Co-expression of low-risk HPV E6/E7 and EBV LMP-1 leads to precancerous lesions by DNA damage.

BACKGROUND: Low-risk human papillomavirus (HPV), such as types 6 and 11, is considered non-oncogenic, but these types have been detected in oral cancer tissue samples, suggesting their possible involvement in oral carcinogenesis. Because double infection of high-risk HPV and Epstein-Barr virus (EBV) is known to be involved in oral carcinogenesis, we hypothesized that low-risk HPV and EBV co-infection can transform the oral cells. To verify our hypothesis, we evaluated the transformation activity of cell lines expressing both low-risk HPV E6/E7 and EBV LMP-1. METHODS: We transduced HPV6, 11 and 16 E6/E7 genes and EBV LMP-1 gene into primary mouse embryonic fibroblasts. The cell lines were examined for indices of transformation activity such as proliferation, induction of DNA damage, resistance to apoptosis, anchorage-independent growth, and tumor formation in nude mice. To evaluate the signaling pathways involved in transformation, NF-κB and p53 activities were analyzed. We also assessed adhesion signaling molecules associated with anchorage-independent growth such as MMP-2, paxillin and Cat-1. RESULTS: Co-expression of low-risk HPV6 E6 and EBV LMP-1 showed increased cell proliferation, elevated NF-κB activity and reduced p53 induction. Moreover, co-expression of low-risk HPV6 E6 and EBV LMP-1 induced DNA damage, escaped from apoptosis under genotoxic condition and suppression of DNA damage response (DDR). Co-expression of low-risk HPV11 E6/E7 and EBV LMP-1 demonstrated similar results. However, it led to no malignant characteristics such as anchorage-independent growth, invasiveness and tumor formation in nude mice. Compared with the cells co-expressing high-risk HPV16 E6 and EBV LMP-1 that induce transformation, co-expression of low-risk HPV6 E6 and EBV LMP-1 was associated with low MMP-2, paxillin and Cat-1 expression. CONCLUSIONS: The co-expression of low-risk HPV E6/E7 and EBV LMP-1 does not induce malignant transformation, but it allows accumulation of somatic mutations secondary to increased DNA damage and suppression of DDR. Thus, double infection of low-risk HPV and EBV could lead to precancerous lesions.

Outcomes after up-front surgery and metronomic neoadjuvant chemotherapy with S-1 or UFT for early tongue squamous cell carcinoma.

BACKGROUND: Our aim was to investigate the disease-free survival in patients with tongue squamous cell carcinoma receiving metronomic neoadjuvant chemotherapy with 5-fluorouracil prodrugs (UFT or S-1) plus bleomycin compared with those who had up-front surgery retrospectively. METHODS: In this retrospective study, 108 patients with stages I to II tongue squamous cell carcinoma who had undergone surgery were divided into the "surgery group" or "neoadjuvant chemotherapy group." RESULTS: A total of 41 patients received up-front surgery; 67 received metronomic neoadjuvant chemotherapy with UFT plus bleomycin (39) or S-1 plus bleomycin (28). The rate of disease-free survival was the primary outcome measure. Neoadjuvant 5-fluorouracil prodrugs did not correlate higher with improved disease-free survival than up-front surgery (72 and 54%, respectively; hazard ratio for recurrence or death, 0.54; 95% confidence interval [CI], 0.28 to 1.03; P = 0.06). Patients who received S-1 were more likely than those who received UFT to have pathological complete response (46% vs. 15%; P = 0.007). Neoadjuvant S-1 significantly improved disease-free survival as compared with up-front surgery (79% vs. 54%; hazard ratio, 0.41; 95% CI, 0.15 to 0.98; P = 0.04). However, neoadjuvant UFT did not improve disease-free survival as compared with up-front surgery (67% vs. 54%, respectively; hazard ratio, 0.66; 95% CI, 0.31 to 1.33; P = 0.24). CONCLUSIONS: Neoadjuvant S-1 chemotherapy, as compared with up-front surgery, significantly improved disease-free survival among patients with tongue squamous cell carcinoma. CLINICAL RELEVANCE: A choice of drugs before neoadjuvant metronomic chemotherapy is needed.

Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice.

AIMS/HYPOTHESIS: Nitric oxide (NO) is synthesised not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. METHODS: To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of L-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. RESULTS: Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota. CONCLUSIONS/INTERPRETATION: These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.

Synchronous quadruple multiple primary cancers of the tongue, bilateral breasts, and kidney in a female patient with a disease-free survival time of more than 5 years: a case report.

BACKGROUND: Reports of synchronous multiple primary cancers in patients with oral cancer have recently been increasing because of progress in radiographic diagnostic techniques. Multiple primary cancers in patients with oral cavity cancer mainly occur in the head and neck region, lung, and esophagus. 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography is usually used to identify synchronous multiple primary cancers. CASE PRESENTATION: We herein describe a 69-year-old woman diagnosed with synchronous quadruple multiple primary cancers, namely a squamous cell carcinoma of the mobile tongue, invasive ductal carcinoma of the right breast, intraductal carcinoma of the left breast, and chromophobe renal cell carcinoma of the right kidney. We removed the four tumors over three surgical procedures to reduce the surgical risk because the patient had diabetes mellitus. To the best of our knowledge, this combination of multiple primary cancers has not been reported to date. Importantly, we followed this case for 5 years after surgery. The patient was alive and well with no clinical or radiologic signs of recurrent or metastatic disease at the time of this writing. CONCLUSIONS: In the present case, the kidney cancer could not be detected by 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography but could be detected by contrast-enhanced computed tomography. To avoid overlooking multiple primary cancers of the kidney, we suggest that contrast-enhanced computed tomography should cover a region extending to the inferior margin of the kidney, rather than only to the liver, in patients with oral cavity cancer.

EphA4 signaling is involved in the phenotype of well-differentiated oral squamous cell arcinoma with decreased tumor immunity.

Metronomic chemotherapy is defined as a high-frequency low-dose schedule of chemotherapy drug administration. Although metronomic chemotherapy is widely used, the mechanisms underlying resistance to metronomic chemotherapy remain unclear. Therefore, we herein conducted a single institutional phase I/II trial to assess the efficacy and safety of metronomic chemotherapy with bleomycin plus S-1, an oral 5-FU prodrug, in the neoadjuvant setting for patients with oral squamous cell carcinoma (OSCC). The response rate of well-differentiated OSCC to metronomic chemotherapy was significantly lower. We investigated differences in molecular profiles between poorly or moderately differentiated head and neck squamous cell carcinoma (HNSCC) and well-differentiated HNSCC from patients with HNSCC TCGA data. EphA4 expression positively correlated with histological differentiation. An upstream regulator analysis correlated with EphA4 expression identified pathways associated with decreased mTORC1 signaling and T cell activation, including TCR, CD3, CD28, and CD40LG. An EphA4 blocking peptide (KYL) induced mTOR activation in well-differentiated OSCC cell lines. Plasmacytoid dendritic cell and CD8+ T cell numbers were higher in the microenvironment of poorly or moderately differentiated HNSCC than in that of well-differentiated HNSCC. Well-differentiated HNSCC had the characteristics of "cold tumors" (immune-excluded tumors). Moreover, KYL used with chemotherapeutic drugs synergistically increased cancer cell death. Well-differentiated OSCC is depleted of immune cells, which may be partly explained by the receptor tyrosine kinase EphA4.

Factors associated with bone thickness: Comparison of the cranium and humerus.

Cortical bone thickness is important for the mechanical function of bone. Ontogeny, aging, sex, body size, hormone levels, diet, behavior, and genetics potentially cause variations in postcranial cortical robusticity. However, the factors associated with cranial cortical robusticity remain poorly understood. Few studies have examined cortical robusticity in both cranial and postcranial bones jointly. In the present study, we used computed tomography (CT) images to measure cortical bone thicknesses in the cranial vault and humeral diaphysis. This study clearly showed that females have a greater cranial vault thickness and greater age-related increase in cranial vault thickness than males. We found an age-related increase in the full thickness of the temporal cranial vault and the width of the humeral diaphysis, as well as an age-related decrease in the cortical thickness of the frontal cranial vault and the cortical thickness of the humeral diaphysis, suggesting that the mechanisms of bone modeling in cranial and long bones are similar. A positive correlation between cortical indices in the cranial vault and humeral diaphysis also suggested that common factors affect cortical robusticity. We also examined the association of polymorphisms in the WNT16 and TNFSF11 genes with bone thickness. However, no significant associations were observed. The present study provides fundamental knowledge about similarities and differences in the mechanisms of bone modeling between cranial and postcranial bones.

HPV16E6-dependent c-fos expression contributes to AP-1 complex formation in SiHa cells.

To date, the major role of HPV16E6 in cancer has been considered to be its ability to inhibit the p53 tumor-suppressor protein, thereby thwarting p53-mediated cytotoxic responses to cellular stress signals. Here, we show that HPV16E6-dependent c-fos oncogenic protein expression contributes to AP-1 complex formation under oxidative stress in SiHa cells (HPV16-positive squamous cell carcinoma of the cervix). In addition, we examined the role of HPV16E6 in TGF-α-induced c-fos expression and found that the c-fos protein expression induced by TGF-α is HPV16E6 dependent. Thus, our results provide the first evidence that HPV16E6 contributes to AP-1 complex formation after both ligand-dependent and independent EGFR activation, suggesting a new therapeutic approach to the treatment of HPV-associated tumors.

The human EDAR 370V/A polymorphism affects tooth root morphology potentially through the modification of a reaction-diffusion system.

Morphological variations in human teeth have long been recognized and, in particular, the spatial and temporal distribution of two patterns of dental features in Asia, i.e., Sinodonty and Sundadonty, have contributed to our understanding of the human migration history. However, the molecular mechanisms underlying such dental variations have not yet been completely elucidated. Recent studies have clarified that a nonsynonymous variant in the ectodysplasin A receptor gene (EDAR 370V/A; rs3827760) contributes to crown traits related to Sinodonty. In this study, we examined the association between the EDAR polymorphism and tooth root traits by using computed tomography images and identified that the effects of the EDAR variant on the number and shape of roots differed depending on the tooth type. In addition, to better understand tooth root morphogenesis, a computational analysis for patterns of tooth roots was performed, assuming a reaction-diffusion system. The computational study suggested that the complicated effects of the EDAR polymorphism could be explained when it is considered that EDAR modifies the syntheses of multiple related molecules working in the reaction-diffusion dynamics. In this study, we shed light on the molecular mechanisms of tooth root morphogenesis, which are less understood in comparison to those of tooth crown morphogenesis.

A molecular signature of well-differentiated oral squamous cell carcinoma reveals a resistance mechanism to metronomic chemotherapy and novel therapeutic candidates.

Well-differentiated head and neck squamous cell carcinoma (HNSCC), accounts for approximately 10% of all HNSCCs and, while these cases are associated with good prognosis after surgery, these are resistant to chemotherapy. Here we designed a retrospective study to evaluate the effects of histological differentiation on tongue squamous cell carcinoma (TSCC) patients undergoing surgery or metronomic neoadjuvant chemotherapy. The metronomic neoadjuvant chemotherapy significantly improved overall survival of patients with poorly or moderately differentiated tumour, but not those with well-differentiated tumour. Analysis of the Cancer Genome Atlas (TCGA) showed that FAT1 mutations were significantly enriched in more differentiated HNSCC while ASPM mutations were significantly enriched among the poorly differentiated HNSCC. Interestingly, Wnt/ß-catenin pathway was activated in well-differentiated HNSCC. Active ß-catenin is translocated to the nucleus in the well-differentiated oral squamous cell carcinoma cell lines. Wnt inhibitor, Wnt974, were synergistic with methotrexate in killing well-differentiated oral squamous cell carcinoma (OSCC) cell lines. TCGA data analyses reveal a signature in patients with well-differentiated HNSCC who have no benefits from metronomic neoadjuvant chemotherapy, suggesting that there might be novel nosology and therapeutic candidates for improving HNSCC patient survival. Well-differentiated OSCC is synergistically killed by combination chemotherapy with Wnt inhibitor, making it promising therapeutic candidates.

miR-935 Inhibits Oral Squamous Cell Carcinoma and Targets Inositol Polyphosphate-4-phosphatase Type IA (INPP4A).

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is a common malignancy with poor prognosis. Therefore, novel therapeutic options are needed to improve prognosis of OSCC. Recently, microRNAs (miRs) have received increasing attention as a potential therapeutic tool for carcinomas. However, no definitive miR-based drugs for patients with OSCC have been reported to date. The aim of this study was to identify new miRs potentially involved in cellular processes associated with OSCC malignancy, which could lead to novel therapeutic strategies. MATERIALS AND METHODS: We identified miRs that are modulated in OSCC and possibly regulate OSCC malignancy, using miR microarray on OSCC cell lines. RESULTS: miR-935 and miR-509-3p were down-regulated in OSCC cell lines and patient tissues. When miR-935 was overexpressed in HSC-3-M3 cells, proliferation, migration, and invasion of the cell line was suppressed, whereas apoptosis was increased. Moreover, we showed that the gene inositol polyphosphate-4-phosphatase type I A (INPP4A) is a potential target whose expression is positively regulated by miR-935. CONCLUSION: miR-935 may function as a tumor suppressor by inhibiting OSCC malignancy via INPP4A induction. Therefore, miR-935 can be a new therapeutic candidate for OSCC treatment.

Oral health behavior of children and guardians' beliefs about children's dental caries in Vientiane, Lao People's Democratic Republic (Lao PDR).

Dental caries is considered a major health problem among schoolchildren in Lao People's Democratic Republic (Lao PDR). According to Health Belief Model (HBM)-based research, children's oral health behavior can be determined by their guardians' beliefs. This study aimed to describe children's oral health behavior and its association with childhood dental caries, as well as to assess associations between children's tooth-brushing behavior and guardians' beliefs in an urban area of Lao PDR, using HBM. Data were collected from ten primary schools in the Sisattanak district, the Vientiane capital, between 2013 and 2014. Ten dentists with the help of dental hygienists and schoolteachers conducted dental health check-ups at the schools that diagnosed dental caries based on visual inspection. They also conducted a questionnaire-based survey with the schoolchildren's guardians to collect data including socio-economic and demographic information, their children's oral health behavior, and guardians' beliefs derived from HBM, including perceived susceptibility to and perceived severity of child dental caries, perceived benefit of and perceived barrier to child's tooth brushing, and self-efficacy in making their children brush their teeth twice daily. A mixed-effects logistic regression model assessed the association between dental caries and children's oral health behavior and between children's tooth-brushing behavior and guardians' beliefs. Data from 1161 of 1304 (89.0%) children registered at the schools were used. The prevalence of dental caries was 82%. Children who brushed their teeth ≥ twice/day were significantly less likely to have dental caries than those brushing once or seldom (OR: 0.64, 95% CI: 0.45 to 0.91). The number of children who brushed twice daily also significantly increased with the increased level of guardians' self-efficacy (OR: 2.14, 95% CI: 1.91 to 2.41). In conclusion, childhood dental caries was associated with daily tooth brushing. Children's tooth-brushing behavior was associated with guardians' self-efficacy in making their children brush twice daily.

Thymoma appearing 9 years after the resection of squamous cell carcinoma of the lip: A case report of triple primary tumors and literature review.

The occurrence of second primary tumor (SPT)following malignancy treatment is common. In patients with head and neck (H&N) cancer, SPTs principally occur in the H&N region, lungs or esophagus. Therefore, patient follow-up after cancer treatment is important in order to detect recurrence, metastasis and new primary tumors. However, no standard guidelines on lifelong follow-up imaging are available. Herein, we report a patient who presented with three metachronous primary tumors-squamous cell carcinoma (SCC) of the tongue, SCC of the lip and type A thymoma. The third tumor was incidentally detected during follow-up using contrast-enhanced computed tomography (CT) 9 years following resection of the second tumor. To the best of our knowledge, this specific combination of metachronous tumors has not yet been reported. Based on the literature review, we observed that thymoma occurs following H&N cancer treatment. Therefore, to ensure that the presence of subsequent thymomas is not overlooked, we suggest regular lifelong follow-up using contrast-enhanced CT in patients who had previously been diagnosed with H&N cancer. The literature review revealed that thymomas occur in patients with H&N cancer and should be detected at the earliest convenience.

K1 gene transformation activities in AIDS-related and classic type Kaposi's sarcoma: Correlation with clinical presentation.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes both AIDS-related Kaposi's sarcoma (KS) and classic KS, but their clinical presentations are different, and respective mechanisms remain to be elucidated. The KSHV K1 gene is reportedly involved in tumorigenesis through the immunoreceptor tyrosine-based activation motif (ITAM). Since we found the sequence variations in the K1 gene of KSHV isolated from AIDS-related KS and classic KS, we hypothesized that the transformation activity of the K1 gene contributes to the different clinical presentations. To evaluate our hypothesis, we compared the transformation activities of the K1 gene between AIDS-related KS and classic KS. We also analyzed ITAM activities and the downstream AKT and NF-κB. We found that the transformation activity of AIDS-related K1 was greater than that of classic K1, and that AIDS-related K1 induced higher ITAM activity than classic K1, causing more potent Akt and NF-κB activities. K1 downregulation by siRNA in AIDS-related K1 expressing cells induced a loss of transformation properties and decreased both Akt and NF-κB activities, suggesting a correlation between the transformation activity of K1 and ITAM signaling. Our study indicates that the increased transformation activity of AIDS-related K1 is associated with its clinical aggressiveness, whereas the weak transformation activity of classic type K1 is associated with a mild clinical presentation and spontaneous regression. The mechanism of spontaneous regression of classic KS may provide new therapeutic strategy to cancer.

[Long-term dietary nitrite and nitrate deficiency causes metabolic syndrome, endothelial dysfunction, and cardiovascular death in mice].

Nitric oxide (NO) is synthesized not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, however whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency induces metabolic syndrome (MetS) in mice. To this end, we prepared a low nitrite/nitrate diet (LND) consisting of an amino acid-based low nitrite/nitrate chow in which the contents of L-arginine, fat, carbohydrates, protein, and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. Intriguingly, in comparison with a regular diet, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia, and glucose intolerance; 18 months of the LND significantly provoked increased body weight, hypertension, insulin resistance, and impaired endothelium-dependent relaxations to acetylcholine; and 22 months of the LND significantly led to death due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS down-regulation, adiponectin insufficiency, and gut microbiota dysbiosis. These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to MetS, endothelial dysfunction, and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in MetS and its vascular complications.

Targeting EphA4 abrogates intrinsic resistance to chemotherapy in well-differentiated cervical cancer cell line.

Alkylating reagent chemotherapy for human cancers is not curative, and relapse occurs due to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD cells after chemotherapy, a phenomenon referred to as intrinsic resistance, depends on reactive oxygen species. Well-differentiated regions of the tumor are intrinsically resistant to chemotherapy. Receptor tyrosine kinase erythropoietin-producing human hepatocellular receptor A4 (EphA4) protein is highly expressed in the well-differentiated tumor-derived cervical cancer cell line Caski, but not in poorly differentiated tumor-derived cervical cancer cell lines such as HeLa or SiHa. Here, we report that reactive oxygen species produced by cisplatin exposure induce tyrosine phosphorylation of EphA4. After observing that EphA4 is activated by cisplatin, we rationalized a combination chemotherapy that induces well-differentiated cervical cancer death. Pharmacological inhibition of EphA4 increased cisplatin-induced cell death in Caski cells. Moreover, we observed increased expression levels of the senescence marker cyclin-dependent kinase inhibitor 2A (p16) in the absence of EphA4 kinase function after stimulation of Caski cells with cisplatin exposure. Mechanistically, cisplatin induces chemotherapy resistance of Caski cells by upregulating Lyn, a Src family kinase (SFK) that interacts with EphA4, through a pathway involving reactive oxygen species. Thus, the reactive oxygen species-SFK-EphA4 axis presents new potential drug targets for chemotherapy resistance.

Outcomes of an international volunteer surgical project for patients with cleft lip and/or cleft palate: A mission in developing Laos.

Cleft lip and/or palate (CL/P) is a common birth defect of complex etiology. CL/P surgery is generally performed in infancy to allow for improvements in esthetics, suckling, and speech disorders as quickly as possible. We have engaged in activities such as free-of-charge surgery for CL/P a total of 12 times from 2001 to 2016 in Lao People's Democratic Republic (Laos). The United Nations has designated Laos as a Least Developed Country; it is one of the poorest countries in Asia. We have carried out our activities for a long time, primarily in CL/P patients who cannot undergo surgery for financial reasons, and we have performed CL/P-related surgeries for 283 patients up to 2016. When we began our activities in 2001, the mean age at first cheiloplasty was 11.6 years, which dropped over time until 2016 when the mean age was 1.8 years. A linear regression analysis showed a significant difference between the age at first lip plasty and the year of first operation (ß = -0.35; P < 0.001). This was likely an effect of continuing to train local medical staff in surgical techniques and donating surgical tools and facilities over a period of 16 years while building a good relationship with local staff. However, the healthcare system in Laos is an obstacle to some patients who still cannot undergo CL/P surgery in infancy for financial reasons. We therefore need to support Laos to provide treatment on their own as we continue to carry out our activities for CL/P patients.

Dedifferentiated liposarcoma of the oral floor: A case study and literature review of 50 cases of head and neck neoplasm.

Dedifferentiated liposarcoma (DDLS) has a relatively poor prognosis, however this neoplasm rarely occurs in the head and neck. To date, no definite protocol has been established for the diagnosis and treatment of head and neck DDLS. The present study reports the case of a 69-year-old male patient with DDLS of the oral floor. To the best of our knowledge, this is the first documented case of oral floor DDLS. In addition, this is the first reported case with the development of a second primary malignancy following the treatment of head and neck DDLS. A literature review of 50 cases of head and neck DDLS revealed that preoperative biopsy is not reliable for the diagnosis of these tumors and an accurate pathological diagnosis with total resection is preferred.

Triple primary cancer of the head and neck, skin and prostate: A case report and literature review.

Second primary cancer (SPC) is an important prognostic factor for patients with head and neck cancer (HNC); therefore, the association between the prognosis and development of SPC has been well-reported. The use of 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) is valuable to examine cancer stage, evaluate treatment responses and investigate suspected relapses or metastases. In the present study, the case of a male patient who was diagnosed with three primary cancer types, including well to moderately differentiated squamous cell carcinoma (SCC) of the mandible, axillary cutaneous poorly differentiated SCC and prostate adenocarcinoma, was described. Among these, mandible cancer was the first diagnosed when the patient was 70 years of age. Synchronous skin and prostate cancer (PRC) types then developed 3 years later. To the best of our knowledge, this is the first report of the aforementioned combination of cancer types. Postoperative FDG-PET was not performed as no lesions of recurrence or metastases of mandible cancer were found. Three years later, the PRC was asymptomatic and was incidentally detected by FDG-PET performed for a preoperative evaluation of skin cancer. It was indicated that FDG-PET could be utilized in patients with HNC due to there being no accurate FDG-PET protocol to detect SPC over a long-term follow-up.

MicroRNA-196a-5p is a potential prognostic marker of delayed lymph node metastasis in early-stage tongue squamous cell carcinoma.

MicroRNAs (miRs) are expected to serve as prognostic tools for cancer. However, many miRs have been reported as prognostic markers of recurrence or metastasis in oral squamous cell carcinoma patients. We aimed to determine the prognostic markers in early-stage tongue squamous cell carcinoma (TSCC). Based on previous studies, we hypothesized that miR-10a, 10b, 196a-5p, 196a-3p, and 196b were prognostic markers and we retrospectively performed miR expression analyses using formalin-fixed paraffin-embedded sections of surgical specimens. Total RNA was isolated from cancer tissues and adjacent normal tissue as control, and samples were collected by laser-capture microdissection. After cDNA synthesis, reverse transcription-quantitative polymerase chain reaction was performed. Statistical analyses for patient clinicopathological characteristics, recurrence/metastasis, and survival rates were performed to discern their relationships with miR expression levels, and the 2-ΔΔCq method was used. miR-196a-5p levels were significantly upregulated in early-stage TSCC, particularly in the lymph node metastasis (LNM) group. The LNM-free survival rate in the low miR-196a-5p ΔΔCq value regulation group was found to be lower than that in the high ΔΔCq value regulation group (P=0.0079). Receiver operating characteristic analysis of ΔΔCq values revealed that miR-196a-5p had a P-value=0.0025, area under the curve=0.740, and a cut-off value=-0.875 for distinguishing LNM. To our knowledge, this is the first study to examine LNM-related miRs in early-stage TSCC as well as miRs and 'delayed LNM' in head and neck cancer. miR-196a-5p upregulation may predict delayed LNM. Our data serve as a foundation for future studies to evaluate miR levels and facilitate the prediction of delayed LNM during early-stage TSCC, which prevent metastasis when combined with close follow-up and aggressive adjuvant therapy or elective neck dissection. Moreover, our data will serve as a foundation for future studies to evaluate whether miR-196a-5p can serve as a therapeutic marker for preventing metastasis.

Triple primary malignancies of surface osteosarcoma of jaw, myelodysplastic syndrome and colorectal cancer as a second primary cancer detected by PET2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography: A case report.

Second primary malignancy (SPM) is a severe issue for cancer survivors, particularly for osteosarcoma (OS) survivors. To date, the associations between subsequent SPM and OS have been well reported. Hematogenic and solid malignancies tend to occur following OS treatment. Reportedly, 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is mainly used in OS patients for initial cancer staging, to evaluate the response of neoadjuvant chemotherapy, and when recurrence or metastasis is clinically suspected. The present case report describes a 70-year-old man diagnosed with three primary malignancies: jaw OS, myelodysplastic syndrome and colorectal adenocarcinoma. To the best of our knowledge, this combination of malignancies has not been reported previously. Until now, there is no specific protocol of postoperative FDG-PET for OS patients. Few studies have described OS follow-up methods; therefore, there is no consensus on proper follow-up methods. In the present case report, the colorectal early-stage SPM was observed, without any symptoms, by FDG-PET/computed tomography. To avoid overlooking solid SPMs, it is suggested that FDG-PET should be performed in the long-term follow-up of OS patients.