Genomic Signature of Mismatch Repair Deficiency in Areca Nut-Related Oral Cancer.

Areca nut (AN) chewing contributes to an increase of oral squamous cell carcinoma (OSCC) cases in South and Southeast Asia; however, genomic events underlying the carcinogenesis process of AN-related OSCC remain unclear. Here, we comprehensively describe the genomic and transcriptome alterations of 113 Chinese OSCC patients (89 AN related and 24 AN negative) by whole-exome sequencing and RNA sequencing, and we compared the genomic differences between AN-related and AN-negative samples by integrating sequencing data of 325 OSCC patients from The Cancer Genome Atlas database and 50 from a published Taiwanese study. We identified 11 significantly mutated genes for OSCC, including 4 novel ones (ATG2A, WEE1, DST, and TSC2), of which WEE1 and ATG2A mutated with significantly higher rates in AN-related samples (P = 0.04 and P = 0.003, respectively). Mutational signature analysis revealed that AN-related OSCCs were specially characterized by the genomic signature of mismatch repair deficiency (dMMR), which could also predict the prognosis status of AN-related OSCC. In addition, an elevated PD-L1 expression was also observed in both AN-related patients (P = 3.71 × 10-11) and those with a high dMMR level (P = 1.99 × 10-4). Further differential expression analysis and in vitro experiments confirmed the role of dMMR in the development of OSCC induced by AN exposure. Taken together, this study first revealed the molecular profiles and highlighted the role of dMMR in AN-related OSCC among the Chinese population and identified that AN-related OSCC may represent a potential cohort for effective anti-PD-1/L1 immunotherapy.

Incorporation of log odds of positive lymph nodes into the AJCC TNM classification improves prediction of survival in oral cancer.

OBJECTIVES: To assess the prognostic performance of a new N classification that incorporates the log odds of positive lymph nodes (LODDS) into the routinely used pathological N classification for oral squamous cell carcinoma (OSCC) patients. DESIGN: Retrospective cohort study utilising LODDS into pN category was performed, and the AJCC TNM stage and T-New N-M stage were compared with respect to 5-year disease-specific survival (DSS) rates. The discriminability was evaluated from the linear trend chi-square test, Akaike information criterion (AIC) and Harrell's c-statistic. SETTING: Medical centrer in Taiwan. PARTICIPANTS: A total of 463 patients received primary surgery and neck dissection between 2004 and 2013 for OSCC. MAIN OUTCOME MEASURES: The discriminability for 5-year DSS rates. RESULTS: The median follow-up period was 54 months, the mean patient age was 54 ± 11 years and 428 patients (92.4%) were male. The patients with higher LODDS had worse 5-year DSS rates. Incorporation of LODDS into the prognostic model based on the seventh edition of the TNM classification significantly improved discriminative performance for 5-year DSS with a lower AIC (1883 versus 1897), and higher prediction accuracy (Harrell's c-statistic: 0.768 versus 0.764). CONCLUSIONS: By utilising a merger of the LODDS and pN classifications to create a new N classification has better discriminatory and predictive ability than pathological TNM staging and could help identify high-risk patients for intense adjuvant therapy.

Correlation between liver cirrhosis and risk of death from oral cancer: Taiwan cohort study.

BACKGROUND: A nationwide population-based cohort was used to examine the severity of liver cirrhosis and risk of mortality from oral cancer. METHODS: The cohort consisted of 3583 patients with oral cancer treated by surgery between 2008 and 2011 in Taiwan. They were grouped on the basis of normal liver function (n = 3471), cirrhosis without decompensation (n = 72) and cirrhosis with decompensation (n = 40). The primary endpoint was mortality. Hazard ratios of death were also determined. RESULTS: The mortality rates in the respective groups were 14.8 per cent, 20.8 per cent and 37.5 per cent at one year (p < 0.001). The adjusted hazard ratios of death at one year for each group compared to the normal group were 2.01 (p = 0.021) for cirrhotic patients without decompensation, 4.84 (p < 0.001) for those with decompensation and 2.65 (p < 0.001) for those receiving chemotherapy. CONCLUSION: Liver cirrhosis can be used to predict one-year mortality in oral cancer patients. Chemotherapy should be used with caution and underlying co-morbidities should be managed in cirrhotic patients to reduce mortality risk.

Experimental study of fat grafting under negative pressure for wounds with exposed bone.

BACKGROUND: The combination of fat grafting and negative pressure (VAC) therapy represents a synergistic interaction of all essential components for wound healing. The aim of this experimental study was to determine whether it could promote healing of wounds with exposed bone. METHODS: Full-thickness wounds with denuded bone in Sprague-Dawley rats were treated with either polyurethane foam dressing, fat grafting alone, polyurethane foam dressing with VAC, or polyurethane foam dressing with VAC combined with a single, or two administrations of fat graft. Wound healing kinetics, tissue growth, cell proliferation (Ki-67) and angiogenesis (platelet endothelial cell adhesion molecule 1 and α-smooth muscle actin) were investigated. Messenger RNA levels related to angiogenesis (vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF)), profibrosis (platelet-derived growth factor A and transforming growth factor ß), adipocyte expression (fatty acid-binding protein (FABP) 4 and peroxisome proliferator activated receptor γ), and extracellular matrix remodelling (collagen I) were measured in wound tissues. RESULTS: Wounds treated by VAC combined with fat grafting were characterized by cell proliferation, neoangiogenesis and maturation of functional blood vessels; they showed accelerated granulation tissue growth over the denuded bone compared with VAC- or foam dressing-treated wounds. Fat grafting alone over denuded bone resulted in complete necrosis. Expression of angiogenesis markers (VEGF and b-FGF) and adipocyte expression factors (FABP-4) was upregulated in wounds treated with VAC combined with fat grafting. CONCLUSION: Fat grafting with VAC therapy may represent a simple but effective clinical solution for a number of complex tissue defects, and warrants testing in clinical models. SURGICAL RELEVANCE: The combination of fat grafting and vacuum therapy represents a synergistic interaction of regenerative cells, hospitable wound matrix and stimulating micromechanical forces. It could accelerate complex wound healing through cell proliferation, neoangiogenesis and maturation of functional blood vessels. The efficacy of a multimodal wound healing approach is established in this experimental model; it could easily be translated into clinical trials of treatment for difficult wounds.

Thermal response of a dental tissue induced by femtosecond laser pulses.

This paper reports a theoretical and experimental study for thermal transport in a thin slice of human tooth induced by a 120 fs, 800 nm pulse laser at a repetition rate of 1 kHz. The surface reflectivity of enamel and the convection heat transfer coefficient were determined using an inverse heat transfer analysis. Instead of a fully three-dimensional modeling, two simplified two-dimensional (2D) planar and axisymmetric heat conduction models were proposed to simulate the temperature fields. The temperature responses obtained from the 2D planar and axisymmetric model agree well with the experimental measurements. On the other hand, the one-dimensional (1D) result significantly differs from the 2D axisymmetric one, suggesting that care should be taken when a 1D thermal model is considered for estimating temperature response.

MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma.

MicroRNAs (miRNAs) are a family of small non-coding RNA molecules of about 20-23 nucleotides in length, which negatively regulate protein-coding genes at post-transcriptional level. Using a stem-loop real-time-PCR method, we quantified the expression levels of 270 human miRNAs in 13 nasopharyngeal carcinoma (NPC) samples and 9 adjacent normal tissues, and identified 35 miRNAs whose expression levels were significantly altered in NPC samples. Several known oncogenic miRNAs, including miR-17-92 cluster and miR-155, are among the miRNAs upregulated in NPC. Tumour suppressive miRNAs, including miR-34 family, miR-143, and miR-145, are significantly downregulated in NPC. To explore the roles of these dysregulated miRNAs in the pathogenesis of NPC, a computational analysis was performed to predict the pathways collectively targeted by the 22 significantly downregulated miRNAs. Several biological pathways that are well characterised in cancer are significantly targeted by the downregulated miRNAs. These pathways include TGF-Wnt pathways, G1-S cell cycle progression, VEGF signalling pathway, apoptosis and survival pathways, and IP3 signalling pathways. Expression levels of several predicted target genes in G1-S progression and VEGF signalling pathways were elevated in NPC tissues and showed inverse correlation with the down-modulated miRNAs. These results indicate that these downregulated miRNAs coordinately regulate several oncogenic pathways in NPC.

MEG localization of rolandic spikes with respect to SI and SII cortices in benign rolandic epilepsy.

The purpose of this study was to study the relationship between interictal spike sources and somatosensory cortices in benign rolandic epilepsy of childhood (BREC) using a whole-scalp neuromagnetometer. We recorded spontaneous magnetoencephalography (MEG) and EEG signals and cortical somatosensory-evoked magnetic fields (SEFs) to electric stimulation of the median nerve in 9 children with BREC. Interictal rolandic discharges (RDs) and SEFs were analyzed by equivalent current dipole (ECD) modeling. Based on the orientation and locations of corresponding ECDs, we compared generators of RDs with primary (SI) and second somatosensory cortices (SII). Our results showed that RDs and SII responses had similar ECD orientation on the magnetic field maps. The ECDs of RDs were localized 15.3 +/- 1.9 and 12.2 +/- 2.8 mm anterior to SI and SII, respectively. The spatial distance on average from the location of RDs to SII (21.9 +/- 1.6 mm) cortex was significantly shorter than to SI cortex (29.7 +/- 1.7 mm) (P<0.01, Wilcoxon signed-rank test). In conclusion, the cortical generators for RDs in patients with BREC are localized in the precentral motor cortex, closer to hand SII than to SI cortex.

Short report: distribution and feeding preference of the sand flies Phlebotomus sergenti and P. papatasi in a cutaneous leishmaniasis focus in Sanliurfa, Turkey.

Sand flies (Diptera: Psychodidae) and rodents were collected in the endemic focus of urban cutaneous leishmaniasis in Sanliurfa, Turkey. Phlebotomus sergenti and P. papatasi represented 99% of the sand fly population. These flies were trapped in highest numbers in animal sheds, followed by cellars. However, P. sergenti was relatively more abundant in rooms. An enzyme-linked immunosorbent assay of the gut contents from blood-fed females detected immunoglobulins specific to birds and mammals, suggesting that both species are opportunistic feeders, although poultry is a frequent blood source of P. sergenti. Blood sources include black rats (Rattus rattus) and house mice (Mus domesticus); these rodents are abundant inside houses, and might have a role in parasite circulation.

Emergence of zoonotic canine leishmaniasis in the United States: isolation and immunohistochemical detection of Leishmania infantum from foxhounds from Virginia.

Previously considered an exotic disease, canine leishmaniasis caused by Leishmania infantum has recently been detected within the foxhound population in the United States and parts of Canada. Leishmania infantum is the etiologic agent of visceral leishmaniasis in many areas of the world and dogs are considered a major reservoir host for human Leishmania infections. Human visceral leishmaniasis has recently emerged as an opportunistic infection among individuals co-infected with HIV/AIDS and in persons taking immunosuppressive drugs. We report the isolation of L. infantum from 3 naturally infected foxhounds from Virginia by culture of popliteal lymph node and bone marrow, and the development of an immunohistochemical test to detect the parasite in tissues.

Sand flies (Diptera: Phlebotominae) in Sanliurfa, Turkey: relationship of Phlebotomus sergenti with the epidemic of anthroponotic cutaneous leishmaniasis.

Sand fly (Diptera: Phlebotominae) fauna were surveyed in various districts of Sanliurfa in southeast Turkey for 3 yr immediately after an epidemic of cutaneous leishmaniasis (Leishmania tropica). Sticky papers and CDC light traps collected a total of 10,937 sand flies, of which 10,919 (4,158 females and 6,761 males) were identified as Phlebotomus and 18 (11 females and seven males) as Sergentomyia (S. theodori Parrot; S. adleri Theodor). Eight Phlebotomus spp. were identified: P. sergenti Parrot (72.3%), P. papatasi (Scopoli) (27.2%), P. brevis Theodor & Mesghali (0.20%), P. neglectus Leger & Pesson (0.13%), P. perfiliewi Parrot (0.05%), P. mascitti Grassi, P. halepensisTheodor, and P. alexandri Sinton (0.01%). Phlebotomus mascitti and P. neglectus, along with both Sergentomyia sp., have not been previously described from the study area. Similar results were obtained when both trapping methods were applied in the same houses, indicating that local P. sergenti and P. papatasi populations were equally attracted to the light. P. sergenti was consistently abundant, agreeing with the general view that this species is the vector of leishmaniasis in the region. There was no apparent decrease in the relative abundance of this vector versus the other species, suggesting that factor (s) other than a change in the dynamics of sand fly populations precipitated the decline of the human leishmaniasis epidemic in Sanliurfa.

An alternative dressing for skin graft immobilization: negative pressure dressing.

The key difficulty of skin grafting is keeping the graft immobilized on uneven surfaces involved with motion, such as the nuchal area, axilla, web spaces, and the perineal area. This study reports the development of a new idea of negative pressure dressing (NPD) to maintain good immobilization of the skin graft and, at the same time, not cause any significant distress in the patient's daily life. Furthermore, the components of this dressing are available in ordinary hospitals. In this report, there are eight cases of skin grafts which were applied by this method, and the average success rate was approximately 97%. Therefore, use of negative pressure dressings to safeguard immobilization of the skin graft is an appropriate alternative method for grafts on uneven or mobile surfaces.

Power spectrum analysis of heart rate variability in children with epilepsy.

OBJECT: Children with epilepsy have been found to be at increased risk of death during childhood. Sudden unexpected death (SUDEP) has accounted for at least 12% of deaths of children with epilepsy. The exact mechanisms of SUDEP are unknown; however, theories suggested have, to date, focused on autonomic instability. The purpose of this study was to investigate autonomic function in children with chronic epilepsy by means of power spectrum analysis of heart rate variability. METHODS: Thirty patients with epilepsy and 30 control subjects, all between the ages of 4 and 10 years, were enrolled in this study. Power spectrum analysis of heart rate variability (HRV) was performed under standardized conditions after the patients had rested for 15 min. Each patient was tested in a supine position first and then again in a head-up tilted position, with 15 min between the two tests. RESULTS: There was no significant difference between the low-frequency component (LF) and the high-frequency component (HF) of heart rate variability, or the LF/HF ratio, between the study and control groups, whether the test subjects were in the supine or the head-up tilt position. In the control group, however, the subjects showed a significantly greater LF component and a smaller HF component of heart rate variability, and a greater LF/HF ratio in the head-up position than in the supine position. This implies a normal sympathovagal balance. This phenomenon was not observed in the study group. This implies that the modulating effects on autonomic function deriving from the hemisphere were probably disturbed, owing to the brain lesions that each of the study group patients had already sustained. CONCLUSIONS: A disturbed balance of activity between the sympathetic and parasympathetic nervous system might result from the loss of hemispheric influence in patients with epilepsy. Nevertheless, further investigation is clearly necessary to ascertain the possible association of this disturbed balance with SUDEP. Further investigation is also needed to establish the exact location of the region in the brain that gives rise to this modulating influence.

The nurse specialist role in Hong Kong: perceptions of nurse specialists, doctors and staff nurses.

AIM: The purpose of this study is to review and delineate the impact in terms of the perceived importance as well as the role components of nurse specialists in Hong Kong. RATIONALE: The Nurse Specialist Scheme was launched in 1994 in Hong Kong. Studies in the West showed that there were impacts on the roles of other members among the health care team. However, minimal local published work has been carried out in reviewing the scheme. DESIGN: The design of the study was nonexperimental. Data were collected by self-administered questionnaires. The questionnaire adopted was developed by O'Mullan (1995), and the five roles studied were administration, clinical practice, consultation, education and research. To ensure the contextual relevancy and consistency of the questionnaire, content validity and test-retest reliability tests were performed. The content validity index was 0.85 and the test-retest reliability (Spearman's rho coefficient) ranged from 0.57 to 0.97. Subjects were obtained by stratified convenience sampling technique. The ratios for subject selection among the doctors, ward managers, nursing officers and registered nurses were 3:1:3:10, respectively. Because of the small numbers for nurse specialists, they were all included in the study. The final sample consisted of 11 nurse specialists, 47 ward managers, 56 nursing officers, 110 registered nurses and 15 doctors (n=239). RESULTS: The results showed that there were significant differences in the perceptions of importance of the administration, clinical practice, education and research roles, and the frequency of occurrence of the clinical practice and research roles. This was further verified by the Fisher's Least Significant Differences (LSD) test. CONCLUSIONS: A regulatory system of the nurse specialist was recommended to monitor the development of the nurse specialist role and practice and to ensure the safety of the public with regard to the emerging role. Both the implications and limitations are discussed.

Differentiation of recurrent nasopharyngeal carcinoma and skull base osteoradionecrosis by Epstein-Barr virus-derived latent membrane protein-1 gene.

OBJECTIVES: In patients with nasopharyngeal carcinoma (NPC), the differentiation between recurrent primary cancer and osteoradionecrosis (ORN) is clinically difficult. Epstein-Barr virus (EBV)-derived latent membrane protein-1 (LMP-1) has been demonstrated to be highly associated with NPC. The objective of this study is to define the role of the LMP-1 gene in the differential diagnosis of recurrent NPC and ORN. STUDY DESIGN: Prospective. METHODS: From July 1998 to June 2000, 15 postirradiated patients with NPC who were initially diagnosed to have skull base ORN underwent endoscopic sequestrectomy. The sequestra were examined for the presence of the LMP-1 gene and cancer. RESULTS: Two of 15 patients had recurrent cancer and only these two patients demonstrated a positive LMP-1 gene in their surgically removed sequestra. The presence of the LMP-1 gene in the sequestrum coincided with biopsy-proven local recurrence. CONCLUSIONS: The LMP-1 gene is a potential marker to differentiate between recurrent NPC and ORN. The presence of the LMP-1 gene in patients with ORN may indicate local recurrence.

Endoscopic excision of benign tumors in the forehead and brow.

Twenty-five cases of benign tumor of the forehead and brow were excised successfully with endoscope-assisted surgery. The access incision was selected strategically behind the front hairline. For tumors in the middle of the forehead, the tumor was approached by subgaleal dissection. For those in the brow or temporal area, the dissection plane was just superficial to the deep temporal fascia. Patient age ranged from 3 to 59 years. The mass varied in size from 1.0 x 0.5 to 2.0 x 2.0 cm. There were 18 lipomas, 6 dermoid cysts, and 1 pilomatricoma. There was no residual mass or recurrence 1 to 24 months postoperatively. There was no paresthesia or numbness in the scalp. Patients and their families were greatly satisfied with this operation and the absence of visible scarring.

Seizure outcomes after anterior callosotomy in patients with posterior-dominant and with anterior-dominant epileptiform discharges.

OBJECTS: We wished to find whether there was any difference in the postoperative seizure outcome between patients with bisynchronous anterior-dominant and those with posterior-dominant EDs after anterior callosotomy. METHODS: Seizure outcomes after anterior callosotomy in 7 patients with bisynchronous posterior-dominant epileptiform discharges and in 54 patients with anterior-dominant seizures were compared. All 61 cases had been followed up for more than 2 years after operation. One patient (14.3%) had become seizure free. Two patients (28.6%) had more than 50% reduction in seizure frequency, but 4 patients (57.2%) showed no improvement at all. The percentage of cases with significant improvement (more than 50% reduction of seizure frequency) was 43% (3 in 7), which is lower than in the patients with bisynchronous anterior-dominant EDs (64.8%). CONCLUSIONS: Our preliminary results suggest that anterior partial callosotomy could still be helpful in cases with bisynchronous posterior-dominant epileptiform discharges but the prognosis may be less optimistic than for those with anteriorly located discharges.