Neuronal-immune axis alters pain and sensory afferent damage during dental pulp injury.

ABSTRACT: Dental pulp tissue is densely innervated by afferent fibers of the trigeminal ganglion. When bacteria cause dental decay near the pulpal tissue, a strong neuronal and immune response occurs, creating pulpitis, which is associated with severe pain and pulp tissue damage. Neuroimmune interactions have the potential to modulate both the pain and pathological outcome of pulpitis. We first investigated the role of the neuropeptide calcitonin gene-related peptide (CGRP), released from peptidergic sensory afferents, in dental pain and immune responses by using Calca knockout (Calca -/- ) and wild-type (Calca +/+ ) mice, in a model of pulpitis by creating a mechanical exposure of the dental pulp horn. We found that the neuropeptide CGRP, facilitated the recruitment of myeloid cells into the pulp while also increasing spontaneous pain-like behavior 20% to 25% at an early time point. Moreover, when we depleted neutrophils and monocytes, we found that there was 20% to 30% more sensory afferent loss and increased presence of bacteria in deeper parts of the tissue, whereas there was a significant reduction in mechanical pain response scores compared with the control group at a later time point. Overall, we showed that there is a crosstalk between peptidergic neurons and neutrophils in the pulp, modulating the pain and inflammatory outcomes of the disease.

The value of the International Association for the Study of Pain to career development: perspectives of trainee and early career members.

ABSTRACT: Supporting its young members has been a key priority of the International Association for the Study of Pain (IASP) for the past 5 decades. The IASP, along with its federations, chapters, and special interest groups, has provided benefits to its trainee and early career members for their career development. This article summarizes various key IASP initiatives and benefits offered to IASP members and how these benefits have positively impacted their careers, including examples from the authors of this article. Suggestions are made for future directions that the IASP could implement to enhance the value provided to its trainee and early career members, which will in turn contribute to IASP achieving its mission to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide.

Dynamics of Innate Immune Response in Bacteria-Induced Mouse Model of Pulpitis.

INTRODUCTION: During pulpitis, as bacteria penetrate deeper into the dentin and pulp tissue, a pulpal innate immune response is initiated. However, the kinetics of the immune response, how this relates to bacterial infiltration during pulpitis and an understanding of the types of immune cells in the pulp is limited. METHODS: Dental pulp exposure in the molars of mice was used as an animal model of pulpitis. To investigate the kinetics of immune response, pulp tissue was collected from permanent molars at different time points after injury (baseline, day 1, and day 7). Flow cytometry analysis of CD45+ leukocytes, including macrophages, neutrophils monocytes, and T cells, was performed. 16S in situ hybridization captured bacterial invasion of the pulp, and immunohistochemistry for F4/80 investigated spatial and morphological changes of macrophages during pulpitis. Data were analyzed using two-way ANOVA with Tukey's multiple comparisons. RESULTS: Bacteria mostly remained close to the injury site, with some expansion towards noninjured pulp horns. We found that F4/80+ macrophages were the primary immune cell population in the healthy pulp. Upon injury, CD11b + Ly6Ghigh neutrophils and CD11b + Ly6GintLy6Cint monocytes constituted 70-90% of all immune populations up to 7 days after injury. Even though there was a slight increase in T cells at day 7, myeloid cells remained the main drivers of the immune response during the seven-day time period. CONCLUSIONS: As bacteria proliferate within the pulp chamber, innate immune cells, including macrophages, neutrophils, and monocytes, predominate as the major immune populations, with some signs of transitioning to an adaptive immune response.

Lipopolysaccharide-Induced TRPA1 Upregulation in Trigeminal Neurons is Dependent on TLR4 and Vesicular Exocytosis.

Pain from bacterial infection was believed to be the consequence of inflammation induced by bacterial products. However recent studies have shown that bacterial products can directly activate sensory neurons and induce pain. The mechanisms by which bacteria induce pain are poorly understood, but toll-like receptor (TLR)4 and transient receptor potential A1 (TRPA1) receptors are likely important integrators of pain signaling induced by bacteria. Using male and female mice we show that sensory neuron activation by bacterial lipopolysaccharides (LPS) is mediated by both TRPA1 and TLR4 and involves the mobilization of extracellular and intracellular calcium. We also show that LPS induces neuronal sensitization in a process dependent on TLR4 receptors. Moreover, we show that TLR4 and TRPA1 are both involved in sensory neurons response to LPS stimulation. Activation of TLR4 in a subset of sensory neurons induces TRPA1 upregulation at the cell membrane through vesicular exocytosis, contributing to the initiation of neuronal sensitization and pain. Collectively these data highlight the importance of sensory neurons to pathogen detection, and their activation by bacterial products like LPS as potentially important to early immune and nociceptive responses.SIGNIFICANCE STATEMENT Bacterial infections are often painful and the recent discovery that bacteria can directly stimulate sensory neurons leading to pain sensation and modulation of immune system have highlighted the importance of nervous system in the response to bacterial infection. Here, we showed that lipopolysaccharide, a major bacterial by-product, requires both toll-like receptor (TLR)4 and transient receptor potential A1 (TRPA1) receptors for neuronal activation and acute spontaneous pain, but only TLR4 mediates sensory neurons sensitization. Moreover, we showed for the first time that TLR4 sensitize sensory neurons through a rapid upregulation of TRPA1 via vesicular exocytosis. Our data highlight the importance of sensory neurons to pathogen detection and suggests that TLR4 would be a potential therapeutic target to modulate early stage of bacteria-induced pain and immune response.

Utilization of Circulating Tumor DNA in the Surveillance Setting.

INTRODUCTION: National guidelines give recommendations regarding cancer surveillance follow-up. In many early staged cancers radiographic imaging and labs are not routinely recommended unless patients are symptomatic. This can cause a gap in care because commonly when patients present symptomatically, they have progressed and transitioned to later-stage cancer. This study demonstrates how circulating tumor DNA (ctDNA) can be used alongside current guidelines to help screen patients for recurrence in the surveillance setting. METHODS: A retrospective chart review was performed. Fifty-five charts were reviewed of patients who received ctDNA testing drawn in follow-up after their primary tumor or metastatic disease was rendered surgically or radiographically disease-free. A customized signature profile, using the sixteen most prevalent genomic markers from a patient's primary tumor or biopsy, is developed by whole-exome sequencing. Serial blood draws are then drawn to assess for specific DNA markers using polymerase chain reaction (PCR) assays. RESULTS: Fifty-five charts were reviewed in patients who had stage I-III breast, pancreatic, melanoma, and colorectal cancer. Of the fifty-five, a total of seven had a positive test. Of the seven positive tests, six patients were found to have recurrent/metastatic disease. One positive test was performed four weeks postoperatively but by the second draw ten weeks postoperatively had non-detectable ctDNA. The remaining forty-eight patients had non-detectable ctDNA levels and to date have not had any evidence of recurrence based on standard follow-up guidelines. CONCLUSION: The utilization of ctDNA in the surveillance setting can be used to help detect recurrence in the surveillance setting.

Excess Growth Hormone Triggers Inflammation-Associated Arthropathy, Subchondral Bone Loss, and Arthralgia.

Growth hormone (GH) is a key mediator of skeletal growth. In humans, excess GH secretion due to pituitary adenoma, seen in patients with acromegaly, results in severe arthropathies. This study investigated the effects of long-term excess GH on the knee joint tissues. One year-old wild-type (WT) and bovine GH (bGH) transgenic mice were used as a model for excess GH. bGH mice showed increased sensitivity to mechanical and thermal stimuli, compared with WT mice. Micro-computed tomography analyses of the distal femur subchondral bone revealed significant reductions in trabecular thickness and significantly reduced bone mineral density of the tibial subchondral bone-plate associated with increased osteoclast activity in both male and female bGH compared with WT mice. bGH mice showed severe loss of matrix from the articular cartilage, osteophytosis, synovitis, and ectopic chondrogenesis. Articular cartilage loss in the bGH mice was associated with elevated markers of inflammation and chondrocyte hypertrophy. Finally, hyperplasia of synovial cells was associated with increased expression of Ki-67 and diminished p53 levels in the synovium of bGH mice. Unlike the low-grade inflammation seen in primary osteoarthritis, arthropathy caused by excess GH affects all joint tissues and triggers severe inflammatory response. Data from this study suggest that treatment of acromegalic arthropathy should involve inhibition of ectopic chondrogenesis and chondrocyte hypertrophy.

Elevated Cytokine Levels in Gingival Crevicular Fluid of Teeth with Apical Periodontitis.

INTRODUCTION: Biomarkers assayed from gingival crevicular fluid (GCF) are a potential tool for endodontic diagnosis and for monitoring treatment response. This cross-sectional study measured cytokines in GCF from teeth with apical periodontitis and evaluated their relationship with preoperative pain and other clinical findings. METHODS: Participants presenting for root-end resection surgery due to apical periodontitis diagnosis (n = 56) underwent standardized clinical testing and completed preoperative questionnaires. GCF from diseased and control teeth were collected, processed, and analyzed. Mann-Whitney U and Wilcoxon tests were used to examine the cytokine levels in diseased compared to healthy control teeth. We also assessed the relationship of cytokine levels with clinical findings. RESULTS: Interleukins (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ, and tumor necrosis factor-⍺ (TNF-⍺) were detected in GCF. TNF-⍺ levels were significantly higher in GCF collected from diseased versus control teeth (P = .02) and increased IL-1ß levels in diseased teeth were detected (P = .06). Lower IL-10 levels were observed in teeth with a sinus tract and/or swelling compared to teeth without a sinus tract and/or swelling (P = .08). Cytokine levels did not clearly relate to the presence of pain. CONCLUSIONS: Elevated levels of proinflammatory cytokines, including TNF-⍺ and IL1- ß, were detected in GCF from diseased teeth compared to the healthy controls. Additional studies are needed to further investigate the utility of these biomarkers for objectively evaluating periradicular pathology.

Contribution of Endodontic Pathology to Persistent Orofacial Pain: A Case Report.

Identifying the etiology and correct diagnoses for long-standing orofacial pain can be very challenging, especially in patients who have both odontogenic and nonodontogenic pain. This case report describes the successful management of a complex case of chronic orofacial pain in a patient with nonodontogenic chronic pain conditions and a maxillary molar tooth with persistent periapical pathology after endodontic treatment. The debilitating orofacial pain began after initial nonsurgical root canal treatment of the maxillary molar 3 years before presenting to our clinic. The initial clinical and radiographic assessment by our multidisciplinary team found that there were potentially both peripheral endodontic pathology and central pain mechanisms contributing to the long-standing pain. The diagnosis was shared with the patient's neurologist, who prescribed gabapentin, a centrally acting analgesic, and partial pain reduction was achieved. The odontogenic component of the orofacial pain was then addressed, by treating the persistent periapical infection and buccal bone fenestration of the roots of the maxillary molar. Treatments included both nonsurgical retreatment and surgical endodontic therapy (including root resection, root-end preparation, and retrofilling), and each significantly improved the patient's ongoing orofacial pain. After the successful endodontic treatments, the patient reported minimal pain and normal oral function. The case report highlights the importance of systematically treating endodontic pathology in a patient with long-standing orofacial pain, with both odontogenic and nonodontogenic components.

Patient Centered Outcomes among a Cohort Receiving Regenerative Endodontic Procedures or Apexification Treatments.

INTRODUCTION: This multicentered cohort study evaluated factors associated with patient-centered outcomes of immature permanent teeth that received regenerative endodontic procedures (REPs) or apexification treatment (APEX). METHODS: A record review identified teeth treated with REPs or APEX between September 2005 and December 2014. Data regarding treatment and patient-centered outcomes were extracted from records with a 3-month minimum recall. When possible, participants presented for an in-person prospective research visit. Patient-centered success was defined as an asymptomatic, functional tooth not requiring further endodontic or surgical intervention after completion of the original treatment during the study observation. Risk ratios and adjusted and unadjusted Cox proportional hazard ratios were calculated. RESULTS: The analytic cohort of 187 individuals included 211 teeth (93 REPs and 118 APEX) with an average follow-up of 32 months. Most cases were successful (81% REPs and 92% APEX) and survived the observation period (96% REPs and 97% APEX). The success rate of REPs was lower than APEX and decreased more rapidly over time. Cox regression analysis demonstrated that when controlling for other variables, the association between treatment type and outcome is not significant. Preoperative infection, teeth with more immature roots, and REP treatment are potentially important predictors. Among teeth receiving REPs, a lower failure rate was observed for teeth that received multiantibiotic paste (3/43) compared with calcium hydroxide (11/45). CONCLUSIONS: Teeth receiving REPs required clinical intervention earlier than teeth that received APEX treatment, although a preoperative abscess and more immature root also affected this outcome. Using multiantibiotic paste versus calcium hydroxide in REPs may improve success.

Outcomes of referrals from endodontic to orofacial pain specialists: A retrospective cohort study.

OBJECTIVES: Diagnosis and treatment of non-odontogenic pain is challenging for endodontists. The purpose of the study was to investigate the outcomes of referrals to orofacial pain specialists made for patients with suspected non-odontogenic pain, after evaluation and/or treatment by an endodontist. MATERIALS AND METHODS: A retrospective review of dental records was conducted for 60 patients referred from a postgraduate endodontic clinic to an orofacial pain clinic. Patient demographics, pain history, endodontic, and orofacial pain diagnoses were collected. Number of visits, length of treatment, and treatments prescribed were recorded. For analysis of outcomes, data pertinent to resolution/persistence of symptoms and patient compliance were analyzed. RESULTS: Thirty-five patients were included in the study. The most frequent pulpal and periapical diagnoses were previously treated (62%) and symptomatic apical periodontitis (72%), respectively. The most common orofacial pain diagnosis was temporomandibular disorder. The average time spent to diagnose and treat the pain was 17 months. Pain reduction varied and was documented for 51% of patients. Indications of non-compliance with orofacial pain appointments and treatments were documented for 66% of patients. CONCLUSIONS: Non-odontogenic pain diagnosis and treatment are challenging. Patients may have an increased predilection for developing persistent pain after endodontic treatment and/or have an undiagnosed, chronic orofacial pain condition as a true source of their chief complaint. It may be helpful for endodontists to set expectations of typical treatment times/plans when referring patients for evaluation and treatment of non-odontogenic pain.

Associations between Pain Severity, Clinical Findings, and Endodontic Disease: A Cross-Sectional Study.

INTRODUCTION: Thorough pain assessment and thermal and mechanical testing are the primary diagnostic tools used to assess the status of pulp and periapical tissues in teeth with potential endodontic pathology. This study evaluated predictors of acute odontogenic pain to better understand the relationship between endodontic pain, clinical testing, endodontic disease, and diagnoses. METHODS: Participants (N = 228) presenting with acute odontogenic pain underwent standardized clinical testing and reported their pain intensity. Univariate and multiple regression analyses were performed to evaluate the predictors of acute endodontic pain. Chi-square tests with Bonferroni adjustments were conducted to measure the frequency of endodontic diagnostic test findings and clinical observations in patients with different pulpal diagnoses. RESULTS: A negative response to cold stimulation on the causative tooth and percussion hypersensitivity on the healthy adjacent tooth were the strongest predictors of higher levels of acute endodontic pain. Percussion hypersensitivity on the healthy adjacent tooth was present in a quarter of the cohort and was reported with equal frequency in teeth diagnosed with irreversible pulpitis, necrotic pulp, and previously initiated/treated teeth. Although painful percussion on the causative tooth was more frequently reported in teeth diagnosed with necrotic pulp, painful palpation was more frequently reported on teeth diagnosed with previously initiated/treated teeth. CONCLUSIONS: Percussion hypersensitivity on the healthy adjacent tooth may reveal a lowered pain threshold and heightened pain sensitization. It is also possible that the 2 commonly performed mechanical sensory tests, percussion and palpation hypersensitivity, may detect different aspects of endodontic pathophysiology and pain processing.

Glia and Orofacial Pain: Progress and Future Directions.

Orofacial pain is a universal predicament, afflicting millions of individuals worldwide. Research on the molecular mechanisms of orofacial pain has predominately focused on the role of neurons underlying nociception. However, aside from neural mechanisms, non-neuronal cells, such as Schwann cells and satellite ganglion cells in the peripheral nervous system, and microglia and astrocytes in the central nervous system, are important players in both peripheral and central processing of pain in the orofacial region. This review highlights recent molecular and cellular findings of the glia involvement and glia-neuron interactions in four common orofacial pain conditions such as headache, dental pulp injury, temporomandibular joint dysfunction/inflammation, and head and neck cancer. We will discuss the remaining questions and future directions on glial involvement in these four orofacial pain conditions.

Integration of a 31-Gene Expression Profile Into Clinical Decision-Making in the Treatment of Cutaneous Melanoma.

BACKGROUND: The practice of utilizing gene expression profile (GEP) for the evaluation and treatment of cutaneous melanomas has been found to predict the risk of sentinel-node metastasis and recurrence. Information obtained from this assay has been used to determine clinical decision-making, including serving as an indication for sentinel lymph node biopsy and also for the intensity of screening measures. METHODS: Herein we present our early experience in utilizing 31-GEP in intermediate melanomas and its effect on clinical management. A retrospective review was conducted of patients who had undergone treatment for melanoma whose tumors had been subjected to 31-GEP. Additionally, patient characteristics, attributes of the original tumor biopsied, findings on final pathology, and procedures performed were evaluated. RESULTS: 31-GEP stratified patients into 4 groups; groups 1A and 1B are considered low risk of metastasis or recurrence, while 2A and 2B are considered high risk. Over the study period, 31-GEP was conducted on 26 cutaneous melanoma patients. Testing and treatment data are available for 23 of these patients. Eleven patients were found to be low risk (9 as 1A, 2 as 1B), 12 were found to be high risk (4 as 2A, 8 as 2B). Decision-making was altered such that sentinel lymph node biopsy was omitted in 2 cases in which the patients were found to be low risk with age >65 years. DISCUSSION: In 8 cases of node-negative disease in genetically high-risk patients, surveillance measures were augmented with positron emission tomography/computed tomography. Utilization of 31-GEP is ongoing at our institution.

Effects of Calcitonin Gene-related Peptide on Dental Pulp Stem Cell Viability, Proliferation, and Differentiation.

INTRODUCTION: Pulpitis is an inflammation of dental pulp caused by bacterial proliferation near or within pulpal tissues. In advanced stages, when the inflammation is associated with pulp necrosis, pulp preservation is dependent on dental pulp stem cells (DPSCs) that can differentiate into odontoblastlike cells and produce reparative dentin. In this study, we evaluated the influence of sensory neurons through calcitonin gene-related peptide (CGRP) on DPSC viability and proliferation and the ability of DPSCs to differentiate into mineralizing cells. METHODS: Commercially available DPSCs were treated with varying doses of CGRP, and metabolic activity, viability, proliferation, and cell death were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays, trypan blue staining, 5-bromo-2'-deoxyuridine cell proliferation assay, and caspase-3 staining, respectively. DPSC differentiation was assessed with alizarin red staining and by quantifying messenger RNA expression of odontoblast makers. RESULTS: CGRP induced a dose-dependent decrease of DPSC metabolic activity that was prevented by the CGRP receptor antagonist CGRP 8-37. The decrease in the proportion of live cells induced by CGRP is associated with a decrease of cell proliferation but not with caspase-3-dependent apoptosis. Interestingly, dexamethasone-induced DPSC differentiation into mineralizing cells was neither inhibited nor enhanced by CGRP treatment. CONCLUSIONS: The neuropeptide CGRP has an inhibitory effect on DPSC proliferation but does not enhance or inhibit the differentiation of DPSCs into mineralizing cells. This suggests that CGRP might negatively influence the ability of DPSCs to contribute to regenerative or tissue repair processes.

Evoked and spontaneous pain assessment during tooth pulp injury.

Injury of the tooth pulp is excruciatingly painful and yet the receptors and neural circuit mechanisms that transmit this form of pain remain poorly defined in both the clinic and preclinical rodent models. Easily quantifiable behavioral assessment in the mouse orofacial area remains a major bottleneck in uncovering molecular mechanisms that govern inflammatory pain in the tooth. In this study we sought to address this problem using the Mouse Grimace Scale and a novel approach to the application of mechanical Von Frey hair stimuli. We use a dental pulp injury model that exposes the pulp to the outside environment, a procedure we have previously shown produces inflammation. Using RNAscope technology, we demonstrate an upregulation of genes that contribute to the pain state in the trigeminal ganglia of injured mice. We found that mice with dental pulp injury have greater Mouse Grimace Scores than sham within 24 hours of injury, suggestive of spontaneous pain. We developed a scoring system of mouse refusal to determine thresholds for mechanical stimulation of the face with Von Frey filaments. This method revealed that mice with a unilateral dental injury develop bilateral mechanical allodynia that is delayed relative to the onset of spontaneous pain. This work demonstrates that tooth pain can be quantified in freely behaving mice using approaches common for other types of pain assessment. Harnessing these assays in the orofacial area during gene manipulation should assist in uncovering mechanisms for tooth pulp inflammatory pain and other forms of trigeminal pain.

Sensory testing associates with pain quality descriptors during acute dental pain.

BACKGROUND: Pain descriptors capture the multidimensional nature of pain and can elucidate underlying pathophysiological mechanisms. This study determined whether the pain descriptors chosen by subjects experiencing acute dental pain associate with the outcomes of two commonly performed dental sensory tests. The goal of the study is to clarify whether pain descriptors are useful in discriminating the underlying biological processes contributing to dental pain. METHODS: Participants (n = 228) presenting with acute toothache underwent standardized clinical dental sensory testing and described their pain in reference to 22 pain quality descriptors. Univariate and two-way ANOVA determined the relationship between groups defined by cold detection (positive or negative) and percussion hypersensitivity (painful or not) on the affected tooth, and pain descriptor reporting. RESULTS: Subjects experiencing painful toothache most frequently reported evoked pain to temperature and chewing, and pain descriptors such as "throbbing" and "aching." They also reported neuropathic pain descriptors such as "tingling" and "electric shock." Subjects who detected a cold stimulus (thermal) on the affected tooth, frequently reported high intensity paroxysmal shooting pain compared to those that did not detect cold. By contrast, patients with percussion (mechanical) hypersensitivity on the affected tooth, reported higher levels of global pain intensity at rest and in function, and reported significantly higher intensity "radiating" and "throbbing" pain, than subjects with non-painful percussion. CONCLUSIONS: The reporting of neuropathic pain descriptors by subjects experiencing acute toothache was more frequent than expected, suggesting that neuropathic mechanisms could contribute to typical toothache pain. Subjects experiencing toothache with mechanical hypersensitivity experience more intense pain overall. SIGNIFICANCE: In subjects experiencing acute toothache, specific pain descriptors associate with the responses to routine clinical sensory tests performed on the injured tooth. The frequent reporting of neuropathic pain descriptors suggests that neuropathic mechanisms could create a diagnostic challenge to differentiate toothache from intraoral neuropathic conditions. Persons experiencing toothache with mechanical hypersensitivity experience more intense pain overall, suggesting patients with this clinical feature will have distinct clinical pain management needs.

Clinical comparison between neuroendocrine and endometrioid type carcinoma of the uterine corpus.

OBJECTIVE: To compare the clinicopathologic features and survival outcomes of neuroendocrine tumor of the uterine corpus (NET-U) to endometrioid type endometrial carcinoma (EC). METHODS: From 1993 to 2012, the Surveillance, Epidemiology and End Results cancer registry was queried for women diagnosed with EC or NET-U. Data regarding stage, grade, presence of extra-uterine disease, lymph node metastasis, receipt of adjuvant radiation, surgical intervention and overall survival (OS) was extracted. Chi-square tests, t-tests and Kaplan Meir curves were used for statistical analysis. RESULTS: A total of 98,363 patients were identified: 98,245 with EC and 118 with NET-U. The mean age at diagnosis for EC was 61.7 years and 64.8 years for NET-U (p=0.01). NET-U cases were more likely to be poorly differentiated (97.0% vs. 15.6%; p≤0.01) and have nodal metastasis (56.4% vs. 11.1%; p≤0.01) when compared to EC. Presence of extrapelvic disease at the time of diagnosis was observed more frequently in NET-U compared to EC, 49.1% vs. 4.8%, respectively (odds ratio=18; 95% confidence interval=13.1-27.2; p≤0.01). Significant improvement in OS was observed in NET-U patient who received radiation (OS: 7.7 vs. 3.3 years; p≤0.01) or underwent surgical management (5.6 vs. 0.9 years; p≤0.01). The OS for EC was 14.4 vs. 4.6 years for NET-U (p≤0.01). CONCLUSION: NET-U represents an aggressive form of uterine malignancy. When compared to EC, patients with NET-U present at more advanced stage, have more frequent extra-uterine disease and lower OS.

Clinicopathologic features, incidence, and survival trends of gynecologic neuroendocrine tumors: a SEER database analysis.

BACKGROUND: Primary gynecologic neuroendocrine tumors are uncommon malignant neoplasms associated with poor prognosis. Clinically, these tumors present a significant challenge because of the lack of standardized management guidelines. OBJECTIVE: The objective of this study is to evaluate the clinicopathologic features, incidence, and survival trends in gynecologic neuroendocrine tumors. MATERIALS AND METHODS: The Surveillance, Epidemiology and End Results (SEER) cancer registry was queried for women diagnosed with primary gynecologic neuroendocrine tumors from 1987 to 2012. Data regarding stage, grade, presence of extrauterine disease, receipt of adjuvant radiation, surgical intervention, incidence, and overall survival were extracted. Patients were classified as having early-stage disease (International Federation of Gynecology and Obstetrics Stage I/II) or advanced-stage disease (Stage III/IV). Extrauterine disease was defined as either regional or distant metastasis. χ2 Tests, Pearson correlation, and Kaplan-Meier curves were used for statistical analysis. RESULTS: In all, 559 cases of gynecologic neuroendocrine tumors were identified during the study period: 242 cervical, 160 ovarian, 118 uterine, and 39 vulvar/vaginal. The majority of patients in all subsets of gynecologic neuroendocrine tumors presented with poorly differentiated tumors, extrauterine disease spread, and advanced-stage disease. Poorly differentiated tumors represented 65.0% of cervical tumors, 45.3% of ovarian tumors, and 57.4% of uterine tumors. Extrauterine disease at the time of diagnosis was present in the case of 66.9% of cervical tumors, 83.5% of ovarian tumors, and 83.6% of uterine tumors. The overall incidence of gynecologic neuroendocrine tumors increased 4-fold during the study period, from 0.3 in 1987 to 1.30 per million in 2012. The study period was divided into two 13-year periods (1987-1999 and 2000-2012) for time trend mean survival analysis. We observed no significant change in overall survival across all gynecologic neuroendocrine tumor subtypes. The mean survival time of cervical neuroendocrine tumors was 74.3 vs 45.4 months (P = .31), ovarian neuroendocrine tumors 47.8 vs 41.2 months (P = .56), and uterine neuroendocrine tumors 42.9 vs 47.7 months (P = .44) for each time period, respectively. CONCLUSION: Neuroendocrine tumors of the gynecologic tract are uncommon aggressive malignancies. These poorly differentiated tumors present at advanced stage, with a high incidence of extrauterine disease. Despite 25 years of advances in cancer therapy, we observed no improvement in overall survival.

TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold.

Sensory neurons innervating the dental pulp have unique morphological and functional characteristics compared to neurons innervating other tissues. Stimulation of dental pulp afferents whatever the modality or intensity of the stimulus, even light mechanical stimulation that would not activate nociceptors in other tissues, produces an intense pain. These specific sensory characteristics could involve receptors of the Transient Receptor Potential channels (TRP) family. In this study, we compared the expression of the cold sensitive receptors TRPM8 and TRPA1 in trigeminal ganglion neurons innervating the dental pulp, the skin of the cheek or the buccal mucosa and we evaluated the involvement of these receptors in dental pulp sensitivity to cold. We showed a similar expression of TRPM8, TRPA1 and CGRP in sensory neurons innervating the dental pulp, the skin or the mucosa. Moreover, we demonstrated that noxious cold stimulation of the tooth induced an overexpression of cFos in the trigeminal nucleus that was not prevented by the genetic deletion of TRPM8 or the administration of the TRPA1 antagonist HC030031. These data suggest that the unique sensory characteristics of the dental pulp are independent to TRPM8 and TRPA1 receptors expression and functionality.

Lesion Index-Guided Ablation Facilitates Continuous, Transmural, and Durable Lesions in a Porcine Recovery Model.

BACKGROUND: The Lesion Index (LSI) is a proprietary algorithm from Abbott Medical combining contact force, radiofrequency application duration, and radiofrequency current. It can be displayed during ablation with the TactiCath contact force catheter. The LSI Index was designed to provide real-time lesion formation feedback and is hypothesized to estimate the lesion diameter. METHODS AND RESULTS: Before ablation, animals underwent cardiac computed tomography to assess atrial tissue thickness. Ablation lines (n=2-3 per animal) were created in the right atrium of 7 Göttingen mini pigs with point lesions (25 W). Within each line of ablation, the catheter tip was moved a prescribed distance (D/mm) according to 1 of 3 strategies: D=LSI+0 mm; D=LSI+2 mm; or D=LSI+4 mm. Two weeks after ablation, serial sections of targeted atrial tissue were examined histologically to identify gaps in transmural ablation. LSI-guided lines had a lower incidence of histological gaps (4 gaps in 69 catheter moves, 5.8%) than LSI+2 mm lines (7 gaps in 33 catheter moves, 21.2%) and LSI+4 mm lines (15 gaps in 23 catheter moves, 65.2%, P<0.05 versus D=LSI). ΔLSI was calculated retrospectively as the distance between 2 adjacent lesions above the mean LSI of the 2 lesions. ΔLSI values of ≤1.5 were associated with no gaps in transmural ablation. CONCLUSIONS: In this model of chronic atrial ablation, delivery of uninterrupted transmural linear lesions may be facilitated by using LSI to guide catheter movement. When ΔLSI between adjacent lesions is ≤1.5 mm, no gaps in atrial linear lesions should be expected.