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Trismus/reduced mouth opening (RMO) is a common side effect of radiotherapy (RT) for head and neck cancer (HNC). The objective was to measure RMO, identify risk factors for RMO, and determine its impact on quality of life (QOL). OraRad is an observational, prospective, multicenter cohort study of patients receiving curative intent RT for HNC. Interincisal mouth opening measurements (n = 565) and patient-reported outcomes were recorded before RT and every 6 months for 2 years. Linear mixed-effects models were used to evaluate change in mouth opening and assess the relationship between trismus history and change in QOL measures. Interincisal distance decreased from a mean (SE) of 45.1 (0.42) mm at baseline to 42.2 (0.44) at 6 months, with slight recovery at 18 months (43.3, 0.46 mm) but no additional improvement by 24 months. The odds of trismus (opening <35 mm) were significantly higher at 6 months (odds ratio [OR] = 2.21, 95% CI: 1.30 to 3.76) and 12 months (OR = 1.87, 95% CI: 1.08 to 3.25) compared with baseline. Females were more likely to experience trismus at baseline and during follow-up (P <.01). Patients with oral cavity cancer had the highest risk for trismus at baseline and post-RT (P <.01). RMO was associated with higher RT dose to the primary site and receiving concomitant chemotherapy (P <.01). Trismus was associated with self-reported difficulty opening the mouth and dry mouth (P <.01). A decrease in mouth opening is a common treatment-related toxicity after RT, with some recovery by 18 months. Trismus has a significant impact on survivor QOL. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to examine effects of radiation therapy (RT) for head and neck cancer (HNC) on periodontal disease and relationships to caries.Study Design: A multicenter prospective observational cohort study (OraRad) was conducted in patients undergoing RT for HNC. Assessments were conducted by calibrated examiners at the pre-RT (baseline) visit (n = 533), the 12-month visit (n = 414), and the 24-month visit (n = 365).Results: The average whole mouth mean (standard error (SE)) distance from the cementoenamel junction to the gingival margin (CEJ-GM) decreased significantly from 0.43 (0.04) mm at baseline to 0.24 (0.04) mm at 12 months and 0.11 (0.04) mm at 24 months (P ≤ .001). Whole mouth mean (SE) percentage of sites with CEJ-GM distance of <0 mm increased significantly from 23.3% (1.0%) at baseline to 28.5% (1.0%) at 12 months and 30.5% (1.1%) at 24 months (P ≤ .02). Higher mean radiation dose to the mandible was associated with a greater increase in the percentage of mandibular sites with CEJ-GM distance of <0 mm (P = .003). Both mean CEJ-GM distance and the percentage of sites with a CEJ-GM distance <0 mm were strongly associated with whole mouth mean proportion of decayed, missing, and filled surfaces, as well as proportion of decayed or filled facial/buccal surfaces specifically, (P < .001), with greater gingival recession associated with increased caries.Conclusions: RT for HNC leads to mandibular gingival recession in a dose-dependent manner. This gingival recession may contribute to increased risk for cervical caries seen in these patients. [ABSTRACT FROM AUTHOR]

Tributaries provide spawning habitat for three of four major sub-stocks of Lake Erie walleye (Sander vitreus). Despite anthropogenic degradation and the extirpation of other potamodromous species, the Maumee River, Ohio, USA continues to support one of the largest fish migrations in the Laurentian Great Lakes. To determine if spawning habitat availability and quality could limit production of Maumee River walleye, two habitat suitability models were created for the lower 51 km of the Maumee River and the distribution and numbers of walleye eggs deposited in a 25 km stretch of river were assessed. Walleye eggs were collected using a diaphragm pump at 7 and 10 sites from March/April to May 2014 and 2015. The habitat suitability models showed that <3% of the river yielded 'good' walleye spawning habitat and 11–38% yielded 'moderate' walleye spawning habitat, depending on the model. However, a large set of rapids at river kilometer 28 and more than five river kilometers of less suitable habitat separated areas of 'good' habitat. The rapids may present a migratory barrier for many spawning walleye, as modeled water velocities exceed maximum estimated walleye swim speeds 71–100% of days during pre-spawn migration and spawning during the study period. In both study years, there was a sharp decline in mean egg numbers from spawning sites downstream of the rapids (439.7 eggs/2 min tow ± 990.6 SD) to upstream sites (5.9 eggs/2 min tow ± 19.4 SD). Physical barriers like rapids may reduce spawning habitat connectivity and could limit walleye production in the Maumee River. [ABSTRACT FROM AUTHOR]

G-protein–coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. In the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication among cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of more than one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have shown that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs and has shown opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Cancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that chronic cancer pain as well as high-dose opioid use lead to mu-opioid receptor downregulation. In this study we explore downregulation of the mu-opioid receptor gene (OPRM1), as a mechanism for opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high-dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on 2 main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons.Perspective: We demonstrate that epigenetic regulation of OPRM1 contributes to opioid tolerance in cancer patients, and that targeted gene therapy could treat cancer-induced nociception and opioid tolerance in a mouse cancer model. [ABSTRACT FROM AUTHOR]

The problem of classifying traffic flows in networks has become more and more important in recent times, and much research has been dedicated to it. In recent years, there has been a lot of interest in classifying traffic flows by application, based on the statistical features of each flow. Information about the applications that are being used on a network is very useful in network design, accounting, management, and security. In our previous work we proposed a classification algorithm for Internet traffic flow classification based on Artificial Immune Systems (AIS). We also applied the algorithm on an available data set, and found that the algorithm performed as well as other algorithms, and was insensitive to input parameters, which makes it valuable for embedded systems. It is also very simple to implement, and generalizes well from small training data sets. In this research, we expanded on the previous research by introducing several optimizations in the training and classification phases of the algorithm. We improved the design of the original algorithm in order to make it more predictable. We also give the asymptotic complexity of the optimized algorithm as well as draw a bound on the generalization error of the algorithm. Lastly, we also experimented with several different distance formulas to improve the classification performance. In this paper we have shown how the changes and optimizations applied to the original algorithm do not functionally change the original algorithm, while making its execution 50–60% faster. We also show that the classification accuracy of the Euclidian distance is superseded by the Manhattan distance for this application, giving 1–2% higher accuracy, making the accuracy of the algorithm comparable to that of a Naïve Bayes classifier in previous research that uses the same data set. [ABSTRACT FROM AUTHOR]

Chronic cancer pain is a serious complication of malignancy or its treatment. Currently, no comprehensive, universally accepted cancer pain classification system exists. Clarity in classification of common cancer pain syndromes would improve clinical assessment and management. Moreover, an evidence-based taxonomy would enhance cancer pain research efforts by providing consistent diagnostic criteria, ensuring comparability across clinical trials. As part of a collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) and the American Pain Society (APS), the ACTTION-APS Pain Taxonomy initiative worked to develop the characteristics of an optimal diagnostic system. After the establishment of these characteristics, a working group consisting of clinicians and clinical and basic scientists with expertise in cancer and cancer-related pain was convened to generate core diagnostic criteria for an illustrative sample of 3 chronic pain syndromes associated with cancer (ie, bone pain and pancreatic cancer pain as models of pain related to a tumor) or its treatment (ie, chemotherapy-induced peripheral neuropathy). A systematic review and synthesis was conducted to provide evidence for the dimensions that comprise this cancer pain taxonomy. Future efforts will subject these diagnostic categories and criteria to systematic empirical evaluation of their feasibility, reliability, and validity and extension to other cancer-related pain syndromes.Perspective: The ACTTION-APS chronic cancer pain taxonomy provides an evidence-based classification for 3 prevalent syndromes, namely malignant bone pain, pancreatic cancer pain, and chemotherapy-induced peripheral neuropathy. This taxonomy provides consistent diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms for these potentially serious cancer pain conditions that can be extended and applied with other cancer-related pain syndromes. [ABSTRACT FROM AUTHOR]

Chemically intensive crop production depletes wildlife food resources, hinders animal development, health, survival, and reproduction, and it suppresses wildlife immune systems, facilitating emergence of infectious diseases with excessive mortality rates. Gut microbiota is crucial for wildlife's response to environmental stressors. Its composition and functionality are sensitive to diet changes and environmental pollution associated with modern crop production. In this study we use shotgun metagenomics (median 8,326,092 sequences/sample) to demonstrate that exposure to modern crop production detrimentally affects cecal microbiota of sharp-tailed grouse (Tympanuchus phasianellus : 9 exposed, 18 unexposed and greater prairie chickens (T. cupido ; 11, 11). Exposure to crop production had greater effect on microbiota richness (t = 6.675, P < 0.001) and composition (PERMANOVA r 2 = 0.212, P = 0.001) than did the host species (t = 4.762, P < 0.001; r 2 = 0.070, P = 0.001) or their interaction (t = 3.449; r 2 = 0.072, both P = 0.001), whereas sex and age had no effect. Although microbiota richness was greater in exposed (T. cupido chao1 = 152.8 ± 20.5; T. phasianellus 115.3 ± 17.1) than in unexposed (102.9 ± 15.1 and 101.1 ± 17.2, respectively) birds, some beneficial bacteria dropped out of exposed birds' microbiota or declined and were replaced by potential pathogens. Exposed birds also had higher richness and load of virulome (mean ± standard deviation; T. cupido 24.8 ± 10.0 and 10.1 ± 5.5, respectively; T. phasianellus 13.4 ± 6.8/4.9 ± 2.8) and resistome (T. cupido 46.8 ± 11.7/28.9 ± 10.2, T. phasianellus 38.3 ± 16.7/18.9 ± 14.2) than unexposed birds (T. cupido virulome: 14.2 ± 13.5, 4.5 ± 4.2; T. cupido resistome: 31.6 ± 20.2 and 13.1 ± 12.0; T. phasianellus virulome: 5.2 ± 4.7 and 1.4 ± 1.5; T. phasianellus resistome: 13.7 ± 16.1 and 4.0 ± 6.4). [Display omitted] • Cropland grouse exhibit dysbiosis and elevated virulence and antibiotic resistance. • Crop production similarly affects microbiota in both study species. • Crop production affects microbiota to a greater extent than host species. • Naturally distinct microbiotas of study species converge in croplands. • Sex or age of grouse do not affect cecal microbiota, virulome, or resistome. [ABSTRACT FROM AUTHOR]

Interindividual variability exists in persistent breast pain following breast cancer surgery. Recently, we used growth mixture modeling to identify 3 subgroups of women (N = 398) with distinct persistent breast pain trajectories (ie, mild, moderate, severe) over 6 months following surgery. The purposes of this study were to identify demographic and clinical characteristics that differed among the breast pain classes and, using linear mixed effects modeling, to examine how changes over time and in sensitivity in the breast scar area, pain qualities, pain interference, and hand and arm function differed among these classes. Several demographic and clinical characteristics differentiated the breast pain classes. Of note, 60 to 80% of breast scar sites tested were much less sensitive than the unaffected breast. Significant group effects were observed for pain qualities and interference scores, such that, on average, women in the severe pain class reported higher scores than women in the moderate pain class. In addition, women in the moderate pain class reported higher scores than women in the mild pain class. Compared to women in the mild pain class, women in the severe pain class had significantly impaired grip strength, and women in the moderate and severe pain classes had impaired flexion and abduction. Perspective Subgroups of women with persistent postsurgical breast pain differed primarily with respect to the severity rather than the nature or underlying mechanisms of breast pain. Pervasive sensory loss and the association between persistent breast pain and sustained interference with function suggest the need for long-term clinical follow-up. [ABSTRACT FROM AUTHOR]

Abstract: Plexiform schwannoma is a soft tissue tumor that rarely presents in the lower extremity. We have reported on 2 cases of plexiform schwannomas that occurred in the foot and ankle. Owing to the relative obscurity of this condition in the lower extremity, we have also provided an overview of plexiform schwannomas and discussed the differences between this and other suspicious nodular soft tissue masses. The first patient was a 38-year-old female, who had a soft tissue mass located on the lateral aspect of her right foot that became symptomatic. The second patient was an 11-year-old male, who had a symptomatic soft tissue mass on the plantar aspect of his right foot. Both patients underwent surgical excision of the tumor. [Copyright &y& Elsevier]

Abstract: Persistent pain following breast cancer surgery is a significant clinical problem. Although immune mechanisms may play a role in the development and maintenance of persistent pain, few studies have evaluated for associations between persistent breast pain following breast cancer surgery and variations in cytokine genes. In this study, associations between previously identified extreme persistent breast pain phenotypes (ie, no pain vs severe pain) and single nucleotide polymorphisms (SNPs) spanning 15 cytokine genes were evaluated. In unadjusted analyses, the frequency of 13 SNPs and 3 haplotypes in 7 genes differed significantly between the no pain and severe pain classes. After adjustment for preoperative breast pain and the severity of average postoperative pain, 1 SNP (ie, interleukin [IL] 1 receptor 2 rs11674595) and 1 haplotype (ie, IL10 haplotype A8) were associated with pain group membership. These findings suggest a role for cytokine gene polymorphisms in the development of persistent breast pain following breast cancer surgery. Perspective: This study evaluated for associations between cytokine gene variations and the severity of persistent breast pain in women following breast cancer surgery. Variations in 2 cytokine genes were associated with severe breast pain. The results suggest that cytokines play a role in the development of persistent postsurgical pain. [Copyright &y& Elsevier]

Purpose: Surgical resection of midface neoplasms and subsequent reconstruction have been shown to have significant negative effects on quality of life (QOL). The purpose of this pilot study was to assess individuals' health-related QOL after maxillectomy and reconstruction with a prosthetic obturator. Materials and Methods: The QOL of 25 of 43 patients who underwent maxillectomy and prosthetic obturator reconstruction at the University of California–San Francisco was assessed using 3 questionnaires: University of Washington Quality of Life version 4 (UWQOL), Obturator Functioning Scale (OFS), and Mental Health Inventory (MHI). Results: The response rate to the QOL questionnaires was 92% (23 of 25 patients). Time elapsed from maxillectomy and prosthetic obturator reconstruction to the QOL survey response ranged from 0.3 to 6.6 years (mean, 2.7 years; standard deviation [SD], 1.9 years). The post-treatment mean QOL scores were 77.3 (SD, 13.6) for UWQOL, 72.0 (SD, 12.6) for OFS, and 4.5 (SD, 0.9) for Mental Health Inventory. Individuals who received adjuvant radiation scored lower for speech and appearance (OFS, P = .05, P = .03, respectively) as well as for saliva and overall QOL (UWQOL, P = .02, P = .08, respectively). There was a strong correlation between QOL scores in OFS and UWQOL questionnaires (r = 0.78, P < .001). Conclusion: The results of this pilot study suggest that postoperative radiation therapy was the strongest variable affecting QOL in patients with maxillectomy and prosthetic obturator reconstruction. There is further need for a multicenter trial with a larger sample to identify how factors affecting QOL of patients after maxillectomy might influence the choice of reconstruction. [Copyright &y& Elsevier]

Abstract: Study purposes were to determine the prevalence of persistent pain in the breast; characterize distinct persistent pain classes using growth mixture modeling; and evaluate for differences among these pain classes in demographic, preoperative, intraoperative, and postoperative characteristics. In addition, differences in the severity of common symptoms and quality of life outcomes measured prior to surgery, among the pain classes, were evaluated. Patients (n = 398) were recruited prior to surgery and followed for 6 months. Using growth mixture modeling, patients were classified into no (31.7%), mild (43.4%), moderate (13.3%), and severe (11.6%) pain groups based on ratings of worst breast pain. Differences in a number of demographic, preoperative, intraoperative, and postoperative characteristics differentiated among the pain classes. In addition, patients in the moderate and severe pain classes reported higher preoperative levels of depression, anxiety, and sleep disturbance than the no pain class. Findings suggest that approximately 25% of women experience significant and persistent levels of breast pain in the first 6 months following breast cancer surgery. Perspective: Persistent pain is a significant problem for 25% of women following surgery for breast cancer. Severe breast pain is associated with clinically meaningful decrements in functional status and quality of life. [Copyright &y& Elsevier]

Posterior tongue defects present a unique reconstructive challenge. The various reconstructive options available for treating the defect created by a posterior hemiglossectomy frequently result in a distorted tongue and functional impairment. This paper describes a novel sliding anterior hemitongue flap to allow reconstruction of moderate resection defects (i.e. for T1-T2 tongue squamous cell carcinomas) of the posterior tongue. By mobilizing the anterior tongue, near normal mobility and tongue length are maintained. This surgical technique may be performed alone intraorally or in combination with a neck dissection. [ABSTRACT FROM AUTHOR]

Purpose: To compare vascularity and angiogenic activity in aggressive and nonaggressive giant cell lesions (GCLs) of the jaws. Materials and Methods: This is a retrospective study of 14 GCLs treated at the University of California, San Francisco. Immunohistochemistry was used to determine of the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), CD34, and CD31. VEGF and bFGF expression in giant cells (GCs) and surrounding mononuclear stroma was classified into 1) high immunoreactivity (>50% staining) and 2) low immunoreactivity (<50% staining). CD31- and CD34-stained vessels were counted at 200× magnification. Clinical and radiographic records were reviewed to classify lesions as aggressive or nonaggressive. Results: Of the lesions, 8 were aggressive and 6 were nonaggressive. High VEGF expression was found within the GCs in 4 of 8 aggressive lesions compared with 1 of 6 nonaggressive lesions. The stroma in both groups had low staining. High staining of the GCs for bFGF was found in 6 of 8 aggressive lesions compared with 3 of 6 nonaggressive lesions. The stroma of all aggressive cases showed high expression of bFGF compared with 3 of 6 nonaggressive cases. The aggressive group had a mean of 20.1 ± 5.4 vessels/high-powered field (hpf) stained for CD31 compared with 11.5 ± 5.6 vessels/hpf in the nonaggressive group. The aggressive group had 24.6 ± 7.0 vessels/hpf stained with CD34 compared with 18.5 ± 4.0 vessels/hpf in the nonaggressive group. Conclusions: The vascularity and level of angiogenesis within aggressive GCLs are higher than those in nonaggressive lesions. [Copyright &y& Elsevier]

Abstract: Cancer patients often suffer from pain and most will be prescribed μ-opioids. μ-opioids are not satisfactory in treating cancer pain and are associated with multiple debilitating side effects. Recent studies show that μ and δ opioid receptors are separately expressed on IB4 (−) and IB4 (+) neurons, which control thermal and mechanical pain, respectively. In this study we investigated IB4 (+) and IB4 (−) neurons in mechanical and thermal hypersensitivity in an orthotopic mouse oral cancer model. We used a δ opioid receptor agonist and a P2X3 antagonist to target IB4 (+) neurons and to demonstrate that this subset plays a key role in cancer-induced mechanical allodynia, but not in thermal hyperalgesia. Moreover, selective removal of IB4 (+) neurons using IB4-saporin impacts cancer-induced mechanical but not thermal hypersensitivity. Our results demonstrate that peripherally administered pharmacological agents targeting IB4 (+) neurons, such as a selective δ-opioid receptor agonist or P2X3 antagonist, might be useful in treating oral cancer pain. Perspective: To clarify the mechanisms of oral cancer pain, we examined the differential role of IB4 (+) and IB4 (−) neurons. Characterization of these 2 subsets of putative nociceptors is important for further development of effective clinical cancer pain relief. [Copyright &y& Elsevier]

Abstract: The purposes of this study were to determine the occurrence rate for preoperative breast pain; describe the characteristics of this pain; evaluate for differences in demographic and clinical characteristics; and evaluate for variations in pro- and anti-inflammatory cytokine genes between women who did and did not report pain. Patients (n = 398) were recruited prior to surgery and completed self-report questionnaires on a number of pain characteristics. Genotyping was done using a custom genotyping array. Women (28.2%) who reported breast pain were significantly younger (P < .001); more likely to be nonwhite (P = .032); reported significantly lower Karnofsky Performance Status scores (P = .008); were less likely to be postmenopausal (P = .012); and had undergone significantly more biopsies (P = .006). Carriers of the minor allele for a single nucleotide polymorphism in interleukin (IL)1-receptor 1 (IL1R1) (rs2110726) were less likely to report breast pain prior to surgery (P = .007). Carriers of the minor allele for a single nucleotide polymorphism in IL13 (rs1295686) were more likely to report breast pain prior to surgery (P = .019). Findings suggest that breast pain occurs in over a quarter of women who are about to undergo breast cancer surgery. Based on phenotypic and genotypic characteristics found, inflammatory mechanisms contribute to preoperative breast pain. Perspective: In women with breast cancer, preoperative pain may be associated with increases in inflammatory responses associated with an increased number of biopsies. In addition, differences in cytokine genes may contribute to this preoperative breast pain. [Copyright &y& Elsevier]

Abstract: We previously reported that endothelin A (ET-A) receptor antagonism attenuates carcinoma-induced pain in a cancer pain mouse model. In this study, we investigated the mechanism of ET-A receptor-mediated antinociception and evaluated the role of endogenous opioid analgesia. Squamous cell carcinoma (SCC) cell culture treated with the ET-A receptor antagonist (BQ-123) at 10−6 M and 10−5 M significantly increased production and secretion of β-endorphin and leu-enkephalin, respectively. Behavioral studies were performed by inducing tumors in the hind paw of female nude mice with local injection of cells derived from a human oral SCC. Significant pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, began at 4 days after SCC inoculation and lasted to 18 days, the last day of measurement. Local administration of either naloxone methiodide (500 μg/kg), selective antagonists for μ-opioid receptor (CTOP, 500 μg/kg), or δ-opioid receptor (naltrindole, 11 mg/kg) but not κ-opioid receptor (nor-BNI, 2.5 mg/kg) significantly reversed antinociception observed from ET-A receptor antagonism (BQ-123, 92 mg/kg) in cancer animals. These results demonstrate that antagonism of peripheral ET-A receptor attenuates carcinoma pain by modulating release of endogenous opioids to act on opioid receptors in the cancer microenvironment. Perspective: This article proposes a novel mechanism for ET-A receptor antagonist drugs in managing cancer-induced pain. An improved understanding of the role of innate opioid analgesia in ET-A receptor–mediated antinociception might provide novel alternatives to morphine therapy for the treatment of cancer pain. [Copyright &y& Elsevier]

Purpose: Perineural invasion (PNI) in oral squamous cell carcinoma (SCC) is recognized as a significant predictor of outcome. PNI is associated with locoregional recurrence and decreased survival of patients with head and neck SCC. Nerve growth factor (NGF) has been shown to be involved in PNI in several malignancies, including breast, prostate, and pancreatic cancers. We investigated the hypothesis that NGF and its high-affinity receptor tyrosine kinase A (TrkA) are highly expressed in cases of oral SCC that have histologic evidence of PNI. Materials and Methods: We performed immunohistochemistry on archived oral tongue SCC specimens from the established oral and general pathology databases at the University of California, San Francisco. The following groups were evaluated: 1) 21 T1/T2 oral tongue SCC cases with PNI and 2) 21 T1/T2 oral tongue SCC cases without histologic evidence of PNI. Results: Strong homogeneous cytoplasmic staining for NGF and TrkA was detected in the malignant cells in the PNI-positive group of tumors. In group II (PNI negative) NGF and TrkA were detected in the stroma cells or were very weakly expressed by the malignant cells. We were able to show the presence of NGF and TrkA in the cytoplasm of malignant squamous cells in tumors with histologic evidence of PNI. Immunostaining for NGF (P = .0001) and TrkA (P = .039) was significantly higher in the PNI-positive oral SCC group than in the PNI-negative oral SCC group. Conclusion: This study shows that oral SCC with evidence of PNI shows increased expression of NGF and TrkA and suggests that NGF and TrkA are involved with the mechanism leading to PNI. Further investigations are warranted to determine the potential for use of NGF and TrkA as candidate biomarkers to predict progression and outcome. [Copyright &y& Elsevier]

Objectives: Acute respiratory tract infections represent a significant burden on pediatric emergency departments (ED) and families. We hypothesized that early and rapid diagnosis of a viral infection alleviates the need for ancillary testing and antibiotic treatment. Study design: We conducted a randomized, controlled trial of children 3 to 36 months of age with febrile acute respiratory tract infections at a pediatric ED. Two hundred four subjects were randomly assigned to receive rapid respiratory viral testing on admission or a routine ED admission protocol. Outcome measures were: mean length of visits, rate of ancillary tests, and antibiotic prescription in the ED. A follow-up call was made to all study subjects to inquire about further healthcare visits, ancillary testing, and antibiotic prescription after ED discharge. Results: We did not find a statistically significant difference in ED length of visits, rate of ancillary testing, or antibiotic prescription rate in the ED between the study groups. There was, however, a significant reduction in antibiotic prescription after ED discharge (in the group who had rapid viral testing RR = 0.36; 95% CI = 0.14, 0.95). Conclusions: Rapid multi-viral testing in the ED did not significantly affect ED patient treatment but may reduce antibiotic prescription in the community after discharge from the ED, suggesting a novel strategy to alter community physician antibiotic prescription patterns. [Copyright &y& Elsevier]

Purpose: Head and neck neoplasms requiring surgical resection of the mandible can have negative consequences on patient quality of life. For patients with segmental resections, the vascularized fibular free flap and nonvascularized iliac crest are frequently used. The fibula has surpassed the iliac crest in popularity due to the success associated with a vascularized graft; however, there still remain significant advantages with the nonvascularized graft. There has not been a study comparing the quality of life associated with these two methods of mandibular reconstruction. We carried out the following study to compare quality of life of both grafts in an attempt to help guide therapeutic decisions. Patients and Methods: Twenty-nine patients at the University of California, San Francisco undergoing mandibular resection with subsequent reconstruction with either a vascularized fibular free flap or nonvascularized iliac crest bone graft were identified. Patient quality of life was assessed with a modified version of the University of Washington Quality of Life Questionnaire, version 4. Results: Eighteen patients responded (10 reconstructed previously with a fibula, 8 with iliac crest reconstructions). Patients with an iliac crest bone graft had significantly better chewing and swallowing scores (P = .04, P = .049 respectively). There was also a trend for better taste (P = .067). When patients with a history of radiation therapy were excluded, differences in chewing and swallowing were not significant (P = .26 and P = .31 respectively), whereas taste was (P = .038). Conclusions: These findings suggest that reconstruction with the iliac crest had benefits in improved function (chewing, swallowing, and taste) rather than esthetics, donor site morbidity, or psychologic discomfort as was anticipated. However, prior radiation, a relatively frequent therapy in this patient population, presents an important confounding factor. Radiation therapy is difficult to control for without limiting an already scarce patient pool, and bears with it significant morbidity that likely influenced these findings. Further study is warranted to confirm the results and further distinguish the 2 groups. [Copyright &y& Elsevier]

Purpose: Squamous cell carcinomas of the hard palate, maxillary gingiva, and maxillary alveolus occur at relatively low rates compared with squamous cell carcinomas in other oral sites. There is little within the surgical literature to guide treatment for maxillary squamous cell carcinoma. To date, only 1 other group has addressed neck management in the oral maxillary squamous cell carcinoma patient presenting with a clinically negative neck. Adequate characterization of maxillary gingival carcinoma behavior with respect to regional cervical metastasis is wanting. Patients and Methods: We present a retrospective review of our own clinical experience as well as a review of the existing literature. Results: In our University of California San Francisco patient group, cervical disease was detected in 20% of those individuals with maxillary squamous cell carcinoma presenting for initial consultation. After ablative surgery, those individuals who presented with clinically negative necks had a 21.4% rate of regional node metastasis. Ultimately, 50% of our patients with squamous cell carcinomas of the palate, maxillary gingiva, and maxillary alveolus developed regional or metastatic distant disease; 42.9% of the patients manifested disease to the cervical lymph nodes alone. Conclusions: The cases of oral maxillary squamous cell carcinomas reviewed herein exhibit aggressive regional metastatic behavior comparable to that of such carcinomas of the tongue, floor of the mouth, and mandibular gingiva. Based on the findings presented herein, we recommend selective neck dissection in the setting of a clinically negative neck as a primary management strategy for patients with oral maxillary squamous cell carcinomas involving the palate, maxillary gingiva, and maxillary alveolus. [Copyright &y& Elsevier]

Purpose: Resecting oral squamous cell carcinoma (SCC) with an appropriate margin of uninvolved tissue is critical in preventing local recurrence and making the decision regarding postoperative radiation therapy. This task can be difficult due to the discrepancy between margins measured intraoperatively and those measured microscopically by the pathologist after specimen processing. The goal of this study is to quantify and compare the amount of margin discrepancy observed based on tumor location and staging. Materials and Methods: Forty-one patients who underwent resective surgery with curative intent for primary oral SCC were included in this study. All patients underwent resection of the tumor with a measured 1 cm margin by one attending surgeon. Specimens were then submitted for processing and reviewing and histopathologic margins were measured. The closest histopathologic margin was compared with the in situ margin (1 cm) to determine percentage discrepancy. Percent discrepancies were grouped by locations (buccal mucosa, mandibular alveolar ridge, and retromolar trigone in group 1; maxillary alveolar ridge and palate in group 2; and oral tongue in group 3) and analyzed. Percent discrepancies grouped by stages T1/T2 or T3/T4 were compared. Results: The mean discrepancy for all patients was a statistically significant 59.02% (P < .0001). The mean discrepancy was 71.90% for group 1, 53.33% for group 2, and 42.14% for group 3 (P = .0133). The mean discrepancy in T1/T2 tumors was 51.48% and in T3/T4 tumors was 75.00% (P = .0264). Conclusions: Oral SCC margin discrepancies after resection and specimen processing are highly significant. Tumors located in the buccal mucosa, retromolar trigone, and mandibular alveolar ridge show significantly greater discrepancies than tumors of the maxilla or oral tongue. Late stage tumors also show significantly greater margin discrepancies. These findings suggest that it might be prudent to consider oral site and staging when outlining margins to ensure adequacy of resection. [Copyright &y& Elsevier]

Abstract: The aim of this study was to validate the published University of California San Francisco (UCSF) Oral Cancer Pain Questionnaire. To test for validity of the questionnaire, 16 patients with oral cancer completed the 8-item questionnaire immediately before and after treatment (surgical resection) of their oral cancer. For all 8 questions, the difference between mean preoperative and mean postoperative responses were statistically significant (P < .05), confirming the validity of the questionnaire to measure oral cancer pain. Internal consistency of the questionnaire was evaluated by using Cronbach’s α, which provides an estimate of reliability based on all correlations between the items (questions) of the instrument (questionnaire). In the oral cancer pain questionnaire, questions 1, 3, and 5 evaluate the intensity, sharpness, and throbbing nature of pain when the patient is not engaged in oral function (talking, eating, and drinking). Questions 2, 4, and 6 measure the intensity, sharpness, and throbbing nature of pain during oral function. Cronbach’s α for questions 1, 3, and 5 is 0.87 and Cronbach’s α for questions 2, 4, and 6 is 0.94; values greater than 0.7 indicate reliability. In this study, we have validated the UCSF Oral Cancer Pain Questionnaire as an effective tool in quantifying pain from oral cancer. Perspective: The study validates an oral cancer pain questionnaire. The questionnaire can be used to reliably measure pain levels before and after surgical resection in patients with oral cancer. [Copyright &y& Elsevier]

Purpose: The workup for oral malignancy involving the mandible typically involves a head and neck exam, laboratory studies, a panoramic radiograph, and computed tomography (CT) or magnetic resonance imaging of the head and neck to evaluate the primary lesion and cervical lymph nodes. Panoramic plain film radiography of the mandible is often unreliable for detecting bony invasion; therefore, other imaging studies are necessary before staging is complete. Bony invasion is typically imaged with the use of conventional CT scanners. In this article we relate the use of cone beam computed tomography (CBCT) to image the mandible with less cost and morbidity to the patient and its use in the evaluation and treatment planning of mandibular cancer. Materials and Methods: A retrospective review of 3 patients with mandibular malignancies was performed. All patients had a panoramic radiograph, magnetic resonance imaging, and chest radiograph, in addition to laboratory studies. CBCT scans were ordered, after bony involvement was suspected, and compared with the other imaging studies. Results: Two patients with squamous cell carcinoma of anterior mandible and 1 patient with osteogenic sarcoma were reviewed. In all cases CBCT aided the evaluation of the mandible. The cone beam panoramic view, as part of the CBCT, was used to determine extent of resection. Conclusion: CBCT can accurately aid in evaluating and treatment planning for malignant tumors of the mandible with less cost and decreased radiation to the patient relative to conventional CT. [Copyright &y& Elsevier]

Purpose: The treatment of locally aggressive lesions of the mandible can have a profound effect on a patient’s quality of life (QOL), both functionally and psychologically. The more knowledge available on this subject, the better a patient can be prepared and counseled. Patients and Methods: Patients undergoing mandibular resection with immediate insertion of a reconstruction plate and subsequent staged reconstruction for the management of locally aggressive lesions of the mandible at the University of California at San Francisco were studied over a 6-year period from 1999 to 2005. The staged reconstruction involved bone grafting, removal of the reconstruction plate, vestibuloplasty, implant insertion, and construction of an implant-supported prosthesis. Each patient completed a modified University of Washington Quality of Life version 4 questionnaire after reaching his or her highest level of reconstruction. Results: A total of 26 patients were identified as fulfilling the criteria for this study. Eight patients did not progress beyond resection, bone grafting, and subsequent removal of the bone plate. Seven patients progressed all the way through the 7 stages to an implant-supported prosthesis. The most important determinants of the patient’s subsequent QOL were time interval from initial resection and stage of reconstruction; the greater the time interval from initial resection and the further the stage of reconstruction reached, the better the QOL. Resections involving the mandibular angle had a negative effect on appearance, and resections involving the parasymphysis and symphysis region carried a worse overall QOL, possibly due to difficulty with chewing and lip support. Males reached a higher overall QOL than females. Although most patients seemed satisfied with their overall QOL, 73% had some concerns regarding appearance, 42% had concerns with chewing, 42% had concerns regarding their mood, 35% felt more anxious since the surgery, 23% had some residual pain and discomfort, 19% had concerns with swallowing, and 15% had concerns with taste. Conclusion: These and other findings necessitate further investigation and confirmation. [Copyright &y& Elsevier]

Purpose: The aim of this study was to review and describe techniques for the reconstruction of large, complex perioral defects after resection of oral squamous cell carcinoma with emphasis on cosmetic and functional outcome. Patients and Methods: A review of techniques and selected case presentations using different flap designs for the reconstruction of large perioral defects following resection of squamous cell carcinoma was performed. The Bernard and Karapandzic flaps were used for large lower lip defects. A Zisser flap technique was used to reconstruct a large commissure defect. Results: All reconstructed patients had acceptable functional results and healed without complication. The large lower lip defects were easily closed with the Bernard and Karapandzic flaps. The commissure defect was reconstructed using the Zisser technique. While cosmesis was acceptable in all cases, the commissure was the most difficult region to reconstruct with a favorable appearance. There were no flap failures. The Karapandzic flap led to greater rounding of the commissure area and the composite resection resulted in a lack of lower lip support that was improved with prosthesis. Function was noted to be excellent in the Bernard and Karapandzic flaps, with the patients able to purse lips and blow up balloon-type devices. Conclusion: The Bernard, Karapandzic, and Zisser flaps provide a predictable method to reconstruct large perioral defects following resection for oral cancer. Subsequent fabrication of a prosthesis can aid in lip support for the resected area. [Copyright &y& Elsevier]

• Nanoparticle based drug delivery devices allow for targeted pain treatment with enhanced therapeutic efficacy. • Gene therapy allows for long term pain treatment using both viral and nonviral vectors. • Pro-active scavenging of overproduced molecules using immunomodulatory nanomaterials can reduce pain. [Display omitted] Pain is one of the most common medical conditions and affects more Americans than diabetes, heart disease, and cancer combined. Current pain treatments mainly rely on opioid analgesics and remain unsatisfactory. The life-threatening side effects and addictive properties of opioids demand new therapeutic approaches. Nanomedicine may be able to address these challenges as it allows for sensitive and targeted treatments without some of the burdens associated with current clinical pain therapies. This review discusses the physiology of pain, the current landscape of pain treatment, novel targets for pain treatment, and recent and ongoing efforts to effectively treat pain using nanotechnology-based approaches. We highlight advances in nanoparticle-based drug delivery to reduce side effects, gene therapy to tackle the source of pain, and nanomaterials-based scavenging to proactively mediate pain signaling. [ABSTRACT FROM AUTHOR]

Oral cancers are often severely painful and clinically difficult to manage. Few researchers have investigated the neurobiologic factors responsible for cancer pain; however, the study of oral cancer pain might inform us about the fundamental biology of cancer. The purpose of the present report was to summarize the clinical challenges inherent in oral cancer pain management, oral cancer pain mechanisms and mediators, and the convergence of the investigation of carcinogenesis and pain. [ABSTRACT FROM AUTHOR]