Search

Supplemental Table 6: mRNA:miRNA pairs enriched in LNMs subtypes.

Supplemental Methods, Supplemental Tables 1, 3, 4, 6, 7, 8, Supplemental Figures 1-12 Supplemental Table 1. Overall patient characteristics. Supplemental Table 3. Patient Characteristics by lymph node molecular classification. Supplemental Table 4. Univariate and multivariate analysis for locoregional control. Supplemental Table 7. Accuracy of existing classifiers to predict Group 2 LNM subtype. Supplemental Table 8. 73 gene classifier Supplemental Figure 1. Patient selection. Supplemental Figure 2. Metrics of the 73 gene classifier. (A) Metrics of 73 gene classifier. (B) Misclassification error for C2 and C13 groups. (C) Misclassification of entire classifier. Supplemental Figure 3. Outcomes in HNSCC cohort.Kaplan-Meier analysis of: (A) Locoregional control. (B) Local-only control. (C) Relapse free survival. (D) Regional control. (E) Distant control. (F) Overall survival. Supplemental Figure 4. Outcomes by molecular subtypes of LNMs.Kaplan-Meier analysis of: (A) Regional control. (B) Distant control. Supplementary Figure 5: DEmiRNAsin LNMs subtypes. Supplemental Figure 6. Consensus clustering of pairwise DEGs for other predefined cluster numbers does not identify other LNMs subtypes that predict for disease recurrence. Supplemental Figure 7. Enrichment of KEGG pathways in LNMs subtypes. Supplemental Figure 8. Estimated abundance of immune cells. Supplemental Figure 9. LNMs subtypes cluster separately from non-metastatic lymph nodes in the same cohort. Supplemental Figure 10. LNMs subtypes cluster separately from normal lymph nodes derived from publically available microarray databases. Supplemental Figure 11. The transcriptome of lymph node metastasis better predicts for patients at higher risk of relapse or death. Supplemental Figure 12. Receiver-Operator Curve for 73 gene LNM-classifier.

Supplemental Table 2. LN classification by iCluster and PAM classifier.

Supplemental Table 5. DEmRNAs and DEmiRNAs in LNMs.

Purpose:In advanced stage head and neck squamous cell cancers (HNSCC), approximately half of the patients with lymph node metastases (LNM) are not cured. Given the heterogeneous outcomes in these patients, we profiled the expression patterns of LNMs to identify the biological factors associated with patient outcomes.Experimental Design: We performed mRNAseq and miRNAseq on 72 LNMs and 29 matched primary tumors from 34 patients with HNSCC. Clustering identified molecular subtypes in LNMs and in primary tumors. Prediction Analysis of Microarrays algorithm identified a 73-gene classifier that distinguished LNM subtypes. Gene-set enrichment analysis identified pathways upregulated in LNM subtypes.Results:Integrative clustering identified three distinct LNM subtypes: (i) an immune subtype (Group 1), (ii) an invasive subtype (Group 2), and (iii) a metabolic/proliferative subtype (Group 3). Group 2 subtype was associated with significantly worse locoregional control and survival. LNM-specific subtypes were not observed in matched primary tumor specimens. In HNSCCs, breast cancers, and melanomas, a 73-gene classifier identified similar Group 2 LNM subtypes that were associated with worse disease control and survival only when applied to lymph node sites, but not when applied to other primary tumors or metastatic sites. Similarly, previously proposed prognostic classifiers better distinguished patients with worse outcomes when applied to the transcriptional profiles of LNMs, but not the profiles of primary tumors.Conclusions:The transcriptional profiles of LNMs better predict outcomes than transcriptional profiles of primary tumors. The LNMs display site-specific subtypes associated with worse disease control and survival across multiple cancer types.

Supplemental Table 9. Breast cancer characteristics

Supplemental Table 10. Melanoma characteristics.

Objectives Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor. Materials and methods This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle. Results A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome. Conclusions IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.

Purpose: In advanced stage head and neck squamous cell cancers (HNSCC), approximately half of the patients with lymph node metastases (LNM) are not cured. Given the heterogeneous outcomes in these patients, we profiled the expression patterns of LNMs to identify the biological factors associated with patient outcomes. Experimental Design: We performed mRNAseq and miRNAseq on 72 LNMs and 29 matched primary tumors from 34 patients with HNSCC. Clustering identified molecular subtypes in LNMs and in primary tumors. Prediction Analysis of Microarrays algorithm identified a 73-gene classifier that distinguished LNM subtypes. Gene-set enrichment analysis identified pathways upregulated in LNM subtypes. Results: Integrative clustering identified three distinct LNM subtypes: (i) an immune subtype (Group 1), (ii) an invasive subtype (Group 2), and (iii) a metabolic/proliferative subtype (Group 3). Group 2 subtype was associated with significantly worse locoregional control and survival. LNM-specific subtypes were not observed in matched primary tumor specimens. In HNSCCs, breast cancers, and melanomas, a 73-gene classifier identified similar Group 2 LNM subtypes that were associated with worse disease control and survival only when applied to lymph node sites, but not when applied to other primary tumors or metastatic sites. Similarly, previously proposed prognostic classifiers better distinguished patients with worse outcomes when applied to the transcriptional profiles of LNMs, but not the profiles of primary tumors. Conclusions: The transcriptional profiles of LNMs better predict outcomes than transcriptional profiles of primary tumors. The LNMs display site-specific subtypes associated with worse disease control and survival across multiple cancer types.

Oral tongue squamous cell carcinoma (TSCC) is a complex disease with extensive genetic and epigenetic defects, including microRNA deregulation. The aims of the present study were to test the feasibility of performing the microRNA profiling analysis on archived TSCC specimens and to assess the potential diagnostic utility of the identified microRNA biomarkers for the detection of TSCC. TaqMan array-based microRNA profiling analysis was performed on 10 archived TSCC samples and their matching normal tissues. A panel of 12 differentially expressed microRNAs was identified. Eight of these differentially expressed microRNAs were validated in an independent sample set. A random forest (RF) classification model was built with miR-486-3p, miR-139-5p, and miR-21, and it was able to detect TSCC with a sensitivity of 100% and a specificity of 86.7% (overall error rate = 6.7%). As such, this study demonstrated the utility of the archived clinical specimens for microRNA biomarker discovery. The feasibility of using microRNA biomarkers (miR-486-3p, miR-139-5p, and miR-21) for the detection of TSCC was confirmed.

Overgrowths of epithelial, ectomesenchymal, and/or mesenchymal elements of the tooth-forming apparatus are quite variable with respect to their histopathologic characteristics and biological behaviors. Investigations of a variety of odontogenic lesions have led to an enhanced comprehension of many salient diagnostic features. This discussion provides an update with respect to the understanding of odontogenic tumors and tumor-like malformations and attempts to assist pathologists in the recognition and classification of these lesions.

Acute pancreatitis (AP), although most often a mild and self-limiting inflammatory disease, worsens to a characteristically necrotic severe acute pancreatitis (SAP) in about 20% of cases. Obesity, affecting more than one-third of American adults, is a risk factor for the development of SAP, but the exact mechanism of this association has not been identified. Coincidental with chronic low-grade inflammation, activation of the nucleotide-binding domain, leucine-rich containing family, pyrin-domain containing 3 (NLRP3) inflammasome increases with obesity. Lean mice genetically deficient in specific components of the NLRP3 inflammasome are protected from experimentally induced AP, indicating a direct involvement of this pathway in AP pathophysiology. We hypothesized that inhibition of the NLRP3 inflammasome with the sulfonylurea drug glyburide would reduce disease severity in obese mice with cerulein-induced SAP. Treatment with glyburide led to significantly reduced relative pancreatic mass and water content and less pancreatic damage and cell death in genetically obese ob/ob mice with SAP compared with vehicle-treated obese SAP mice. Glyburide administration in ob/ob mice with cerulein-induced SAP also resulted in significantly reduced serum levels of interleukin 6, lipase, and amylase and led to lower production of lipopolysaccharide-stimulated interleukin 1β release in cultured peritoneal cells, compared with vehicle-treated ob/ob mice with SAP. Together, these data indicate involvement of the NLRP3 inflammasome in obesity-associated SAP and expose the possible utility of its inhibition in prevention or treatment of SAP in obese individuals.

Context.— Some dental abnormalities have environmental causes. Other odontogenic alterations are idiopathic and may have hereditary etiologies. Investigations of these conditions are ongoing.Objective.— —To provide a discussion of developmental odontogenic abnormalities and benign odontogenic overgrowths and neoplasms for which genetic alterations have been well demonstrated and well documented.Data Sources.— Relevant peer-reviewed literature.Conclusions.— —The understanding of benign odontogenic lesions at a molecular level is rather well developed for some lesions and at the initial stages for many others. Further characterization of the molecular underpinnings of these and other odontogenic lesions would result in an enhanced comprehension of odontogenesis and the pathogenesis of a variety of odontogenic aberrations. These advancements may lead to better prevention and treatment paradigms and improved patient outcomes.

Ameloblastic fibro-odontoma is a rare, benign, and slowly growing neoplasm of the jaw composed of proliferating odontogenic epithelium in ectomesenchymal tissue along with dental hard tissue formation. Herein, we describe a case of an ameloblastic fibro-odontoma in 12-year-old female with paresthesia of the chin and lower lip. Panoramic radiography showed a radio-opacity in the right posterior mandible near the mandibular canal and associated with the right mandibular third molar. Histologically, the lesion contained epithelial and mesenchymal odontogenic components in close proximity to odontoma-like elements. Enucleation and curettage of the affected site in the mandible resulted in resolution of the paresthesia postoperatively.

Background The genes for PFN1 and TMSB4 are both highly expressed in oral tissue and both encode actin monomer binding proteins thought to play a role in cell motility and possibly other crucial parts of tumor progression. Methods Oral brush cytology of epithelium from oral squamous cell carcinoma (OSCC) was used to measure PFN1 and TMSB4 mRNA in OSCC, while immunohistochemical analysis of tissue was used to check protein levels. Results High but variable expression of mRNAs encoding these two proteins was observed suggesting they may contribute to tumor characteristics in a subset of OSCCs. Both proteins were highly expressed in normal appearing basal epithelium, in the cytoplasm, and perinuclear area, while expression was minimal in upper epithelial layers. In OSCCs, expression of these proteins varied. In tumors classified as later stage, based on size and/or lymph node involvement, PFN1 levels were lower in tumor epithelium. A control gene, KRT13, showed expression in normal differentiated basal and suprabasal oral mucosa epithelial cells and as reported was lost in OSCC cells. Conclusion Loss of PFN1 in tumor cells has been associated with lymph node invasion and metastasis in other tumor types, strengthening the argument that the protein has the potential to be a tumor suppressor in late-stage OSCC.

Background Oral tongue squamous cell carcinoma (OTSCC) is one of the most aggressive forms of head and neck/oral cancer (HNOC), and is a complex disease with extensive genetic and epigenetic defects, including microRNA deregulation. Identifying the deregulation of microRNA-mRNA regulatory modules (MRMs) is crucial for understanding the role of microRNA in OTSCC. Methods A comprehensive bioinformatics analysis was performed to identify MRMs in HNOC by examining the correlation among differentially expressed microRNA and mRNA profiling datasets and integrating with 12 different sequence-based microRNA target prediction algorithms. Confirmation experiments were performed to further assess the correlation among MRMs using OTSCC patient samples and HNOC cell lines. Functional analyses were performed to validate one of the identified MRMs: miR-21-15-Hydroxyprostaglandin Dehydrogenase (HPGD) regulatory module. Results Our bioinformatics analysis revealed 53 MRMs that are deregulated in HNOC. Four high confidence MRMs were further defined by confirmation experiments using OTSCC patient samples and HNOC cell lines, including miR-21-HPGD regulatory module. HPGD is a known anti-tumorigenic effecter, and it regulates the tumorigenic actions of Prostaglandin E2 (PGE2) by converts PGE2 to its biologically inactive metabolite. Ectopic transfection of miR-21 reduced the expression of HPGD in OTSCC cell lines, and the direct targeting of the miR-21 to the HPGD mRNA was confirmed using a luciferase reporter gene assay. The PGE2-mediated upregulation of miR-21 was also confirmed which suggested the existence of a positive feed-forward loop that involves miR-21, HPGD and PGE2 in OTSCC cells that contribute to tumorigenesis. Conclusions We identified a number of high-confidence MRMs in OTSCC, including miR-21-HPGD regulatory module, which may play an important role in the miR-21-HPGD-PGE2 feed-forward loop that contributes to tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2716-0) contains supplementary material, which is available to authorized users.

Summary Objective We previously performed a meta-analysis of microRNA profiling studies on head and neck/oral cancer (HNOC), and identified 11 consistently dysregulated microRNAs in HNOC. Here, we evaluate the diagnostic values of these microRNAs in oral tongue squamous cell carcinoma (OTSCC) using oral cytology samples. Materials and methods The levels of 11 microRNAs were assessed in 39 oral cytology samples (19 OTSCC and 20 normal subjects), and 10 paired OTSCC and adjacent normal tissues. The predictive power of these microRNAs was analyzed by receiver operating characteristic curve (ROC) and random forest (RF) model. A classification and regression trees (CART) model was generated using miR-21 and miR-375, and further validated using both independent oral cytology validation sample set (14 OTSCC and 11 normal subjects) and tissue validation sample set (12 paired OTSCC and adjacent normal tissues). Results Differential expression of miR-21, miR-100, miR-125b and miR-375 was validated in oral cytology training sample set. Based on the RF model, the combination of miR-21 and miR-375 was selected which provide best prediction of OTSCC. A CART model was constructed using miR-21 and miR-375, and was tested in both oral cytology and tissue validation sample sets. A sensitivity of 100% and specificity of 64% was achieved in distinguishing OTSCC from normal in the oral cytology validation set, and a sensitivity of 83% and specificity of 83% was achieved in the tissue validation set. Conclusion The utility of microRNA from oral cytology samples as biomarkers for OTSCC detection is successfully demonstrated in this study.

Obesity increases severity of acute pancreatitis and risk of pancreatic cancer. Pancreatitis and obesity are associated with elevated IL-6, a cytokine involved in inflammation and tumorigenesis. We studied the role of IL-6 in the response of lean and obese mice to pancreatitis induced by IL-12 + IL-18. Lean and diet-induced obese (DIO) WT and IL-6 KO mice and ob/ob mice pretreated with anti-IL-6 antibodies were evaluated at Days 1, 7, and 15 after induction of pancreatitis. Prolonged elevation of IL-6 in serum and visceral adipose tissue was observed in DIO versus lean WT mice, whereas circulating sIL-6R declined in DIO but not lean mice with pancreatitis. The severe inflammation and lethality of DIO mice were also observed in IL-6 KO mice. However, the delayed resolution of neutrophil infiltration; sustained production of CXCL1, CXCL2, and CCL2; prolonged activation of STAT-3; and induction of MMP-7 in the pancreas, as well as heightened induction of serum amylase A of DIO mice, were blunted significantly in DIO IL-6 KO mice. In DIO mice, production of OPN and TIMP-1 was increased for a prolonged period, and this was mediated by IL-6 in the liver but not the pancreas. Results obtained in IL-6 KO mice were confirmed in ob/ob mice pretreated with anti-IL-6 antibodies. In conclusion, IL-6 does not contribute to the increased severity of pancreatitis of obese mice but participates in delayed recovery from acute inflammation and may favor development of a protumorigenic environment through prolonged activation of STAT-3, induction of MMP-7, and sustained production of chemokines.

BACKGROUND: Discordant results of cervical biopsy histology after a cytologic diagnosis of high-grade squamous intraepithelial lesion (HSIL) are often attributed to sampling variation. The purpose of the current study was to determine whether deeper levels and ancillary staining (p16Ink4a and ProExC) reduce the discordant rate. METHODS: A total of 246 cases of HSIL were retrieved from the computerized database from 2005 and 2006. Of these cases, 151 were followed by cervical biopsy. There was cytologic-histologic correlation in 87 cases, as defined by the presence of high-grade (2 or 3) cervical intraepithelial neoplasia (HGCIN). For each discordant biopsy (n = 64), 2 deeper levels for hematoxylin and eosin (H&E) were taken at 30-μ and 90-μ depths, and 4 sections for p16Ink4a and ProExC staining were taken at a 60-μ depth. All cytologic and histologic material from these 64 cases was reviewed by 3 cytopathologists. In 2 cases, the original HSIL diagnoses were downgraded and the cases censored from the study. RESULTS: Fifty-seven of the 62 discordant cases had sufficient tissue for deeper levels and ancillary staining. Two of 57 cases were reclassified to HGCIN. In both of these cases, reclassification was suggested by results of immunostains; however, the H&E sections were necessary for definitive interpretation of the immunostain results. CONCLUSIONS: In the current study, deeper levels and ancillary staining with p16Ink4a and ProExC did not significantly reduce the discordance rate. Although there are many known causes of sampling variation, including factors related to colposcopic technique, regression of infection, and insufficient histologic sectioning, sampling variation remains a valid justification of noncorrelation in women with HSIL followed up by cervical biopsy alone. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.

The goal of this study was to investigate the role of the adipokine adiponectin (APN) in development of spontaneous colitis in IL-10 knockout (KO) mice. To this aim, we generated double IL-10 APN KO mice and compared their disease development to that of single IL-10 KO mice. Both IL-10 KO and double IL-10 APN KO mice spontaneously developed colitis of comparable severity. No significant differences in inflammatory infiltrate or crypt elongation were observed in colonic tissue obtained from IL-10 KO and double IL-10 APN KO mice at either 12 or 20 wk of age. A comparable increase in circulating levels of serum amyloid A and IFN-γ was observed in IL-10 KO and double IL-10 APN KO mice as disease progressed. In vitro stimulation of lymphocytes from mesenteric lymph nodes with anti-CD3 and anti-CD28 induced a significantly higher production of IL-17 and TNF-α in IL-10 KO and double IL-10 APN KO mice compared with their healthy littermates. No significant differences in cytokine production from lymphocytes or colonic mRNA expression of cytokines were observed between IL-10 KO and double IL-10 APN KO mice. Both IL-10 KO and double IL-10 APN KO mice had a similar decrease in body weight and bone mass compared with their respective healthy littermates. Finally, APN deficiency did not lead to development of insulin resistance, either in APN KO or double IL-10 APN KO mice. In conclusion, lack of APN does not play a significant role in the pathogenesis of spontaneous colonic inflammation in the IL-10 KO model.

Fine-needle aspiration biopsy can be utilized effectively in the diagnosis of many bone lesions. Often, these lesions are suspected to be foci of metastatic disease based on clinical and/or radiographic findings. On occasion, microscopic examination of the aspirate yields a diagnosis of a primary neoplasm of chondroid origin. We discuss the cytologic features observed in crush preparations of the most frequently seen primary chondroid tumors of bone and how these lesions can be differentiated from each other and from metastatic lesions.

Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short- and long-term leptin replacement therapy. Short-term leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.

Proliferative verrucous leukoplakia (PVL) is a distinct clinical form of oral leukoplakia defined by its progressive clinical course, changing clinical and histopathologic features, and potential to develop into cancer. PVL behaves in a more aggressive and relentless manner than the more innocuous white oral lesions that it can resemble clinically. We present three cases of PVL that progressed to carcinoma and discuss the histopathologic findings that may either hinder or assist in the diagnosis.

Background: Proliferative verrucous leukoplakia (PVL) is a distinct clinical form of oral leukoplakia defined by its progressive clinical course, changing clinical and histopathological features, and potential to develop into cancer. PVL behaves in a more aggressive and relentless manner than the more innocuous white oral lesions that it can resemble clinically. Methods: A PubMed search was conducted which identified studies that examined patients with PVL and reported data meeting inclusion criteria. Results: PVL is seen much more frequently in females and most often diagnosed after the sixth decade of life. Tobacco use is not strongly linked to the presence of PVL (63% of patients did not use tobacco products). Most (74%) of the patients with PVL progressed to oral carcinoma. Conclusion: PVL is a persistent and progressive oral lesion that requires very close follow-up along with early and aggressive treatment to increase the chances of a favorable outcome.

Synchronous ipsilateral tumor formation within a major salivary gland is a very rare event. In this case, a 54-year-old female tobacco smoker presented with a slowly enlarging left parotid gland. Computed tomography of the neck demonstrated a solid mass superficial to a cystic mass in the deep lobe of the gland. Ultrasound-guided fine needle aspiration yielded oncocytic cells, lymphoid cells, and granular debris along with rare cohesive groups of basaloid cells. Parotidectomy was performed, and the resected gland was found to contain two adjacent but distinct masses. One mass, a predominantly solid, well-circumscribed lesion composed of ribbons of double-layered oncocytic cells and a lymphoid stroma with germinal center formation, was a Warthin tumor. The other mass, a predominantly cystic lesion composed of cords and nests of basaloid cells with associated deposits of basement membrane-like material, was a basal cell adenoma of the membranous type. To our knowledge, this is the first reported case of synchronous Warthin tumor and basal cell adenoma of the parotid gland with cytologic–histologic correlation attributable to each tumor.

Breast disease is of great concern to patients and health care providers alike. Malignancies of the breast and their various presentations can pose tremendous challenges with respect to early diagnosis and effective treatment. Carcinoma of the breast may appear in several forms and produce one or more ectopic substances. Breast carcinomas that display choriocarcinomatous differentiation and produce human chorionic gonadotropin are very rare. Less than a dozen such cases have been described in the medical literature to date. We report a case of breast carcinoma with choriocarcinomatous features, which is the first to show immunohistochemical evidence of the expression of both estrogen receptor and progesterone receptor. We also discuss the cytopathologic aspects observed and conduct a literature review. Diagn. Cytopathol. 2006;34:694–697. © 2006 Wiley-Liss, Inc.

Purpose The purpose of this report is to describe a rare case of delayed metachronous isolated metastases of renal cell carcinoma (RCC) to the parotid gland and the cerebellum. The metastases occurred more than a decade after treatment of the primary tumor without any other systemic involvement. In addition, the potential differential diagnosis of the parotid mass based on presentation and imaging is discussed. Materials and Methods An 83-year-old man presented for evaluation and treatment of a rapidly growing mass at the right parotid region. He had a history of RCC resection 10 years before this presentation and had no evidence of persistent disease at the primary site. The diagnosis of metastatic RCC was made after fine-needle aspiration biopsy examination of the mass. The patient underwent superficial parotidectomy for resection of the tumor. Approximately 1.5 years later, he complained of loss of balance. Further investigation disclosed a cerebellar mass that at biopsy examination was found to represent RCC. He underwent stereotactic ablation of the mass. He currently remains free of disease at the primary site and the parotid and without further known brain metastases. Results This report presents the 29th case of a solitary parotid mass consistent with metastatic RCC 10 years after successful treatment of the primary RCC. Approximately 1.5 years later, the patient presented with new-onset loss of balance. Further investigation disclosed a mass to the cerebellum consistent with metastatic RCC. This case is unique because the brain involvement occurred extremely late, 11.5 years after successful treatment of primary RCC and 1.5 years after resection of a metastatic RCC to the parotid, and without any evidence of other metastases. Conclusions Late distant metastases of RCC are not uncommon and patients require life surveillance follow-up, but such late presentation of metachronous metastases without systemic disease progression is unique. The patterns of metastases of RCC are not clearly defined and this diagnosis should be considered, especially in patients with relevant history.

OBJECTIVE Currently, there is no therapy for severe acute pancreatitis (AP) except for supportive care. The lipase inhibitor orlistat, the peroxisome proliferator-activated receptor γ agonist rosiglitazone, and the chemokine receptor 2 antagonists attenuate the severity of AP in rodents if administered before or at the time of induction of pancreatitis. However, it is unknown whether these treatments are effective if administered therapeutically after induction of pancreatitis. METHODS Male C57BL6 mice with diet-induced obesity received 2 injections of mrIL-12 (150 ng per mouse) and mrIL-18 (750 ng per mouse) intraperitoneally at 24-hour intervals. The mice were injected 2, 24, and 48 hours after the second injection of IL-12 + IL-18 with orlistat (2 mg per mouse), rosiglitazone (0.4 mg per mouse), RS102895 (0.3 mg per mouse), or vehicle (20 μL of DMSO and 80 μL of canola oil) and euthanized after 72 hours. RESULTS Orlistat decreased intra-abdominal fat necrosis compared with vehicle (P < 0.05). However, none of the drug treatments produced significant decreases in pancreatic edema, acinar necrosis, or intrapancreatic fat necrosis. CONCLUSIONS Drugs previously shown to improve the severity of AP when given before or at the time of induction of pancreatitis failed to do so when administered therapeutically in the IL-12 + IL-18 model.

BackgroundIncreased cellular iron exposure is associated with colorectal cancer (CRC) risk. Hepcidin, a liver peptide hormone, acts as the primary regulator of systemic iron status by blocking iron release from enterocytes into plasma. Concentrations are decreased during low iron status and increased during inflammation. The role of hepcidin and the factors influencing its regulation in CRC remains largely unknown. This study explored systemic and tumor level iron regulation in men with CRC.MethodsThe participants were 20 CRC cases and 20 healthy control subjects. Colonic tissue (adenocarcinoma [cases] healthy mucosa [controls]) was subjected to quantitative PCR (hepcidin, iron transporters and IL-6) and Perls' iron staining. Serum was analyzed using ELISA for hepcidin, iron status (sTfR) and inflammatory markers (CRP, IL-6, TNF-α). Anthropometrics, dietary iron intake and medical history were obtained.ResultsCases and controls were similar in demographics, medication use and dietary iron intake. Systemically, cases compared to controls had lower iron status (sTfR: 21.6 vs 11.8nmol/L, p

Most often, mesotheliomas involve the serosal (serous) membranes of the pleura and peritoneum. Sometimes, mesothelial proliferations are identified in other locations. On very rare occasions, a mesothelioma is found within the tunica vaginalis of the paratesticular region. We report a case of papillary mesothelioma of the tunica vaginalis in a 52-year-old man. Although this lesion had papillary structures lined by a single layer of mesothelial cells with predominantly bland nuclear and cytologic features, there was evidence of a minimal presence of mesothelial cells in the underlying stroma. This combination of benign and semimalignant characteristics can make the diagnosis of such a lesion problematic. We think that a diagnosis of “borderline papillary mesothelioma” can be considered for similar mesothelial proliferations to allow for a possible increase in diagnostic accuracy and provide an enhanced informational platform from which patients and clinicians can benefit.

Objective Oral lichen planus (OLP) is a disease of the oral mucosa of unknown cause producing lesions with an intense band-like inflammatory infiltrate of T cells to the subepithelium and keratinocyte cell death. We performed gene expression analysis of the oral epithelium of lesions in subjects with OLP and its sister disease, oral lichenoid reaction (OLR), in order to better understand the role of the keratinocytes in these diseases. Design Fourteen patients with OLP or OLR were included in the study, along with a control group of 23 subjects with a variety of oral diseases and a normal group of 17 subjects with no clinically visible mucosal abnormalities. Various proteins have been associated with OLP, based on detection of secreted proteins or changes in RNA levels in tissue samples consisting of epithelium, stroma, and immune cells. The mRNA level of twelve of these genes expressed in the epithelium was tested in the three groups. Results Four genes showed increased expression in the epithelium of OLP patients: CD14, CXCL1, IL8, and TLR1, and at least two of these proteins, TLR1 and CXCL1, were expressed at substantial levels in oral keratinocytes. Conclusions Because of the large accumulation of T cells in lesions of OLP it has long been thought to be an adaptive immunity malfunction. We provide evidence that there is increased expression of innate immune genes in the epithelium with this illness, suggesting a role for this process in the disease and a possible target for treatment.

Objectives Head and neck/oral cancer, predominantly head and neck squamous cell carcinoma (HNSCC), is the sixth most common cancer in the world. While substantial advances have been made to define the genomic alterations associated with head and neck/oral cancer, most studies are focused on protein coding genes. The aim of this article is to review the current literature on identified genomic aberrations of non-coding genes (e.g., microRNA) in head and neck/oral cancer (HNOC), and their contribution to the initiation and progression of HNOC. Material and Methods A comprehensive review of the available literature relevant to microRNA deregulation in HNSCC/HNOC, was undertaken using PubMed, Medline, Scholar Google and Scopus. Keywords for the search were: microRNA and oral cancer, microRNA and squamous cell carcinoma, microRNA deregulation and oral cancer, microRNA and carcinogenesis in the head and neck/oral cavity. Only full length articles in the English language were included. Results We recently identified a panel of microRNA deregulations that were consistently observed in HNSCC [Chen et al., Oral Oncol. 2012;48(8):686-91], including 7 consistently up-regulated microRNAs (miR-21, miR-7, miR-155, miR-130b, miR-223, miR-34b), and 4 consistently down-regulated microRNAs (miR-100, miR-99a, miR-125b, miR-375). In this review, we will first provide an overview on microRNA and HNSCC. We will then provide a comprehensive review on the roles of microRNA deregulations in HNSCC. The functional significance of the identified HNSCC-associated microRNAs and a number of other relevant microRNAs (e.g., miR-138, miR-98, miR-137, miR-193a and miR-218) will be discussed in detail. Conclusions Based on current literature, microRNA deregulation plays a major role in head and neck/oral cancer.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive life-threatening disease associated with high mortality rates. While efforts have been made to explore the molecular mechanisms that contribute to the initiation and progression of HNSCC, most studies focus on protein-coding genes. Understanding of the genomic aberrations associated with noncoding genes (such as microRNAs) and their effects on HNSCC is still relatively limited. Recent evidence suggests that deregulation of microRNA genes (such as downregulation of miR-138) plays an important role in HNSCC. While deregulation of miR-138 has been frequently observed in HNSCC and other cancer types, the precise roles of miR-138 in tumorigenesis remain elusive. Recent bioinformatics analyses and functional studies using in vitro and in vivo systems have identified a number of functional targets for miR-138. These include genes that participate in essential biological processes that are highly relevant to the initiation and progression of HNSCC, including cell migration, epithelial to mesenchymal transition, cell cycle progression, DNA damage response and repair, senescence, and differentiation. However, the biological systems, study design, and data interpretation from these studies are highly variable, which hinder our understanding of the role of miR-138 in tumorigenesis at molecular level. In this review, we will first introduce the significance of microRNA deregulation in HNSCC. We will then provide a comprehensive review and integrative analysis of the existing studies on miR-138, and aim to define its molecular mechanisms that contribute to the initiation and progression of HNSCC.

Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO) WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acute-phase proteins, number of circulating pro-inflammatory Ly6C(high) monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARγ, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20-week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1α and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation.

OBJECTIVES: Leptin and adiponectin (APN) are adipokines produced by adipocytes that participate in the modulation of immune and inflammatory responses. In Crohn's disease (CD), fat wrapping surrounding the inflamed intestine produces high levels of leptin and APN. In inflammatory bowel disease (IBD), apoptosis resistance of lamina propria T lymphocytes (LPL-T) is one of the mechanisms that maintains chronic inflammation. We addressed the mechanism by which leptin and APN regulate inflammation and apoptosis in IBD. METHODS: Immune cell infiltration, several factors expressed by adipose tissue (AT), and spontaneous release of cytokines by adipocytes were measured. The presence of APN and leptin in intestinal mucosa was detected and their effect on LPL-T apoptosis, signal transducer and activator of transcription 3 (STAT3), Suppressor of Cytokine Signaling 3 (SOCS3), Bcl-2 and Bcl-xL expression, and cytokine production was studied. In addition, the effects of globular and high-molecular-weight (HMW) APN on LPL-T cytokine production and apoptosis were studied. RESULTS: Higher levels of several chemokines, cytokines, and growth factors were present in AT near active than near inactive disease. A significantly higher amount of inflammatory infiltrate was present in AT near active CD than near ulcerative colitis, controls, and near the inactive area of CD. There were no changes in the ratios of APN molecular weight in control and IBD adipocyte products. Leptin and APN inhibited anti-CD3-stimulated-LPL-T apoptosis and potentiated STAT3 phosphorylation, Bcl-2, and Bcl-xL expression in IBD and control mucosa. However, SOCS3 expression was suppressed only in IBD. Both globular and HMW APN have similar effects on LPL-T cytokine production and apoptosis. Leptin and APN enhanced interleukin (IL)-10 production by anti-CD3-stimulated LPL-T in IBD only. APN, but not leptin, increased anti-CD3-induced IL-6 levels in LPL-T only in IBD patients. IL-10 exerts its anti-inflammatory activity in the presence of SOCS3 suppression by leptin or APN. CONCLUSION: Leptin and APN maintain the inhibition of anti-CD3-stimulated LPL-T apoptosis by enhancing Bcl-2 and Bcl-xL overexpression and promoting STAT3 phosphorylation while suppressing SOCS3.

This chapter summarizes the clinical and diagnostic features, treatment, and prognosis of common Human Papillomavirus (HPV) infection. It discusses benign HPV-associated warts that occur exclusively on skin, on mucosa and adjacent skin, and in syndromes. These include: Butcher’s Wart, Cystic Wart (Plantar Epidermoid Inclusion Cyst), Filiform Wart, Verruca Plana (Flat Wart), Verruca Vulgaris (including Oral Verruca Vulgaris, Verruca Plantaris, Mosaic Wart, and Periungual Wart), Bowenoid Papulosis, Condyloma Acuminatum (Genital Wart), Conjunctival Papilloma, Focal Epithelial Hyperplasia (Heck’s Disease), Laryngeal Papillomatosis (Recurrent Respiratory Papillomatosis), Sinonasal Papilloma (Inverted, Fungiform, and Oncocytic types), and verricoses in congenital immunodeficiency diseases including Epidermodysplasia Verruciformis, Netherton Syndrome, WHIM Syndrome, WILD Syndrome, and Generalized Verrucosis.

The category of atypical glandular cells (AGC) in gynecologic cytopathology presents many well-documented diagnostic challenges, the most significant related to high interobserver variability, low specificity, and low positive predictive value. The current Bethesda System provides criteria for specific glandular categories including atypical endocervical cells not otherwise specified (AEC-NOS), AEC favor neoplastic, and atypical endometrial cells. The Bethesda System does, however, acknowledge that in some cases AGC cannot be categorized based upon cell of origin, in which case the generic term "atypical glandular cells" (AGC) may be used. We sought to determine whether further refinement of the current Bethesda System criteria for AEC-NOS might increase the positive predictive value of the general category of AGC. Fifty-three cases of AGC with documented histologic follow-up at the University of Illinois Hospital were reviewed. The cases were graded on each of the eight specific cytologic criteria recommended by the current Bethesda System for AEC-NOS using a study-developed three-tier grading system. Multiple regression analysis showed that four of the cytologic criteria in combination--nuclear enlargement, nuclear pleomorphism, increased nuclear-to-cytoplasmic (N/C) ratio, and cells occurring in sheets and strips with cell crowding and nuclear overlap--discriminated positive histologic outcome slightly better than any single criterion alone. In addition, simple logistic regression analysis showed nuclear enlargement to have a marginal independent association with positive histologic outcome (P = 0.0566). No other criterion was independently associated with outcome. Ancillary methods seem indicated to increase the positive predictive value of AGC at this time.