Forensic cardiac device analysis at the Los Angeles County Department of the Coroner: A 20-year experience.

Cardiac implantable electronic devices (CIEDs) store information continuously; however, the log of these devices is rarely analyzed in forensic practice. We retrospectively reviewed all cases referred for CIED interrogation by the Los Angeles County Department of Medical Examiner-Coroner between 2001 and 2020. According to the Department's practice, CIED interrogation may be requested for decedents in which details or cause of death are not clear from autopsy and clinical history. The CIED analysis was considered informative for the coroner's investigation either if it detected an arrhythmia or malfunction likely related to decedent's terminal event or if it was essential to determine time of death or identity of decedent. A total of 57 CIEDs were evaluated during the 20-year period. In almost half of cases (26/57: 45.6%), device analysis was informative for coroner's investigation. Arrhythmias likely related to terminal event were commonly detected (21/57: 36.8%). Device malfunction was identified as the likely cause of death in almost 10% of decedents (5/57: 8.8%), including three cases of battery depletion (3/57: 5.3%), one case of misclassification of ventricular tachycardia as supraventricular tachycardia with failure to deliver therapy (1/57: 1.7%), and one case of lead failure due to a broken pacing wire (1/57: 1.7%). Not infrequently, CIED interrogation was essential for determination of time of death (9/57: 15.8%), and there was one case (1/57: 1.7%) in which interrogation was essential for identifying the decedent. Our study shows that postmortem CIED interrogation can provide unique information regarding mechanism and time of death, and decedent's identity.

B7-H1 expression model for immune evasion in human papillomavirus-related oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV) is associated with oropharyngeal squamous cell carcinomas. Persistent viral infection is postulated to lead to carcinogenesis, although infection of benign adjacent epithelium is not typically observed. It is known that immune evasive tumor cells can provide an ideal niche for a virus. The B7-H1/PD-1 cosignaling pathway plays an important role in viral immune evasion by rendering CD8+ cytotoxic T cells anergic. We hypothesized that HPV-related oropharyngeal squamous cell carcinomas express B7-H1 as a mechanism for immune evasion. A tissue microarray was utilized, for which HPV E6/E7 mRNA by in situ hybridization was previously performed. Immunohistochemistry was performed to detect B7-H1 and staining was characterized by pattern, distribution, and intensity. B7-H1 was expressed by 84 of the 181 (46.4%) cases. Both tumor cell membranous and cytoplasmic expression were present and cytoplasmic expression was identified in some peritumoral lymphocytes. Expression was analyzed in several different ways and then considered binarily as positive versus negative. Tumors expressing B7-H1 were more likely to be HPV positive (49.2 vs. 34.1 %, p = 0.08). B7-H1 expression showed no correlation with disease recurrence in the entire cohort (OR = 1.09, p = 0.66), HPV positive cohort (OR = 0.80, p = 0.69) or HPV negative cohort (OR = 2.02, p = 0.22). However, B7-H1 expression intensity did correlate with the development of distant metastasis (p = 0.03), and B7-H1 intensity of 3+ (versus all other staining) showed a strong trend towards distant metastasis in the HPV positive (OR = 6.67, p = 0.13) and HPV negative (OR = 9.0, p = 0.13) cohorts. There was no correlation between B7-H1 expression and patient survival for any of the different ways in which staining was characterized, whether binarily, by distribution, intensity, or combined scores. B7-H1 is expressed in the majority of oropharyngeal squamous cell carcinomas with transcriptionally-active HPV. This suggests that B7-H1 expression by tumor cells may play a role in harboring persistent HPV infection.

Transcriptionally-active high-risk human papillomavirus is rare in oral cavity and laryngeal/hypopharyngeal squamous cell carcinomas--a tissue microarray study utilizing E6/E7 mRNA in situ hybridization.

AIMS: Human papillomavirus is well established in oropharyngeal squamous cell carcinoma as both causative and prognostic, but its significance in non-oropharyngeal tumours is unclear. In particular, the significance of finding viral DNA is not known. We sought to evaluate nonoropharyngeal squamous cell carcinomas for transcriptionally-active human papillomavirus and to compare this with the presence of viral DNA. METHODS: We evaluated an 87 patient tissue microarray cohort of oral cavity and laryngeal/hypopharyngeal squamous cell carcinomas for high risk human papillomavirus DNA and E6 and E7 mRNA transcripts by in situ hybridization, and for p16 expression by immunohistochemistry. RESULTS: We found only two of the 73 (2.7%) evaluable cases to harbour transcriptionally-active human papillomavirus. Both of these tumours were from the larynx, one was positive for human papillomavirus DNA by in situ hybridization, and both were extensively positive for p16. All oral cavity and hypopharyngeal tumours were negative for human papillomavirus. CONCLUSIONS: Transcriptionally-active human papillomavirus appears to be rare in laryngeal, hypopharyngeal, and oral cavity squamous cell carcinomas. As such, it appears unlikely to be a 'driver' or to be clinically significant in most established tumours.

High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV) is established as causative in oropharyngeal squamous cell carcinomas (OSCCs), being detected in 50% to 80% of tumors by DNA in situ hybridization (ISH) and/or polymerase chain reaction. However, these tests do not assess viral transcription. Many consider E6/E7 messenger ribonucleic acid (mRNA) the best indicator of HPV status, but it has not been detected in situ in OSCC. We constructed tissue microarrays (TMAs) from a cohort of OSCC for which p16 immunohistochemistry and HPV DNA ISH were previously performed on whole sections. We utilized a novel, chromogenic RNA ISH assay called RNAscope to detect E6/E7 mRNA of HPV-16 and other high-risk types on these TMAs. RNA ISH results were obtained for 196 of 211 TMA cases, of which 153 (78.1%) were positive. p16 immunohistochemistry and HPV DNA ISH were positive in 79.0% and 62.4% of cases, respectively. Concordance between RNA and p16, DNA and p16, and RNA and DNA were 96.4%, 78.7%, and 83.5%, respectively. Only 7 cases (3.6%) were discrepant between RNA ISH and p16. In univariate analysis, all 3 tests correlated with better overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) (all P<0.001). In multivariate analysis, OS correlated significantly with RNA (hazard ratio=0.39, P=0.001), DNA (0.53, P=0.03), and p16 (0.30, P<0.001), but DSS and DFS correlated significantly only with p16 (DSS: 0.36, P=0.006; DFS: 0.42, P=0.016). RNA ISH is more sensitive than DNA ISH in detecting HPV in OSCC, and it correlates strongly with p16. Although both tests were comparable, p16 more strongly stratified patient outcomes.

Human papillomavirus-associated oropharyngeal squamous cell carcinomas: primary tumor burden and survival in surgical patients.

OBJECTIVES: We sought to determine whether the primary tumor burden in oropharyngeal squamous cell carcinoma is lower in tumors positive for human papillomavirus (HPV) or in tumors with a smoking- or alcohol-related cause. METHODS: We retrospectively reviewed medical records of patients at our institution who had squamous cell carcinoma of the palatine tonsils, base of tongue, soft palate, or pharynx from 1995 through 2006. The patients underwent primary surgical therapy. The main outcome measures were the HPV status of tumors and nodes and the survival rates (categorized by HPV status). RESULTS: Of 102 treated patients, 48 (47.1%) had HPV-positive carcinomas. Primary tumor size was not significantly different between HPV-positive and HPV-negative tumors (median, 2.5 versus 2.0 cm; p = 0.43). Patients with HPV had a higher prevalence of neck nodal metastases (35% versus 11%; p = 0.003) and high-grade lesions (83% versus 64%; p = 0.03). CONCLUSIONS: Primary tumor burden was not associated with HPV status. Patients with HPV-positive oropharyngeal squamous cell carcinomas had a higher prevalence of neck nodal metastases and high-grade lesions.