Christian Grønhøj Larsen

Human Papillomavirus Shows Highly Variable Prevalence in Esophageal Squamous Cell Carcinoma and No Significant Correlation to p16INK4a Overexpression: A Systematic Review

Introduction: This review investigates the role of p16INK4a as a marker of transcriptionally active human papillomavirus (HPV) in esophageal squamous cell carcinoma (ESCC) and the regional prevalence of HPV in ESCC. Methods: PubMed, EMBASE, and the Cochrane Library were systematically searched with the purpose of identifying all studies published between January 1980 and July 2013 reporting both HPV and p16INK4a results in a minimum of five human ESCC specimens. Results: Twelve studies were identified, providing data on a total of 1383 ESCC specimens collected between 1987 and 2009 from 10 different countries. HPV DNA was detected in 12.0% (n = 161) of 1347 specimens, and p16INK4a was detected in 33.9% (n = 209) of 617 specimens. The HPV presence varied from 0% to 70% among the studies. The prevalence of p16INK4a overexpression in HPV-positive and HPV-negative specimens demonstrated no statistically significant difference, neither for the combined data (p = 0.7507) nor for any individual study, and detection of p16INK4a overexpression did not affect the odds of tumors being HPV positive (odds ratio = 1.0666 with 95% confidence interval 0.7040–1.6157). In a pooled analysis, the sensitivity of p16INK4a overexpression as a marker of HPV DNA presence was 0.35, the specificity 0.67, and the positive predictive value 0.25. Conclusions: This systematic review reports great regional variation in the prevalence of HPV in ESCC and suggests that p16INK4a is not a reliable marker of HPV status in ESCC.

Immune cells and prognosis in HPV-associated oropharyngeal squamous cell carcinomas: Review of the literature

Currently, oropharyngeal squamous cell carcinomas (OPSCC) are treated based on the traditional TNM-classification, although this scheme might be inadequate for the subgroup of human papillomavirus (HPV)-associated OPSCCs. It remains debatable whether this subgroup of patients with favorable prognosis should be offered altered treatment. Besides the well-known biomarkers of HPV and p16, new promising immune cells and markers might nuance the prognosis and treatment for patients with HPV+ OPSCC. We systematically reviewed the literature on immunological features of HPV-associated OPSCCs, and report that a high number of cytotoxic T cells (CD8s) and a low number of CD98 positive cells is associated with better outcome, while an increased CD4/CD8 ratio and a high human leukocyte antigen 1 (HLA1) intensity is most likely associated with worse outcome. These findings might contribute to future OPSCC staging and treatment.

Allergic rhinitis is often undiagnosed and untreated: results from a general population study of Danish adults.

A few earlier studies have indicated that allergic rhinitis (AR) is underdiagnosed and undertreated.

Validation study of HPV DNA detection from stained FNA smears by polymerase chain reaction: Improving the diagnostic workup of patients with a tumor on the neck.

Human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (OPSCC) often presents with cystic cervical metastasis and a small primary tumor localized in the palatine tonsils or base of the tongue, which is diagnostically challenging. Testing for HPV DNA in fine‐needle aspiration (FNA) smears from metastases may facilitate a targeted diagnostic workup for identifying the primary tumor. This study was designed to assess the ability to detect HPV DNA in FNA smears with polymerase chain reaction (PCR).

Regular health checks: cross-sectional survey.

Objective To investigate whether Danish providers of general health checks present a balanced account of possible benefits and harms on their websites and whether the health checks are evidence-based. Methods and Design Cross-sectional study. The search engines Google and Jubii (Danish) were in July and August 2009 used to identify 56 websites using Danish search terms for “health check” and “health examination”. The content of the websites were evaluated using a checklist with 15 officially recommended information items. All tests offered through the websites were registered. The evidence for tests offered through at least 10% of the websites was identified in structured searches using PubMed and The Cochrane Library. Results We found 36 different tests on 56 websites offering health checks. Twenty one tests were offered on at least 10% of the websites. Seventeen (81%) of these tests were unsupported by evidence, or there was evidence against them for screening purposes. We found evidence supporting screening using body-mass-index, blood pressure, cholesterol, and faecal occult blood testing. None of the websites mentioned possible risks or harms. The websites presented a median of 1 of the 15 information items; the highest number from any provider was 2. Conclusions Information from Danish providers of health checks was sparse and tests were often offered against existing evidence or despite lack of evidence. None of the included websites mentioned potential risks or harms.

Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies

Objectives Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. Data Sources PubMed, Embase, the Cochrane Library and Google Scholar were searched. Methods Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. Results Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η’) and elastic modulus (G’), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds. Conclusion The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies.

Surgical Timing of the Orbital “Blowout” Fracture: A Systematic Review and Meta-analysis

Objective The orbital blowout fracture is a common facial injury, carrying with it a risk of visual impairment and undesirable cosmetic results unless treated properly. Optimal timing of the surgical treatment is still a matter of debate. We set out to determine whether a meta-analysis would bring us closer to an answer to this question. Data Sources PubMed, EMBASE, Web of Science, and the Cochrane Library were searched from January 1980 to August 2014. We applied the following inclusion criteria: isolated blowout fractures, presenting early and late surgery groups (<14 and >14 days). Patients were evaluated for diplopia and enophthalmos. Review Methods We followed the statements of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses). Pooled odds ratios were estimated with the fixed effects method of Mantel-Haenszel. Results We identified 5 studies with available outcome data (N = 442). Patients in the late group showed an odds ratio of 3.3 (P = .027) for persistent postoperative diplopia as compared with the early group. We found no significant difference between the groups when assessing postoperative enophthalmos as an isolated symptom. Conclusion We found a significantly increased risk of persistent diplopia in patients who were operated >14 days after the trauma.

Developmentally Delayed Male with Mincer Blade Obstructing the Oesophagus for a Period of Time Suspected to Be 6 Months

Introduction. Sharp, retained foreign bodies in the oesophagus are associated with severe complications. Developmentally delayed patients are especially subject to foreign objects. We describe a 37-year-old, developmentally delayed male with a mincer blade obstructing the oesophagus. Six months prior to surgical intervention, the patient was hospitalized in a condition of sepsis and pneumonia where the thoracic X-ray reveals a foreign body in the proximal oesophagus. When rehospitalized 6 months later, a mincer blade of the type used in immersion blenders was surgically removed. During these 6 months the patients main symptoms were dysphagia, weight loss, and diarrhoea. When developmentally delayed patients present with dysphagia, we strongly encourage the awareness of the possible presence of foreign bodies. To our knowledge this is the first reported case of a mincer blade in the oesophagus.

Who evaluates p16 immunohistochemistry

Large amounts of data exist on the performance and interpretation of p16 immunohistochemistry (p16-IHC) from systematic reviews, retrospective studies and prospective studies (1–5). However, there is no consensus on whether pathologists are required for p16-IHC evaluation. High-risk types of human papilloma virus (HRHPV), such as HPV16/18/33, are known causes of oropharyngeal squamous cell carcinoma (OPSCC), and the presence of HR-HPV has great implications for patient prognosis and survival (6–8). p16 is broadly accepted as a surrogate marker for HPV infection, and the activity of viral oncoproteins indicates whether the infection is biologically active (5, 9–11). Currently, p16-IHC is routinely applied to tissue sections due to its clinical importance, accessibility and low technical costs (5). To the best of our knowledge, no reviews or inter-observer variability studies have assessed which professionals should analyse p16-IHC. This topic is important because evaluation of IHC requires certain skills, including the ability to distinguish between different cells. For an inexperienced person, this can be difficult. Consequently, p16IHC results may be interpreted and reported incorrectly. To address this matter, we aimed to describe how published studies have reported p16 evaluation. We extracted relevant data (Table 1) from a systematic review and meta-analysis on the correlation between the definition of p16 overexpression and HPV status. A total of 39 original studies (n = 3926 patients) were identified through a literature search of PubMed, Embase and the Cochrane Library from 1980 until October 2012 using the following inclusion criteria: a minimum of 20 cases of site-specific OPSCC and HPV with p16 results available. p16 evaluation was performed by a pathologist in 56% of the studies (n = 22/39), whereas 44% (n = 17/39) of the studies did not present data on which professionals evaluated the staining. This number may indicate a lack of reporting or that the stains were evaluated by a non-pathologist. It remains controversial whether the evaluation of p16 staining should be performed by a pathologist. The current data indicate that a large number of studies do not report evaluation-related data. Obviously, the results of p16-IHC evaluation are based on the definition of overexpression, which differs widely, ranging from verbal definitions (e.g. ‘strong cytoplasmic staining’) to various numerical definitions (e.g. ‘>5% staining’ or ‘>70% cytoplasmic and nuclear staining’) (3). New definitions of overexpression still arise, including >40% cytoplasmic and/or nuclear staining (12). It remains debatable whether p16-IHC can be defined as overexpressed if there is no nuclear staining. Furthermore, tumours with 50–75% staining might lack HPV, which is why Lewis proposed that these stains should be further evaluated via HPV-PCR (13). Meta-analyses examining inter-observer variability in IHC studies are difficult to perform due to different laboratory set-ups. In addition, the results may be affected by the use of different antibody clones (3). In true-positive and true-negative p16 stains, some non-neoplastic cells will always stain positive to a certain degree and serve as a positive internal control indicating whether the stain is suitable for evaluation. This interpretation might be a challenge for non-pathologists because false-negative stains can be misinterpreted as truenegatives. The challenge of evaluating IHC is clear in mammary pathology; e.g. the evaluation of HER2-IHC is known to be difficult. In most institutions, specially trained pathologists are responsible for this job because the treatment differs considerably based on whether a tumour is HER2-positive. Treatment of oropharyngeal tumours does not depend on p16 status; however, future regimens might include altered therapy for HPVand p16-positive tumours, including robotic surgery for tongue base and palatine tonsillar tumours and lower dose or field radiotherapy. Because p16 staining is widely used in research and clinical settings, we recommend that data regarding the pathological evaluation are included in these studies. Preferably, guidelines

Detection of HPV-DNA from May-Grunvald-Giemsa Stained Fine Needle Aspiration Specimens Using Polymerase Chain Reaction

Results: IPMC involved >5% of villi in 11 of 17 placentas (65%) from FD cases, but only 1 of 118 from live births (0.8%, p<0.0001). IPMC involved >10% of villi in 5 of 17 placentas (30%) from FD cases and none from live births (0%, p<0.0001). Clinical data for 11 of the 17 FD cases was available. IPMC in >5% of villi were seen in 3 of the 7 cases where fetus was delivered within 1 day, versus 4 of 4 cases where fetus was retained for >1 days after demise (p<.05). Frequency of IPMC in categories other than fetal demise are shown in table 1.