-year incidence rate of secondary cancer was 25.5%, 28.6%, and 41.2% in laryngeal, oropharyngeal, and hypopharyngeal cancers, respectively. Radiotherapy was defined as an independent risk factor in hypopharyngeal cancer patients with secondary cancers. No direct correlation was found between secondary carcinogenesis and alcohol consumption, smoking, or aging. Conclusions: Patients with hypopharyngeal cancer require close follow-up as they are at high risk of developing secondary cancer, possibly because out-of-field radiation exposure may induce systemic secondary carcinogenesis in hypopharyngeal cancer patients with genetic abnormality induced by alcohol consumption. [ABSTRACT FROM AUTHOR]

Purpose: Depending on its histological subtype, salivary gland carcinoma (SGC) may have a poor prognosis. Due to the scarcity of preclinical experimental models, its molecular biology has so far remained largely unknown, hampering the development of new treatment modalities for patients with these malignancies. The aim of this study was to generate experimental human SGC models of multiple histological subtypes using patient-derived xenograft (PDX) and organoid culture techniques. Methods: Tumor specimens from surgically resected SGCs were processed for the preparation of PDXs and patient-derived organoids (PDOs). Specimens from SGC PDXs were also processed for PDX-derived organoid (PDXO) generation. In vivo tumorigenicity was assessed using orthotopic transplantation of SGC organoids. The pathological characteristics of each model were compared to those of the original tumors using immunohistochemistry. RNA-seq was used to analyze the genetic traits of our models. Results: Three series of PDOs, PDXs and PDXOs of salivary duct carcinomas, one series of PDOs, PDXs and PDXOs of mucoepidermoid carcinomas and PDXs of myoepithelial carcinomas were successfully generated. We found that PDXs and orthotopic transplants from PDOs/PDXOs showed similar histological features as the original tumors. Our models also retained their genetic traits, i.e., transcription profiles, genomic variants and fusion genes of the corresponding histological subtypes. Conclusion: We report the generation of SGC PDOs, PDXs and PDXOs of multiple histological subtypes, recapitulating the histological and genetical characteristics of the original tumors. These experimental SGC models may serve as a useful resource for the development of novel therapeutic strategies and for investigating the molecular mechanisms underlying the development of these malignancies. [ABSTRACT FROM AUTHOR]

Background: We previously identified hypopharyngeal cancer as an independent risk factor for the incidence of newly diagnosed secondary cancers after the treatment of early-stage laryngeal, oropharyngeal, and hypopharyngeal cancers. We subsequently used a different patient cohort to validate the usefulness of this factor during the follow-up period in these patients. Methods: Patients who underwent transoral surgery (TOS) as a definitive treatment between April 1, 2016, and September 30, 2020, were included. The incidence of secondary cancer was evaluated in hypopharyngeal and other cancers. Overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS) outcomes were evaluated. Statistical analyses based on the risk factors were also performed. Results: Incidence of new secondary cancer was 30% in hypopharyngeal cancer patients as compared to 11% in other cancer patients, and the risk was 3.60-fold (95% confidence interval 1.07–12.10) higher after definitive treatment for initial head and neck cancers. The 3-year OS, RFS, and DFS rates were 98%, 86%, and 67%, respectively. Conclusions: Among patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma, who were initially treated with TOS, hypopharyngeal cancer patients had a higher risk of newly diagnosed secondary cancers as observed during the follow-up period. [ABSTRACT FROM AUTHOR]

Background: We had previously identified the following risk factors for insufficient control of early T-stage head and neck cancer by transoral surgery (TOS): (1) tumor thickness > 7 mm on enhanced computed tomography (CT), and (2) poor differentiation in pathological examination. We subsequently used a different patient cohort to validate the usefulness of these factors in determining the need for adaptation of TOS. Study setting: A prospective observational study Methods: Patients who received TOS as a definitive treatment between April 1, 2016 and September 30, 2020 were included. Primary control rates (by single TOS and TOS alone) in relation to the above-mentioned risk factors were calculated. Overall (O), recurrence-free (RF), and disease-free (DF) survival (S) outcomes were evaluated. A combination analysis based on the number of risk factors was also performed. Results: Patients with tumor thickness > 7 mm had a 2.88-fold [95% confidence interval (CI) 1.01–8.51] higher risk of incomplete primary resection by single TOS, while patients who showed poor differentiation on pathological assessments had a 13.14-fold (95% CI 3.66–47.14) higher risk of insufficient primary control by TOS alone. The 3 year OS, RFS, and DFS rates were 99%, 83%, and 63%, respectively. Patients with both risk factors had a 93.00-fold (95% CI 4.99–1732.00) higher risk of incomplete primary control by TOS alone. Conclusions: Among patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma, primary control by TOS alone may not be achieved in patients with both risk factors, that is, tumor thickness > 7 mm as measured by enhanced CT and poor differentiation on pathological examination. [ABSTRACT FROM AUTHOR]

Background: Our prospective study of patients with early T-stage head and neck cancer indicated a high incidence of newly diagnosed secondary malignancies during the follow-up period. We aimed to determine the incidence rate and risk factors of secondary malignancies in early-stage head and neck cancer patients. Methods: We sub-analyzed the patient data of a previous study focusing on secondary cancer incidence. The endpoints were statistical analyses of risk factors and survival and incidence rates. Results: The incidence rate of secondary cancer was 37%, the crude incidence of second primary cancers was 10.6 per 100 person-years, and the 5 year secondary cancer-free survival rate was 63%. The hypopharynx as the primary site was an independent significant predictive factor (odds ratio 3.96, 95% confidence interval 1.07–14.6, p = 0.039). Conclusions: Early stages of laryngeal, oropharyngeal, and hypopharyngeal cancer had a risk of secondary cancer, especially hypopharyngeal cancer. Attention to the secondary cancer has to be paid during the follow-up period after controlling the early-stage disease. These findings highlight the need for awareness of the incidence of secondary cancer in cases of early-stage primary head and neck cancer. [ABSTRACT FROM AUTHOR]

Purpose: To confirm the efficacy and safety of cetuximab and docetaxel in postoperative radiotherapy for high-risk head and neck cancer patients who cannot to be administered high-dose cisplatin.Patients and Methods: The eligibility criteria required stage III-IVB head and neck cancer patients who had undergone total resection, and for whom pathological evaluation revealed positive or close margins in the primary site and/or extracapsular nodal extension and/or two or more nodal metastases. In each case, the patients general condition prevented the use of high-dose cisplatin. Instead, they received cetuximab and docetaxel every week during a 66.6 Gy course of postoperative radiotherapy.Results: Eleven patients were enrolled; the median follow-up period was 22 months, and the 1- and 2-year disease free survival rates were 91 and 55%, respectively. Grade 3 adverse events included oral mucositis, radiation dermatitis, reduced white blood cell and neutrophil counts, lung infection, aspiration, and hyponatremia; however, no grade 4 adverse events were observed.Conclusion: Administration of cetuximab and docetaxel during postoperative radiotherapy for high-risk poor condition head and neck cancer patients in poor general condition was both feasible and tolerable. With the safety of this treatment confirmed, we propose a phase trail to further clarify the efficacy of cetuximab and docetaxel use for high-risk cisplatin-intolerant patients. [ABSTRACT FROM AUTHOR]

Background: For primary organ preservation, concurrent chemoradiotherapy (CCRT) is performed for advanced squamous cell carcinoma of the head and neck (SCCHN). In this organ-preservation setting with CCRT, surgery is reserved as a salvage treatment in cases of locoregional failure after CCRT. The purpose of the study was to review our experience with salvage surgery after CCRT for patients with SCCHN and to evaluate the effectiveness and prognostic factors affecting survival. Methods: The records of patients with stage II-IVB SCC of the larynx, oropharynx, or hypopharynx treated with salvage surgery after CCRT between 1998 and 2012 were reviewed. Results: A total of 645 patients with previously untreated, resectable SCC of the larynx, oropharynx, or hypopharynx received CCRT. Salvage surgery was performed for 78 of 225 patients with residual or recurrent tumors. The 5-year overall survival (OS) and disease-specific survival rates for patients who received salvage surgery were 61.0 and 65.5 %, respectively. Stage IV, poorly differentiated, synchronous double cancer, and surgical complications were significant predictors of unfavorable OS on multivariate analysis. Postoperative complications were observed in 30 patients (38.5 %). Conclusions: Salvage surgery is the best therapeutic option for failure after CCRT for SCCHN because of its good survival rate, although a high surgical complication rate is seen. Patients with initial stage IV tumors, poorly differentiated SCC, or synchronous double cancer are considered for further adjuvant treatment. [ABSTRACT FROM AUTHOR]

Background: Definitive chemoradiotherapy (CRT) is used to treat lymph node metastatic head and neck cancer patients. Regional control of the neck disease is important to improve the prognosis, and the accuracy of the method used to evaluate the metastatic lymph node(s) after CRT is crucial to the decision-making process for any following salvage surgery. Methods: Patients undergoing CRT were divided in two groups of patients of those showing complete clinical response (CR) and those showing clinical non-response (non-CR), as assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI), ultrasonography, fluorodeoxyglucose-positron emission tomography (FDG-PET), and fine needle aspiration cytology. The responses (CR vs. non-CR) were compared with the actual clinical outcomes. For the interim analysis, the study period was broken down into two periods, namely, the exploratory phase (patients treated between January 2002 and April 2012) and the validating phase (patients treated between May 2012 and January 2014). Results: The sensitivity, specificity, and accuracy were as follows: CT and/or MRI, 66.7, 73.8, and 72.8 %, respectively, in the exploratory phase; ultrasonography, 91.7, 70.6, and 73.4 %, respectively, in the exploratory phase and 80.0, 82.8, and 82.4 %, respectively, in the validating phase; FDG-PET, 50.0, 97.5, and 91.3 %, respectively, in the exploratory phase and 60.0, 100, and 94.1 %, respectively, in the validating phase; cytology, 68.4, 95.9, and 90.3 %, respectively, in the exploratory phase and 66.7, 100, and 85.7 %, respectively, in the validating phase. Conclusions: Based on our results, CT and/or MRI appear to be inadequate methods for the evaluation of the response of lymph node(s) to CRT. In contrast, ultrasonography appears to be a highly sensitive and useful tool for positive screening at 6-8 weeks after CRT, and FDG-PET appears to be a highly specific and useful tool for negative screening at 8-12 weeks after CRT. [ABSTRACT FROM AUTHOR]

Purpose: Although locally advanced head and neck squamous cell carcinoma (HNSCC) can be effectively treated using chemoradiotherapy (CRT) with docetaxel (DTX), and cisplatin (CDDP) plus 5-fluorouracil (TPF-CRT), severe adverse events (especially neutropenia) can limit treatment adherence. Therefore, we evaluated the safety and efficacy of a new chemotherapy regimen that consisted of DTX and CDDP plus cetuximab (Cmab) with concurrent radiotherapy. Methods: Bio-chemoradiotherapy (B-CRT) using DTX, CDDP, and Cmab was administrated to patients with locally advanced HNSCC, and its safety and efficacy were evaluated. Results: Interim analysis of nine patients revealed severe neutropenia in five patients (56 %) and leukopenia in seven patients (78 %); hence, the study was terminated. One patient experienced disease-free survival using only B-CRT. Conclusions: Neutropenia was equally severe for B-CRT, compared to TPF-CRT. Based on the limited sample size, it is impossible to conclude that B-CRT has non-inferior efficacy, compared to TPF-CRT. [ABSTRACT FROM AUTHOR]

Background: Chemoradiotherapy (CRT) is used to treat cervical lymph node(s) metastatic head and neck cancer patients. Evaluation and treatment of lymph node(s) after CRT is important to improve the prognosis. Methods: Prior to CRT, we determined the TNM stage by visual and imaging examinations. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated from the results of fluorodeoxyglucose-positron emission tomography (FDG-PET). After CRT, the patients were divided in two groups-complete response (CR) and non-CR-and their responses were compared with the clinical characteristics. Results: T4, N2b, N2c and TLG ≥18.8 were statistically significant predictive indices before CRT. The odds ratio, 95 % confidence interval and p value were, respectively-T4: 2.73, 1.15-6.51, 0.0230; N2b: 6.96, 1.50-32.3, 0.0132; N2c: 11.80, 2.37-58.50, 0.00258; and TLG ≥18.8: 6.25, 2.17-18.00, 0.000672. Conclusions: TLG was found to be a good predictive factor for metastatic lymph node(s) prior to CRT treatment. After CRT treatment, FDG-PET was found to be highly specific and useful for negative screening. [ABSTRACT FROM AUTHOR]

The aim of this study was to verify the effectiveness of PET (positron emission tomography) or PET/CT (fusion images of PET with computed tomography) in detecting synchronous cancer in patients with head and neck carcinoma. We reviewed 682 patients with carcinoma of the head and neck between January 2001 and December 2010. In 98 patients, 111 synchronous cancers were diagnosed. Of these 98 patients, the index cancer was predominantly located in the hypopharynx (47 cases), followed by the larynx (23 cases), oropharynx (12 cases) and the oral cavity (6 cases). Esophageal cancer was diagnosed as the most synchronous cancer (57 lesions), followed by gastric cancer (20 lesions), lung cancer (9 lesions) and head and neck cancer (8 lesions). Among these 98 patients, PET or PET/CT was performed in 82 patients. Of these 82 patients, PET or PET/CT detected 34 out of 94 (36.2 %) synchronous cancers. No significant difference was observed between PET and PET/CT in terms of lesion detectability ( p = 0.21). Regarding synchronous T1 and Tis upper gastrointestinal (UGI) cancer, PET or PET/CT detected 4 out of 43 (9.3 %) of the cancers. No statistical difference in detectability was observed in patients who underwent PET or PET/CT scanning before or after histological examination of synchronous UGI cancer. In conclusion, synchronous cancer was most frequently observed in the UGI, especially in the esophagus in patients with head and neck carcinoma. PET and PET/CT have limitations in the detection of these lesions. [ABSTRACT FROM AUTHOR]

We assessed the sensitivity of positron emission tomography (PET) for detecting synchronous multiple primary cancers, particularly synchronous esophageal cancers in head and neck cancer patients. We retrospectively reviewed 230 head and neck cancer patients. All the patients routinely underwent the following examinations: urinalysis, occult blood, tumor marker detection [squamous cell carcinoma (SCC), cytokeratin fragment (CYFRA), and carcinoembryonic antigen (CEA)], esophagogastroduodenoscopy, colonoscopy (when CEA was high or occult blood was positive), abdominal ultrasonography, plain chest computed tomography (CT), and PET. Bronchoscopy was performed when CT revealed lung shadow of central region. Synchronous multiple primary cancers were detected in 42 (18.2%) patients. The diagnostic sensitivity of PET for synchronous primary cancers was as follows: esophagus, 7.6% (1/13); stomach, 25.0% (2/8); lung, 66.7% (4/6); head and neck, 75.0% (3/4); colon, 0% (0/1); kidney, 0% (0/1); and subcutaneous, 100% (1/1). The sensitivity of PET for detecting synchronous esophageal cancers is low because these are early-stage cancers (almost stage 0-I). Therefore, it is necessary to perform esophagogastroduodenoscopy for detecting synchronous esophageal cancers. PET is an important additional tool for detecting synchronous multiple primary cancers because the diagnostic sensitivity of PET in synchronous head and neck cancer and lung cancer is high. But PET has the limitation of sensitivity for synchronous multiple primary cancers because the diagnostic sensitivity of PET in synchronous esophageal cancer is very low. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the feasibility and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP) and 5-fluorouracil (5-FU) (TPF regimen) or with CDDP, 5-FU, methotrexate and leucovorin (PFML regimen) in previously untreated patients with advanced oropharyngeal squamous cell carcinoma (SCC). Methods: Fifty-six eligible patients with stage III or IV oropharyngeal SCC were treated with CCRT. Forty-four patients were men and 12 were women, and the average age of the patients was 58.8 years (range, 37-72 years). In the TPF group, patients received CCRT with the TPF regimen [docetaxel (50 mg/m, day 1), CDDP (60 mg/m, day 4) and a continuous 5-FU infusion (600 mg/m/day, days 1-5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60 mg/m, day 4), a continuous 5-FU infusion (600 mg/m/day, days 1-5), methotrexate (30 mg/m, day 1) and leucovorin (10 mg/m/day, days 1-5)]. The total radiation dose was between 66.6 and 70.2 Gy. Results: The overall 5-year survival rate was 64.6% in all patients, 68.6% in the resectable group and 47.4% in the unresectable group. The 5-year disease-specific survival rate was 72.2% in all patients, 78.1% in the resectable group and 47.7% in the unresectable group. Regarding clinical stage, the 5-year disease-specific survival rates were 91% in stage III, 72% in stage IVa and 44% in stage IVb. Conclusion: CCRT with TPF or PFML regimen for advanced oropharyngeal SCC is tolerable and effective, especially in patients with resectable disease. [ABSTRACT FROM AUTHOR]

The aim of this study was to verify the effectiveness of positron emission tomography (PET) in detecting primary sites in carcinoma of unknown primary (CUP) patients. In this study, CUP represented a group of heterogeneous tumors that shared the clinical manifestation of metastatic carcinoma with no obvious primary site at the time of first diagnosis, which included clinical investigations, computed tomography, magnetic resonance imaging and panendoscopy. We reviewed the records of 24 patients with CUP between January 1995 and December 2009. The patients who demonstrated additional tracer uptake sites other than previously known metastatic lesions by PET scan were done direct biopsies for the sites of accumulation. Patients who had a negative PET scan or for whom the primary site could not be identified by direct biopsies underwent examination under anesthesia of the at-risk occult tumor sites. PET scan demonstrated focal accumulation suspicious for primary tumor in 12 (50.0%) of 24 patients: tonsil 5, nasopharynx 3, hypopharynx 1, tongue 1, larynx 1, and maxillary sinus 1. A subsequent biopsy of these sites revealed primary cancer in 9 (37.5%) of 24 patients: tonsil 5, nasopharynx 1, hypopharynx 1, tongue 1, and maxillary sinus 1. In the remaining three patients, no malignant cells were found by the biopsy of the accumulated area: nasopharynx 2, larynx 1. PET scans increase the yield of primary tumor by 37.5%. The sensitivity, specificity for PET scan were 80.8, 76.9%, respectively. PET scanning is useful in detecting primary cancer of CUP patients. [ABSTRACT FROM AUTHOR]

We compared concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP), and 5-fluorouracil (5-FU) (TPF) with CCRT with CDDP, 5-FU, methotrexate and leucovorin (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) in terms of safety and efficacy on survival. A total of 100 patients were enrolled. The TPF group received CCRT with the TPF regimen [docetaxel (50 mg/m2: day 1), CDDP (60 mg/m2: day 4), and continuous 5-FU infusion (600 mg/m2/day: days 1–5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60 mg/m2: day 4)], continuous 5-FU infusion (600 mg/m2/day: days 1–5), methotrexate (30 mg/m2: day 1) and leucovorin (20 mg/m2/day: days 1–5)]. Both groups received 2 cycles of chemotherapy during definitive radiotherapy. The total radiation dose was between 66.6 and 70.2 Gray. The overall response rates after CCRT were 98 with 90% of a pathologically complete response (pCR) in the TPF group and 94 with 77% in the PFML group. For grade 3/4 adverse events, mucositis was more frequent in the PMFL group, and the TPF group showed a higher incidence of hematological toxicity. CCRT with TPF or PMFL for advanced SCCHN was tolerable and produced excellent survival rates. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the feasibility and toxicity of concurrent chemoradiotherapy (CCRT) with S-1 in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) in elderly cases and/or cases with comorbidity. Fifty eligible patients with stage III (15 cases) or stage IV (35 cases) SCCHN were treated with CCRT. Thirteen cases had an advanced age of over 75 years and 37 cases had comorbidity. Definitive radiotherapy was delivered up to a total dose of 66–70.2 Gy. The patients received two courses of oral S-1 (40 or 50 mg twice a day [80 or 100 mg/day]) for 2 weeks followed by 1 week of rest while receiving CCRT. All the patients received the planned radiotherapy and at least one course of S-1. Grade 3 mucositis occurred in 20% of the patients (10/50). Grade 3 neutropenia occurred in 12% (6/50) and leukocytopenia occurred in 6% (3/50) of the cases. Pathologically, the complete response rates were 93% in stage III and 54% in stage IV. Concurrent chemoradiotherapy with S-1 is a safe, well-tolerated and effective regimen for locally advanced SCCHN in elderly cases and/or cases with comorbidity. [ABSTRACT FROM AUTHOR]

We aimed to clarify the reason for the lower dosage of cis-platinum (CDDP) in patients with head and neck cancer in Japan compared with that in other countries, by evaluating renal function. We studied 375 patients with head and neck cancer who had been hospitalized from January 1998 to October 2005, to evaluate and treat the disease. The creatinine clearance rate (Ccr) was calculated at least three times before beginning the treatments, and the average Ccr was estimated to evaluate the renal function. The Ccr decreased with aging, and the percentages of patients with Ccr lower than 65 ml/min per 1.73 m2 were 27.1% of patients in their fifties, 36.8% in their sixties, 62.3% in their seventies, and 87.5% in their eighties. There was no correlation between renal function and the Japanese lifestyle (i.e., diet. water consumption). The renal function of Japanese decreases rapidly with aging, whereas that of Americans is maintained for longer periods. The poor renal function of Japanese is one of the causes of the need to reduce the dosage of or avoid the administration of CDDP in cancer patients. [ABSTRACT FROM AUTHOR]