Demographic differences in early vs. late-stage laryngeal squamous cell carcinoma.

PURPOSE: This study aims to evaluate how various demographic factors impact the stage at diagnosis and, therefore, prognosis of laryngeal cancer. MATERIALS AND METHODS: Using the National Cancer Database, 96,409 patients were diagnosed with laryngeal squamous cell carcinoma between 2004 and 2020. Early (stage 0 or I) vs. late-stage (stage IV) cancers were compared based on demographic variables utilizing Chi-square and multivariate analysis with a significance of p < 0.05. RESULTS: Female, Black, and generally older patients were more likely to have late-stage cancer than their counterparts. When compared with a community cancer program, patients treated at other facility types were more likely to be diagnosed late. Patients with private insurance, Medicare, or other government insurance were all less likely to have late-stage cancer compared to patients without insurance. Compared to patients in the lowest median household income quartile, patients in the third quartile and fourth quartile were diagnosed earlier. Patients living in an area with the lowest level of high school degree attainment were most likely to be diagnosed late. Living in a more populous area was associated with a lower chance of being diagnosed late. Increasing Charlson-Deyo Score was associated with a stronger likelihood of being diagnosed at a later stage. CONCLUSION: Patients who are female, Black, uninsured, have a low household income, live in less populated and less educated areas, are treated at non-community cancer programs, and have more comorbid conditions have later stage diagnoses. This data contributes to understanding inequities in healthcare.

Chemical Regulation of the Protein Quality Control E3 Ubiquitin Ligase C-Terminus of Hsc70 Interacting Protein (CHIP).

The ubiquitin ligase C-terminus of Hsc70 interacting protein (CHIP) is an important regulator of proteostasis. Despite playing an important role in maintaining proteostasis, little progress has been made in developing small molecules that regulate ubiquitin transfer by CHIP. Here we used differential scanning fluorimetry to identify compounds that bound CHIP. Compounds that bound CHIP were then analyzed by quantitative ubiquitination assays to identify those that altered CHIP function. One compound, MS.001, inhibited both the chaperone binding and ubiquitin ligase activity of CHIP at low micromolar concentrations. Interestingly, we found that MS.001 did not have activity against isolated U-box or tetratricopeptide (TPR) domains, but instead only inhibited full-length CHIP. Using in silico docking we identified a potential MS.001 binding site on the linker domain of CHIP and mutation of this site rendered CHIP resistant to MS.001. Together our data identify an inhibitor of the E3 ligase CHIP and provides insight into the development of compounds that regulate CHIP activity.

ReviSTER: an automated pipeline to revise misaligned reads to simple tandem repeats.

MOTIVATION: Simple tandem repeats are highly variable genetic elements and widespread in genomes of many organisms. Next-generation sequencing technologies have enabled a robust comparison of large numbers of simple tandem repeat loci; however, analysis of their variation using traditional sequence analysis approaches still remains limiting and problematic due to variants occurring in repeat sequences confusing alignment programs into mapping sequence reads to incorrect loci when the sequence reads are significantly different from the reference sequence. RESULTS: We have developed a program, ReviSTER, which is an automated pipeline using a 'local mapping reference reconstruction method' to revise mismapped or partially misaligned reads at simple tandem repeat loci. RevisSTER estimates alleles of repeat loci using a local alignment method and creates temporary local mapping reference sequences, and finally remaps reads to the local mapping references. Using this approach, ReviSTER was able to successfully revise reads misaligned to repeat loci from both simulated data and real data. AVAILABILITY: ReviSTER is open-source software available at http://revister.sourceforge.net. CONTACT: garner@vbi.vt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The Use of Biologic Mesh for Repair of Perianal Fistulas.

This is a case series of three patients who presented with complex anorectal fistulas. Each patient underwent repair of complex anorectal fistulas with biologic mesh. We will discuss each case and our institution's experience with this relatively new technique. This case series demonstrates the use of biologic mesh for the repair of complex anorectal fistulas. Three patients are discussed who underwent repair of perianal fistulas using ACell mesh by two separate surgeons. We will discuss the rationale for offering this treatment, as well as the advantages and disadvantages. The use of biologic mesh in perianal fistulas is a relatively new topic that needs further investigation. Perianal fistulas can be difficult to manage for both patients and surgeons. There are many options for repair, ranging from simple to complex. Biologic mesh for complex fistulas may be a useful option to avoid the morbidity of more complex repairs, such as flaps.

Effects of the probiotic Lactobacillus animalis in murine Mycobacterium avium subspecies paratuberculosis infection.

BACKGROUND: MAP is a suspected zoonotic pathogen and the causative agent of Johne's Disease in cattle and other ruminant animals. With over $1 billion dollars in loss to the dairy industry due to Johne's Disease, efforts to eliminate or reduce MAP from cattle are of importance. The purpose of this study was to determine if daily intake of probiotics could eliminate or reduce Johne's Disease associated symptoms and pathogenesis by MAP. Post infection, animals are often asymptomatic carriers with limited shedding of the pathogen, proving early detection to be difficult. Disease and symptoms often appear 3-4 years after infection with antibiotic treatment proving ineffective. Symptoms include chronic gastrointestinal inflammation leading to severe weight-loss from poor feed and water intake cause a wasting disease. These symptoms are similar to those found in individuals with Crohn's Disease (CD); MAP has been implicated by not proven to be the causative agent of CD. Probiotics administered to livestock animals, including dairy and beef cattle have demonstrated improvements in cattle performance and health. Our objectives included determining the benefits of Lactobacillus animalis (strain name: NP-51) in MAP infected BALB/c mice by evaluating systemic and gastrointestinal response by the host and gut microbiota. Male and female animals were fed 1×106 CFU/g probiotics in sterile, powdered mouse chow daily and infected with 1 × 107 CFU/ml MAP and compared to controls. Animals were evaluated for 180 days to assess acute and chronic stages of disease, with sample collection from animals every 45 days. MAP concentrations from liver and intestinal tissues were examined using real time-PCR methods and the expression of key inflammatory markers were measured during MAP infection (interferon-gamma [IFN-Υ], Interleukin-1α, IL-12, IL-10, IL-6, and Tumor necrosis factor alpha [TNF-α]). RESULTS: Our results demonstrate administration of probiotics reduces production of IFN-Υ and IL-6 while increasing TNF-α and IL-17 in chronic disease; healthful immune responses that reduce chronic inflammation associated to MAP infection. CONCLUSIONS: We observed that the immune system's response in the presence of probiotics to MAP contributes towards host health by influencing the activity of the immune system and gut microbial populations.

Orphan nuclear receptor NR4A2 induces synoviocyte proliferation, invasion, and matrix metalloproteinase 13 transcription.

OBJECTIVE: To address the role of the nuclear receptor 4A (NR4A) family of orphan nuclear receptors in synoviocyte transformation, hyperplasia, and regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in models of inflammatory arthritis. METHODS: NR4A messenger RNA levels in synovial tissue and primary synoviocytes were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). NR4A2 was stably overexpressed in normal synoviocytes, and cell proliferation, survival, anchorage-independent growth, migration, and invasion were monitored in vitro. MMP and TIMP expression levels were analyzed by quantitative RT-PCR, and MMP-13 promoter activity was measured using reporter assays. Stable depletion of endogenous NR4A levels was achieved by lentiviral transduction of NR4A short hairpin RNA (shRNA), and the effects on proliferation, migration, and MMP-13 expression were analyzed. RESULTS: NR4A2 was expressed at elevated levels in normal, OA, and RA synovial tissue and in primary RA synoviocytes. Tumor necrosis factor α (TNFα) rapidly and selectively induced expression of NR4A2 in synoviocytes. Ectopic expression of NR4A2 in normal synoviocytes significantly increased proliferation and survival, promoted anchorage-independent growth, and induced migration and invasion. MMP-13 gene expression was synergistically induced by NR4A2 and TNFα, while expression of TIMP-2 was antagonized. NR4A2 directly transactivated the proximal MMP-13 promoter, and a point mutation in the DNA binding domain of NR4A2 abolished transcriptional activation. Depletion of endogenous NR4A receptors with shRNA reduced synoviocyte proliferation, migration, and MMP-13 expression. CONCLUSION: The orphan nuclear receptor NR4A2 is a downstream mediator of TNFα signaling in synovial tissue. NR4A2 transcriptional activity contributes to the hyperplastic and invasive phenotype of synoviocytes that leads to cartilage destruction, suggesting that this receptor may show promise as a therapeutic target in inflammatory arthritis.

Transanal Minimally Invasive Surgery for Marsupialization of Chronic Abscess Cavity After Colorectal Anastomosis.

Anastomotic leaks are one of the most feared and morbid complications after colorectal anastomosis. Management of leaks depends on the severity of the leak and focuses on controlling sepsis and saving the anastomosis. The lower the anastomosis, the more amenable it is to transanal approaches for salvage. However, when a complication exists higher up in the rectum, the surgeon is more limited in the ability to visualize and intervene. With the advent of transanal minimally invasive surgery (TAMIS) and the advancement of endoscopic procedures, there are now more options for surgeons to visualize and intervene in anastomotic colorectal leaks. Prior reports have described the use of TAMIS for the management of anastomotic leaks in the acute phase. However, this same approach can be useful in the management of chronic leaks. This report highlights the benefit of TAMIS to allow visualization and marsupialization of a chronic abscess cavity following an anastomotic leak.

Relationship between anal cancer recurrence and cigarette smoking.

BACKGROUND: The incidence of anal cancer has been increasing in the United States. Smoking is a well-established risk factor; however, the impact of smoking on disease re-currence and outcome has not been well studied. The aim of this study was to assess the association between anal cancer recurrence and cigarette smoking. AIM: To investigate the relationship between cigarette smoking status and anal cancer treatment outcome. METHODS: The cancer registry from a single, community hospital was screened for patients with anal cancer between 2010 and 2021. The following characteristics were gathered from the database: Age; sex; cigarette smoking history; American Joint Committee on Cancer Clinical Stage Group; response to therapy; recurrence; time to recurrence; mortality; time to death; and length of follow-up. Patients were divided into the following groups: Current smokers; former smokers; and never smokers. SPSSv25.0 software (IBM Corp., Armonk, NY, United States) was used for statistical analysis. RESULTS: A total of 95 patients from the database met the screening criteria. There were 37 never smokers, 22 former smokers, and 36 current smokers. There was no difference between groups in regards to race or sex. There was no difference in the American Joint Committee on Cancer Clinical Stage Group between groups. The former smokers were significantly older when compared to never smokers and current smokers (66.5 ± 13.17 vs 57.4 ± 7.82 vs 63.7 ± 13.80, P = 0.011). Former smokers and current smokers had a higher recurrence rate compared to never smokers (30.8% and 20.8% compared to zero, P = 0.009). There was not a significant difference in recurrence between former smokers and current smokers. There was no difference in the mortality, non-response rate, or time to death between the groups. CONCLUSION: Our data contributes evidence that cigarette smoking status is associated with increased recurrence for patients with anal cancer.

Utilization of Palliative Care in Osteosarcoma: A National Cancer Database Review.

Background: Osteosarcoma is the most common form of bone cancer, but the utilization of palliative care (PC) in patients with this cancer has not previously been investigated in the National Cancer Database (NCDB). Methods: Patients diagnosed with osteosarcoma (2004-2017) were identified within the NCDB. Cross tabulations with Chi-square analysis were performed to evaluate frequencies of palliative care use by patient, facility, and tumor characteristics. Multivariate logistic binary regression was performed to evaluate relationships between patient, treatment facility, and tumor characteristics and the use of palliative care. Results: A total of 7498 patients were analyzed with 2.8% of patients diagnosed having any form of palliative care utilization. Of this group, 53.37% received PC within the first 12 months after diagnosis. Of the 2.8% of patients receiving PC the most common forms of PC utilized were non-curative symptom-directed surgery, radiation, or chemotherapy, or a combination of these modalities (56.7%). Palliative care usage was increased in patients with greater tumor diameter, tumors in the bones of the midline, or stage IV tumors. Palliative care usage was decreased in patients living within 25-49 miles of their treatment facility, those living in pacific states, those with chondroblastic osteosarcoma, or those with private insurance. Conclusion: Palliative care use in patients with osteosarcoma increases with tumor stage, tumor size, or more proximal tumors, but overall utilization remains markedly low. Future studies should further define these patterns of care and help expand the utilization of PC.

Association Between Demographic and Socioeconomic Factors and Diagnosis of Advanced Non-small Cell Lung Cancer: An Analysis of the National Cancer Database.

Introduction Lung cancer is a prevalent and potentially lethal cancer. The stage at initial presentation for diagnosis predicts mortality and helps to guide treatment options. Thus, it is critical to determine what factors impact the stage of cancer at diagnosis. This study sought to determine if certain socioeconomic and demographic factors are associated with receiving an early (Stage 0-I) or advanced (Stage IV) diagnosis of non-small cell lung cancer (NSCLC). Methods Using the National Cancer Database (NCDB), 1,149,539 patients were identified as having an NCDB Analytic Stage Group diagnosis of Stage 0-I (early) versus Stage IV (advanced) NSCLC between 2004 and 2018. Patients with early and delayed diagnoses were compared based on specific characteristics including sex, race, ethnicity, number of comorbid conditions, insurance status, median annual income, level of education, geographic location, and reporting facility. Using IBM SPSS Statistics for Windows, Version 28 (Released 2021; IBM Corp., Armonk, New York, United States), the data underwent analysis using binary multivariate logistic regression, chi-square analyses, and one-way ANOVA. Results Factors associated with an advanced diagnosis of NSCLC include being male, Black, Native American, or Hispanic. Compared to patients with at least one comorbid condition, those without comorbid conditions are more likely to present with advanced disease. Patients with private insurance, Medicaid, Medicare, or other government insurance are all less likely to present with advanced-stage cancer than patients without insurance. Compared to patients in the lowest median household income quartile, those in the second and fourth quartiles are diagnosed earlier. Patients living in areas where a higher proportion of residents lack a high school diploma are more likely to present with advanced NSCLC. Additionally, living in the Midwest and Western United States and presenting to Community Cancer programs are associated with advanced disease at initial presentation. Conclusions Factors that were associated with the advanced presentation of NSCLC included being male, Black, Native American, or Hispanic, having a lack of comorbid conditions or insurance, earning a lower median annual income, and living in a zip code where a higher proportion of residents lack a high school diploma. Additionally, residing in the Midwest and Western United States and seeking care at Community Cancer programs were associated with advanced disease at initial presentation. Understanding that certain socioeconomic and demographic factors impact the stage at initial diagnosis of NSCLC can allow for targeted intervention strategies aimed at the most at-risk individuals, areas, and facilities.

Odds of Stage IV Bone Cancer Diagnosis Based on Socioeconomic and Geographical Factors: A National Cancer Database (NCDB) Review.

BACKGROUND: There are significant differences in prognosis for osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordomas based on the stage at diagnosis. The five-year survival of these bone cancers varies from 75-87% at an early stage of diagnosis and falls to 27-55% at a late stage of diagnosis. PATIENTS AND METHODS: This study retrospectively evaluated the odds of stage I vs stage IV cancer at the time of diagnosis in patients with primary malignant bone tumors (osteosarcoma, chondrosarcoma, Ewing sarcoma and chordoma) diagnosed in the National Cancer Database (NCDB) between 2004 and 2018. Cross tabulations with Chi-square analysis were performed to evaluate frequencies of different socioeconomic and geographical characteristics between patients with stage I vs stage IV cancer. Multivariable binary logistic regression was performed to evaluate relationships between socioeconomic and geographical factors and the odds of stage IV cancer at the time of diagnosis. Statistical significance was set at α = 0.05. RESULTS: 8882 patients with stage I and 3063 with stage IV primary malignant bone tumors were identified. The odds of stage IV bone cancer at diagnosis are increased for patients on Medicaid (odds ratio [OR] = 1.298, 95% confidence interval [CI]: 1.043-1.616) or Medicare (OR = 1.795, 1.411-2.284). Odds of stage IV bone cancer at diagnosis were decreased with female sex (OR = 0.733, 0.671-0.800), private insurance (OR = 0.738, 0.601-0.905), and those treated at community cancer programs (OR = 0.542, 0.369-0.797), comprehensive cancer program (OR = 0.312, 0.215-0.452), or academic/research facilities (OR = 0.370, 0.249-0.550). No significant relationship was identified between the stage at diagnosis and race, ethnicity, Charlson-Deyo score, or education level. Stage IV cancer at diagnosis showed was proportionally lower in chondrosarcomas (17.1%) and chordomas (2.1%) than osteosarcomas (45.0%) and Ewing sarcomas (35.8%). CONCLUSION: Odds of stage IV bone cancer at diagnosis are greater with male sex, Medicaid or Medicare insurance status, or treatment at community cancer programs. Providers should have a low suspicion for additional evaluation when treating patients with symptoms of bone cancer and should be aware of these disparities when treating people in these groups. This is to the authors' knowledge the first such study conducted through the NCDB.

Survey of Palliative Care Use in Primary Malignant Bone Tumors: A National Cancer Database Review.

Background/Objectives: Palliative care (PC) has been associated with reduced patient symptom burden, improved physician satisfaction, and reduced cost of care. However, its use in primary bone tumors has not been well classified. Design/Setting and Subjects: Patients diagnosed with primary malignant bone tumors (osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma) between 2004 and 2018 were identified in the National Cancer Database. Cross tabulations with chi-square analysis were performed to evaluate frequencies of PC use by patient, facility, and tumor characteristics. Multivariate logistic binary regression was performed to evaluate relationships between patient, treatment facility, and tumor characteristics and the use of PC. Results: Around 24,401 patients were identified. Overall, 2.52% had any form of PC utilization. Of those receiving PC, 55.5-65.1% were treated with only noncurative surgery, radiation, chemotherapy, or any combination of these modalities. Odds of PC utilization were decreased for patients with chordomas, patients living >24 miles from the treatment facility, or patients with private insurance, Medicare, or unknown insurance status. Odds of PC utilization were increased in patients with greater tumor diameter or unknown tumor size, tumors in midline, increased tumor grade, stage IV tumors, or living in urban areas. Conclusion: PC use in patients with primary bone tumors increases with tumor stage, tumor grade, tumor size, and if the tumor is midline, and in patients living in urban areas. However, overall utilization remains markedly low. Future studies should be done to investigate these patterns of care and help expand the utilization of PC.

Effects of Socioeconomic and Geographic Factors on Outcomes in Ewing Sarcoma: A National Cancer Database Review.

PURPOSE: Ewing sarcoma is a primary malignant bone tumor that manifests predominantly in the proximal long bones and pelvis and traditionally presents with nonspecific symptoms. This tumor preferentially affects children and young adults, occurring most often in patients of European descent. The most important established prognostic factor is the presence of metastasis at the time of diagnosis followed by primary site, size of the primary neoplasm, patient age, and lactate dehydrogenase (LDH) levels. To the authors' knowledge, this is the first study focused on the effects of socioeconomic and geographic factors on overall survival in Ewings sarcoma. METHODS: A total of 3,920 patients diagnosed with Ewing sarcoma were identified in the National Cancer Database (NCDB) using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) code 9260. Of these, 3,238 met the inclusion criteria and were analyzed. Descriptive statistics, Kaplan-Meier survival curves, and Cox regression tables were all performed using IBM SPSS Statistics for Windows, Version 27.0 (Released 2020; IBM Corp., Armonk, New York, United States). RESULTS: Univariate analysis showed greater mortality for patients of increasing age at the time of diagnosis, at two, five, and 10 years of follow-up, Black race patients at two years, Medicare insurance status at two years, urban or rural residence at two and 10 years, more advanced tumor stage at two and five years, and patients with a comorbidity score of ≥2 at two years. Multivariate analysis showed greater mortality at two years with increasing age, Black race, uninsured status, urban or rural residence, and increasing tumor stage. Mortality also increased for patients at five years of follow-up in patients with increasing age or more advanced tumor stage.  Conclusion: Patient mortality in the first two years after diagnosis is increased for patients of the Black race, those living in urban or rural areas, and for patients that are uninsured or using Medicare as their primary payor at the time of diagnosis. To improve patient outcomes, clinicians should recognize and address not only the unique biology of patients but also their unique challenges in access to healthcare. Patients and providers should work to elicit changes on an individual and community level to improve their personal health and the health of those around them.

YouTube and the Achilles Tendon: An Analysis of Internet Information Reliability and Content Quality.

PURPOSE: To evaluate the educational content, quality, and reliability of YouTube videos regarding the Achilles tendon and Achilles tendon injuries. METHODS: The first 50 videos found on YouTube after searching "Achilles tendon" were evaluated and classified by content type and uploader source. Reliability and accuracy were assessed using the Journal of the American Medical Association (JAMA) benchmark criteria, nonspecific educational content was assessed via the Global Quality Score (GQS), and specific educational content was assessed using the Achilles Tendon Specific Score (ATSS). ANOVA was performed to determine differences in video reliability and educational content quality by video content type and source. Multivariate stepwise regressions were used to evaluate the effects of specific video characteristics on JAMA benchmark criteria, GQS, and ATSS. RESULTS: The 50 videos evaluated had a cumulative view total of 53,323,307, a mean of 1,066,466, and a range of 1,009 to 42,663,665 views per video. Most videos focused on disease-specific information (38%) and exercise training (22%). Most videos were uploaded by non-physicians (34%) or medical sources (health websites) (32%). A higher view ratio was an independent predictor of lower JAMA scores (lower reliability and accuracy) (standardized beta = -0.281, P = 0.048) and increased video duration was an independent predictor of greater GQS (standardized beta = 0.380, P = 0.007) and ATSS scores (standardized beta = 0.364, P = 0.009) (increased quality of nonspecific and specific educational content). CONCLUSION: Videos on YouTube regarding the Achilles tendon were viewed numerous times, but their educational content and reliability were poor. Providers treating patients for Achilles tendon-related pathologies should initiate a dialogue with patients about their use of internet sources and should educate them on their optimal usage. They should warn them of the low quality of YouTube-derived information and provide them with reliable sources that may better give them control over their own care.

Predicting Post-operative Complications in Crohn's Disease: an Appraisal of Clinical Scoring Systems and the NSQIP Surgical Risk Calculator.

BACKGROUND: Surgery is common in patients with Crohn's disease and can contribute significantly to patient morbidity. The National Surgical Quality Improvement Program surgical risk calculator (NSQIP-SRC) that is currently utilized to predict surgical risk does not take Crohn's disease into account and, as a result, seems to underestimate risk in this patient population. This study aimed to evaluate the accuracy of the NSQIP-SRC in Crohn's disease patients and to evaluate the utility of disease severity scores in predicting surgical risk. METHODS: Between 2011 and 2017, there were 176 surgical cases involving Crohn's disease patients. Demographic data and 30-day surgical outcomes were collected. Disease severity scores including Harvey Bradshaw Index (HBI), Crohn's Disease Activity Index (CDAI), Simple Endoscopic Score for Crohn's Disease (SES-CD), and NSQIP-SRC risk percentages were calculated. RESULTS: Patients in remission based on HBI had a complication rate of 8.57% (n = 3), while those with mild or moderate-severe disease had rates of 33.33% (n = 11) and 38.46% (n = 20) respectively (p = 0.0045). In multivariable analysis, those with mild (OR; 8.37, 95% CI; 1.64, 42.78; p = 0.011) or moderate-severe (OR; 11.69, 95% CI; 2.42, 56.46; p = 0.002) disease had increased odds of complication compared to remission. Complication rate was not associated with NSQIP-SRC percent risk of any complication. CONCLUSION: NSQIP-SRC does not accurately predict risk in patients with CD undergoing surgery. Higher disease activity based on HBI is associated with increased odds of complication and may prove to be more predictive of surgical complication in the Crohn's patient population.

Diaphragmatic Hernia Perforation Leading to Fecopneumothorax.

Hiatal hernia is a common diagnosis. Unless symptomatic, most hiatal hernias are not repaired; in rare cases, however, severe complications can develop during conservative treatment. Although fecopneumothorax occurrence has been described in trauma and related to colonic pathology, it has not been described as occurring from spontaneous strangulation of a hiatal hernia. Regardless of the etiology, prompt recognition of the rare occurrence of fecopneumothorax is imperative. This report describes the presentation, diagnosis, and treatment of a patient presenting with a type IV hiatal hernia that resulted in colonic ischemia, perforation, and fecopneumothorax.

ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice.

Glioblastoma multiforme is the most common and lethal form of primary brain cancer. Diagnosis of this advanced glioma has a poor prognosis due to the ineffectiveness of current therapies. Aberrant expression of receptor tyrosine kinases (RTK) in glioblastoma multiformes is suggestive of their role in initiation and maintenance of these tumors of the central nervous system. In fact, ectopic expression of the orphan RTK ROS is a frequent event in human brain cancers, yet the pathologic significance of this expression remains undetermined. Here, we show that a glioblastoma-associated, ligand-independent rearrangement product of ROS (FIG-ROS) cooperates with loss of the tumor suppressor gene locus Ink4a;Arf to produce glioblastomas in the mouse. We show that this FIG-ROS-mediated tumor formation in vivo parallels the activation of the tyrosine phosphatase SH2 domain-containing phosphatase-2 (SHP-2) and a phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling axis in tumors and tumor-derived cell lines. We have established a fully penetrant preclinical model for adult onset of glioblastoma multiforme in keeping with major genetic events observed in the human disease. These findings provide novel and important insights into the role of ROS and SHP-2 function in solid tumor biology and set the stage for preclinical testing of targeted therapeutic approaches.

Genomics of Peritoneal Malignancies.

The peritoneum protects the intraabdominal organs. This function is exploited by aggressive cancers originating from organs within the abdomen, resulting in peritoneal metastasis. We discuss genomic variants that may lead to peritoneal metastasis from multiple cancers. Peritoneal malignancies are attributed to epithelial-mesenchymal transition. These metastatic lesions harbor similar genetic mutations to the primary tumor yet may manifest clone-specific aberrations that promote propagation. Peritoneal metastasis are increasingly being treated with surgical resection as an adjunct to radiation, chemotherapy, and other biologic therapies. We describe genetic and genomic variances that are predictive markers for metastasis and burgeoning indicators for peritoneal malignancies.

Environmental Sound Awareness in Experienced Cochlear Implant Users and Cochlear Implant Candidates.

OBJECTIVE: To determine if postlingually deaf adult cochlear implant (CI) users have better environmental sound awareness (ESA) compared with adult patients eligible for CIs who have not yet undergone implantation. STUDY DESIGN: Cross-sectional cohort study. SETTING: Tertiary referral center. PATIENTS: A group of 39 postlingually deaf adult patients who are experienced CI users (ECI), and a group of 20 postlingually deaf adult patients who are cochlear implant candidates (CIC) awaiting implantation. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURE: Environmental sound awareness as measured by accuracy (percent correct) using the computerized, Familiar Environmental Sounds Test-Identification (FEST-I). RESULTS: There was no significant difference between ESA in our sample of ECI users versus CIC patients. The ECI users scored an average FEST-I accuracy of 59.9% (SD 14.3). In comparison, the CICs had an average FEST-I accuracy of 54.7% (SD 26.4). This difference was not statistically significant. CONCLUSIONS: Our findings suggest that, despite the commonly held notion that improved ESA may be a benefit of cochlear implantation, our sample of ECI users did not demonstrate superior performance compared with CICs.

Sex differences in hedonic judgement of odors in schizophrenia cases and healthy controls.

The neurocircuitries subserving affective and olfactory processes overlap, are sexually dimorphic, and show disruptions in schizophrenia, suggesting their intersection may be a window on the core process producing psychosis. This study investigated diagnostic and sex differences in hedonic judgments of odors and smell identification in 26 schizophrenia cases and 27 healthy controls. Associations between olfaction measures and psychiatric symptoms were also examined. Cases and controls had similar identification accuracy of unpleasant odors, but cases were significantly less accurate in naming pleasant odors. In cases, greater negative symptom severity was related to abnormal hedonic judgments; specifically, higher pleasantness ratings for unpleasant odors and higher unpleasantness ratings for pleasant odors. Greater positive symptom severity was associated with lower pleasantness ratings for neutral odors. Regarding sex differences, male cases and female controls rated pleasant odors as significantly more unpleasant than male controls. Correlations between depression severity and pleasantness ratings of neutral odors were in opposite directions in male and female cases. These results suggest that a normal sexual dimorphism in the circuitry for hedonic odor judgments may interact with schizophrenia pathology, supporting the utility of olfactory hedonics as a sex-specific biomarker of this pathology.