Publications by authors named "James S Lewis"

240 Publications

Rezafungin: a novel antifungal for the treatment of invasive candidiasis.

Future Microbiol 2021 Jan;16:27-36

Department of Pharmacy, Oregon Health & Science University, Portland, OR 97239, USA.

Rezafungin is a novel echinocandin with exceptional stability and solubility and a uniquely long half-life allowing for front-loaded drug exposure with once-weekly dosing. Rezafungin has been shown comparable to other echinocandins, with activity against spp. and spp. including subsets of echinocandin-resistant and azole-resistant isolates. Available clinical data show robust safety and promising efficacy. Phase III trials will provide data on efficacy of rezafungin for the treatment of candidemia and invasive candidiasis and for the prevention of invasive fungal disease in blood and bone marrow transplant recipients. Rezafungin is a promising new candidate in the antifungal arsenal that opens up clinical possibilities based on its impressive half-life, such as early hospital discharge for stable patients and use as prophylaxis in immunocompromised patients.
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http://dx.doi.org/10.2217/fmb-2020-0217DOI Listing
January 2021

Proliferative Verrucous Leukoplakia: An Expert Consensus Guideline for Standardized Assessment and Reporting.

Head Neck Pathol 2021 Jan 7. Epub 2021 Jan 7.

Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL, USA.

The many diverse terms used to describe the wide spectrum of changes seen in proliferative verrucous leukoplakia (PVL) have resulted in disparate clinical management. The objective of this study was to produce an expert consensus guideline for standardized assessment and reporting by pathologists diagnosing PVL related lesions. 299 biopsies from 84 PVL patients from six institutions were selected from patients who had multifocal oral leukoplakic lesions identified over several years (a minimum follow-up period of 36 months). The lesions demonstrated the spectrum of histologic features described in PVL, and in some cases, patients developed oral cavity squamous cell carcinoma (SCC). An expert working group of oral and maxillofacial and head and neck pathologists reviewed microscopic features in a rigorous fashion, in combination with review of clinical photographs when available. The working group then selected 43 single slide biopsy cases for whole slide digital imaging (WSI) review by members of the consensus conference. The digital images were then reviewed in two surveys separated by a washout period of at least 90 days. Five non-PVL histologic mimics were included as controls. Cases were re-evaluated during a consensus conference with 19 members reporting on the cases. The best inter-observer diagnostic agreement relative to PVL lesions were classified as "corrugated ortho(para)hyperkeratotic lesion, not reactive" and "SCC" (chi-square p = 0.015). There was less than moderate agreement (kappa < 0.60) for lesions in the "Bulky hyperkeratotic epithelial proliferation, not reactive" category. There was ≥ moderate agreement (> 0.41 kappa) for 35 of 48 cases. This expert consensus guideline has been developed with support and endorsement from the leadership of the American Academy of Oral and Maxillofacial Pathology and the North American Society of Head and Neck Pathologists to recommend the use of standardized histopathologic criteria and descriptive terminology to indicate three categories of lesions within PVL: (1) "corrugated ortho(para)hyperkeratotic lesion, not reactive;" (2) "bulky hyperkeratotic epithelial proliferation, not reactive;" and (3) "suspicious for," or "squamous cell carcinoma." Classification of PVL lesions based on a combination of clinical findings and these histologic descriptive categories is encouraged in order to standardize reporting, aid in future research and potentially guide clinical management.
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http://dx.doi.org/10.1007/s12105-020-01262-9DOI Listing
January 2021

The Need for Antiviral Drugs for Pandemic Coronaviruses From a Global Health Perspective.

Front Med (Lausanne) 2020 22;7:596587. Epub 2020 Dec 22.

Division of Infectious Diseases, Oregon Health & Science University School of Medicine, Portland, OR, United States.

Respiratory failure due to SARS-CoV-2 has caused widespread mortality, creating an urgent need for effective treatments and a long-term need for antivirals for future emergent coronaviruses. Pharmacotherapy for respiratory viruses has largely been unsuccessful with the exception of early treatment of influenza viruses, which shortens symptom duration and prevents infection in close contacts. Under the rapidly evolving circumstances of the COVID-19 pandemic, most clinical trials of experimental treatments in the United States have focused on later stages of the disease process. Worldwide, the clinical studies of the most impactful drugs, remdesivir and dexamethasone in ACTT-1, RECOVERY, and Solidarity, have studied hospitalized patients. Less than half of clinical trials in the U.S. have investigated oral agents, and the majority have taken place in hospitals at a disease stage where the viral load is already decreasing. The limited success of treatments for respiratory viruses and the viral dynamics of COVID-19 suggest that an antiviral therapy with the greatest impact against pandemic coronaviruses would be orally administered, well-tolerated, target a highly conserved viral protein or host-coronavirus interaction and could be used effectively throughout the world, including resource-poor settings. We examine the treatment of respiratory viral infections and current clinical trials for COVID-19 to provide a framework for effective antiviral therapy and prevention of future emergent coronaviruses and call attention to the need for continued preclinical drug discovery.
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http://dx.doi.org/10.3389/fmed.2020.596587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783399PMC
December 2020

Human Papillomavirus Testing in Head and Neck Squamous Cell Carcinoma: Impact of the 2018 College of American Pathologists Guideline Among Referral Cases at a Large Academic Institution.

Arch Pathol Lab Med 2020 Dec 29. Epub 2020 Dec 29.

and the Departments of Pathology, Microbiology, and Immunology (Ferguson, Mehrad, Ely, Lewis Jr).

Context.—: Given the growing clinical significance of human papillomavirus status in oropharyngeal squamous cell carcinoma, the College of American Pathologists established a set of evidence-based recommendations for high-risk human papillomavirus testing.

Objective.—: To evaluate the impact of the recommendations on human papillomavirus ancillary test ordering habits by comparing compliance before and after the guideline was published.

Design.—: We retrospectively reviewed head and neck squamous cell carcinoma biopsy or resection specimens from outside institutions during a 2.5-year period around guideline publication for whether or not human papillomavirus testing was performed in accordance with the guideline.

Results.—: Human papillomavirus testing deviated from the guideline in 45 of 107 cases (42.1%) before and 93 of 258 cases (36.0%) after their publication (P = .29). This included 6 of 26 cases of oropharyngeal squamous cell carcinoma (23.1%) before and 5 of 55 cases (9.1%) after (P = .16), with 5 of 5 (100.0%) after due to not performing p16 immunohistochemistry. This also included 30 of 68 cases of nonoropharyngeal carcinoma (44.1%) before and 69 of 163 (42.3%) after the guideline was published (P = .88), with 29 of 30 (96.7%) before and 67 of 69 (97.1%) after due to unnecessary use of p16 immunohistochemistry. Nodal metastasis testing deviated in 9 of 13 cases (69.2%) before and 19 of 40 cases (47.5%) after (P = .21) with marked variability in testing, including 3 of 9 (33.3%) before and 8 of 19 (42.1%) after, for not confirming certain p16 immunohistochemistry-positive tumors with human papillomavirus-specific testing.

Conclusions.—: Pathologists continue to deviate from the testing guideline significantly in everyday practice. Further education and discussion about the appropriate handling of head and neck cancer specimens may be needed.
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http://dx.doi.org/10.5858/arpa.2020-0220-OADOI Listing
December 2020

Disseminated Herpes Simplex Infection Presenting as Acute Supraglottitis in an Adult.

Head Neck Pathol 2020 Dec 28. Epub 2020 Dec 28.

Vanderbilt University Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, 1215 21st Ave. S. Suite 7209, Nashville, TN, 37232, USA.

Supraglottitis is a life-threatening, predominantly bacterial disease that is rarely caused by viral etiologies. Herpes Simplex Virus (HSV) supraglottitis has been infrequently reported, but its presentation can mimic that of bacterial supraglottitis or pharyngitis which may lead to delayed diagnosis and increased morbidity. We present a case of supraglottitis in an immunocompetent man initially thought to have bacterial epiglottitis. After receiving a tracheostomy due to impending airway compromise and failing to improve on antibiotic therapy, biopsy of the upper airway tissue revealed infection with HSV type 2. The patient improved after multiple weeks of systemic antivirals. HSV supraglottitis remains an unusual but important diagnostic consideration in patients with dysphonia, dysphagia, ulcerative supraglottal lesions, and acute supraglottic inflammation unresponsive to antibiotics.
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http://dx.doi.org/10.1007/s12105-020-01255-8DOI Listing
December 2020

Sinonasal Small Cell Carcinoma-Case Series of a Rare Malignancy.

Ear Nose Throat J 2020 Oct 22:145561320964640. Epub 2020 Oct 22.

Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

Sinonasal small cell neuroendocrine carcinoma (SNEC) is an extremely rare and aggressive neoplasm that can arise in the sinonasal region. These tumors are associated with high morbidity and mortality, are difficult to diagnose, and are hard to treat. We describe 2 cases of this poorly understood malignancy and review imaging, pathology, and treatment decisions. A 41-year-old male and a 64-year-old female presented to a tertiary center in 2019 after developing nasal obstruction and were found to have sinonasal masses on imaging. Both biopsies showed strong expression of pancytokeratin with dot-like reactivity and expression of neuroendocrine markers chromogranin and synaptophysin. The findings were diagnostic of SNEC. Staging positron emission tomography/computed tomography and brain MRI were performed, and patients were discussed at a multidisciplinary tumor board. Neither had distant metastatic disease at presentation. One patient had no intracranial or orbital disease and underwent a subtotal endoscopic resection with adjuvant chemoradiation. The other patient demonstrated middle cranial fossa, dural, and orbital involvement as well as cranial nerve V palsy. This patient was treated with induction chemotherapy, followed by concurrent chemoradiation. Both patients are presently alive at 4 months follow-up, but one with persistent local disease and the other distant metastasis. Sinonasal small cell neuroendocrine carcinoma is a rare and poorly understood malignancy with an aggressive clinical course. Continued careful review of pathology and study of molecular features are needed for improved understanding of SNEC, and particularly for head and neck SNEC, to establish a staging system and better formulate treatment protocols.
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http://dx.doi.org/10.1177/0145561320964640DOI Listing
October 2020

HPV+ oropharyngeal squamous cell carcinomas from patients with two tumors display synchrony of viral genomes yet discordant mutational profiles and signatures.

Carcinogenesis 2021 Feb;42(1):14-20

Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.

Human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV + OPSCC) is increasing in prevalence in the USA, as are cases of patients with multiple HPV + OPSCCs (mHPV + OPSCC). mHPV + OPSCCs present a unique opportunity to examine HPV + OPSCC mutation acquisition and evolution. We performed sequencing of the viral genome, somatic exome and somatic transcriptome from 8 patients each with 2 spatially distinct HPV + OPSCCs, and 37 'traditional' HPV + OPSCCs to first address if paired tumors are caused by the same viral isolate and next, if acquired alterations, and the underlying processes driving mutagenesis, are shared within pairs. All tumor pairs contained viral genomes from the same HPV type 16 sublineage and differed by 0-2 clonal single nucleotide polymorphisms (SNPs), suggesting infection with the same viral isolate. Despite this, there was significant discordance in expression profiles, mutational burden and mutational profiles between tumors in a pair, with only two pairs sharing any overlapping mutations (3/3343 variants). Within tumor pairs there was a striking discrepancy of mutational signatures, exemplified by no paired tumors sharing high APOBEC mutational burden. Here, leveraging mHPV + OPSCCs as a model system to study mutation acquisition in virally mediated tumors, in which the germline, environmental exposures, immune surveillance and tissue/organ type were internally controlled, we demonstrate that despite infection by the same viral isolate, paired mHPV + OPSCCs develop drastically different somatic alterations and even more strikingly, appear to be driven by disparate underlying mutational processes. Thus, despite a common starting point, HPV + OPSCCs evolve through variable mutational processes with resultant stochastic mutational profiles.
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http://dx.doi.org/10.1093/carcin/bgaa111DOI Listing
February 2021

A MicroRNA Expression Signature as Prognostic Marker for Oropharyngeal Squamous Cell Carcinoma.

J Natl Cancer Inst 2020 Oct 15. Epub 2020 Oct 15.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO USA.

Background: Robust prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) may facilitate individualized patient management. This study was conducted to develop and validate a clinically feasible prognostic classifier based on microRNA sequencing (miRNA-seq) analysis.

Methods: Tumor tissues were collected for miRNA-seq analysis from 324 OPSCC patients treated at Washington University in St. Louis and 130 OPSCC patients treated at Vanderbilt University, used for model training and validation, respectively. OPSCC patients (n = 79) from the TCGA were also included for independent validation. Univariate and multivariate Cox regression analyses were performed to identify miRNAs associated with disease outcomes.

Results: A 26-miRNA signature was identified by miRNA-seq profiling analysis. Based on computed risk scores of the signature, we classified the patients into low- and high-risk groups. In the training cohort, the high-risk group had much shorter overall survival (OS) compared to the low-risk group [hazard ratio (HR) = 3.80, 95% CI = 2.37-6.10, P < .001]. Subgroup analysis further revealed that the signature was prognostic for HPV-positive OPSCCs (HR = 3.07, 95% CI = 1.65-5.71, P < .001). Multivariate analysis indicated that the signature was independent of common clinicopathologic factors for OPSCCs. Importantly, the miRNA signature was a statistically significant predictor of OS in independent validation cohorts (TCGA cohort: HR = 6.05, 95% CI = 2.10-17.37, P < .001; Vanderbilt cohort: HR = 7.98, 95% CI = 3.99-15.97, P < .001; Vanderbilt HPV-positive cohort: HR = 8.71, 95% CI = 2.70-28.14, P < .001).

Conclusion: The miRNA signature is a robust and independent prognostic tool for risk stratification of OPSCCs including HPV-positive OPSCCs.
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http://dx.doi.org/10.1093/jnci/djaa161DOI Listing
October 2020

Impact of a Clostridioides Difficile Testing Computerized Clinical Decision Support Tool on an Adult Stem Cell Transplantation and Hematologic Malignancies Unit.

Biol Blood Marrow Transplant 2020 Oct 9. Epub 2020 Oct 9.

Division of Infectious Diseases, Department of Medicine, Oregon Health & Science University, Portland, Oregon. Electronic address:

Clostridioides difficile infection rates are higher in hospitalized hematopoietic stem cell transplantation (HSCT) recipients and patients with hematologic malignancy (HM) compared with the general population. This is related both to extensive exposure to antibiotics as well as to frequent and often prolonged hospitalization. In this population, with numerous potential causes of diarrhea, a subset of C difficile detected is presumed to represent colonization rather than clinical infection. The use of decision support tools to guide ordering in hospitalized patients has been reported to decrease both C difficile testing and detection rates. Following implementation of a computerized decision support tool on our HSCT/HM unit, we observed a >2-fold decrease in C difficile testing volume and National Healthcare Safety Network-defined laboratory identifications of C difficile. Furthermore, the rate of oral vancomycin use, as well as the incidence of vancomycin-resistant enterococci colonization and bloodstream infection, decreased in the postintervention period. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.005DOI Listing
October 2020

A prognostic gene expression signature for oropharyngeal squamous cell carcinoma.

EBioMedicine 2020 Nov 7;61:102805. Epub 2020 Oct 7.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Background: Robust prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is important for developing individualized treatment plans. This study was conducted to develop and validate a clinically feasible prognostic classifier based on transcriptome-wide gene expression profiles.

Methods: Tumor tissues were collected from 208 OPSCC patients treated at Washington University in St. Louis and 130 OPSCC patients treated at Vanderbilt University, used for model training and validation, respectively. OPSCC patients (n = 70) from the TCGA cohort were also included for independent validation. Based on RNA-seq profiling data, Cox proportional hazards regression analysis was performed to identify genes associated with disease outcomes. Then, Lasso-penalized multivariate survival models were constructed to identify biomarker genes for developing a prognostic gene signature.

Findings: A 60-gene signature was identified by RNA-seq profiling analysis. Computed risk score of the gene signature was significantly predictive of 5-year overall survival of the training cohort (Hazard ratio (HR) 28·32, P = 4·3E-41). Subgroup analysis stratified by HPV status revealed that the signature was prognostic in HPV-positive OPSCC patients (HR 30·55, P = 7·0E-37) and was independent of clinical features. Importantly, the gene signature was validated in two independent patient cohorts, including the TCGA cohort (HR 3·94, P = 0·0018) and the Vanderbilt cohort (HR 8·50, P = 5·7E-09) for overall survival.

Interpretation: The prognostic gene signature is a robust tool for risk stratification of OPSCC patients. The signature remains prognostic among HPV-positive OPSCC patients.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2020.102805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648117PMC
November 2020

Spontaneous Regression of Laryngeal Squamous Cell Carcinoma After Biopsy.

Ear Nose Throat J 2020 Jul 15:145561320939834. Epub 2020 Jul 15.

Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

Approximately 7 cases of spontaneous regression of adult laryngeal carcinoma have been published in the literature since 1900. This case presents a 62-year-old male with a 6-month history of hoarseness who was subsequently diagnosed with a T1aN0M0 left true vocal fold squamous cell carcinoma (SCC) after biopsy. One month following the initial biopsy, histopathological findings on repeat biopsy revealed absence of malignancy and regression of the tumor without radiation. There has been no evidence of tumor recurrence. This case exemplifies how innate immune modulation may play a role in the spontaneous regression of laryngeal SCC, although the mechanism remains unknown.
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http://dx.doi.org/10.1177/0145561320939834DOI Listing
July 2020

Unintended consequences of a reflex urine culture order set on appropriate antibiotic use.

Infect Control Hosp Epidemiol 2020 Sep 23;41(9):1090-1092. Epub 2020 Jun 23.

School of Public Health, Oregon Health & Science University-Portland State University, Portland, Oregon.

We evaluated the impact of reflex urine culture screen results on antibiotic initiation. More patients with positive urine screen but negative culture received antibiotics than those with a negative screen (30.5 vs 7.1%). Urine screen results may inappropriately influence antibiotic initiation in patients with a low likelihood of infection.
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http://dx.doi.org/10.1017/ice.2020.230DOI Listing
September 2020

Childhood tonsillectomy alters the primary distribution of HPV-related oropharyngeal squamous cell carcinoma.

Laryngoscope Investig Otolaryngol 2020 Apr 11;5(2):210-216. Epub 2020 Feb 11.

Department of Radiation Oncology Washington University School of Medicine in St. Louis St. Louis Missouri.

Objectives: We investigated how tonsillectomy during childhood may influence the distribution of human papillomavirus (HPV) positive cancer of the tonsils in adult life using p16 as a surrogate marker for HPV infection.

Study Design: Retrospective observational study.

Methods: A total of 280 patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC) and known p16 status were eligible for this study. Each participant was called to obtain the childhood tonsillectomy history. Respondents were subgrouped by p16 status and the primary tumor location. Patient demographic and clinical information was analyzed for association with Fisher's exact and Wilcoxon rank sum tests. Location of tumor was modeled using univariate (UVA) and multivariate (MVA) logistic regression with associated odds ratios (OR) and 95% confidence intervals.

Results: Of the 280 patients, 115 (41%) were respondents: 104 (90.4%) were p16 positive and 11 (9.6%) were p16 negative. For p16 positive patients, we observed a majority (93%) of intact tonsils in those with tonsil cancer, compared to 45% of intact tonsils in patients with p16 positive cancer elsewhere in the oropharynx ( < .001). MVA logistic regression showed that female gender (OR = 4.16, = .0675), prior smoking history (OR = 2.6, = .0367), and intact tonsils (OR = 15.2,  < .0001) were associated with tonsillar OPSCC.

Conclusion: We found that patients with p16 positive OPSCC at a non-tonsil site were much more likely to have had prior tonsillectomy vs those with p16 positive OPSCC arising within the tonsil. Nevertheless, we do not advocate tonsillectomies as a public health policy to reduce HPV-related OPSCC.

Level Of Evidence: 6.
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http://dx.doi.org/10.1002/lio2.342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178443PMC
April 2020

Determination of high-risk HPV status of head and neck squamous cell carcinoma using the Roche cobas HPV test on cytologic specimens and acellular supernatant fluid.

Cancer Cytopathol 2020 07 4;128(7):482-490. Epub 2020 Mar 4.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: High-risk human papillomavirus-positive (hrHPV+) oropharyngeal squamous cell carcinomas comprise a subset of head and neck squamous cell carcinomas (HNSCCs) with a distinct biology and prognosis. Commonly, the diagnosis of HNSCC is rendered on fine-needle aspiration (FNA). Because cell blocks may be insufficient for determining HPV status using microscopy-based techniques, the ability of liquid-based assays was examined in the current study.

Methods: The performance of the Roche cobas 4800 platform was evaluated on the FNA material from the cell pellet and corresponding cell-free supernatant fluid specimens of primary and metastatic HNSCCs. These results were compared with the p16 immunostain result from the histologic material obtained from the same patient. Discrepant cases were adjudicated using hrHPV RNA in situ hybridization.

Results: A total of 41 samples (23 primary tumors and 18 lymph node metastases) were acquired from 34 patients with HNSCC. Primary tumors included the oropharynx (20 samples), oral cavity (13 samples), larynx (3 samples), and skin (3 samples). In 2 cases, a primary tumor could not be identified. Twenty-three samples (56%) were found to be p16 positive by immunohistochemistry. Twenty-two samples were found to be positive on cobas hrHPV testing from both cell pellet and cell-free supernatant fluid. Two cell-free supernatant fluid specimens yielded indeterminate cobas results. At the time additional hrHPV RNA in situ hybridization analysis was performed, one cobas-positive cell pellet was deemed to be a false-positive result. The sensitivity of the cobas assay was 100% for pellet material and cell-free supernatant fluid, with specificities of 94.7% and 100%, respectively.

Conclusions: cobas hrHPV testing of HNSCC specimens demonstrated high concordance with p16 immunohistochemistry on the corresponding cell block and/or tissue specimen. Using the cell-free supernatant fluid in this platform could provide accurate HPV results while conserving material for cytomorphologic analyses.
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http://dx.doi.org/10.1002/cncy.22258DOI Listing
July 2020

Human Papillomavirus Testing in Head and Neck Squamous Cell Carcinoma in 2020: Where Are We Now and Where Are We Going?

Authors:
James S Lewis

Head Neck Pathol 2020 Jun 2;14(2):321-329. Epub 2020 Mar 2.

Vanderbilt University Medical Center, Nashville, TN, USA.

High risk human papillomavirus (HPV) has transformed head and neck oncology in the past several decades. Now that we have recognized that HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is a unique cancer type with distinct clinicopathologic features and favorable prognosis, it has become essential to test patients in routine practice. We have progressed greatly in our knowledge of this disease and gone, over the past two to three decades, from doing testing in highly variable amounts and methods to, now, with the help of national and international guidelines and patient staging requirements, to a situation where almost all patients with OPSCC are getting accurate classification through at least p16 immunohistochemistry. However, we are still struggling with how to accurately test specimens from cervical lymph nodes, and, in particular, on fine needle aspiration. In addition, many patients with non-oropharyngeal SCC are getting clinically unnecessary p16 and/or HPV-specific testing. The trends suggest progressive improvement in practices, but many practical questions still remain. On the horizon are myriad non-tissue-based tests, such as HPV serology and plasma DNA, DNA-based testing of fine needle aspirate fluid, computerized analysis of digitized pathology and radiology images, and machine learning from clinical and pathologic features, that may render pathologists largely obsolete for establishing HPV status for our patients' tumors. This review takes a brief look back in time to where we have been, then characterizes current practices in 2020 and lingering questions, and, finally, looks ahead into the possible future of HPV testing in patients with head and neck SCC.
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http://dx.doi.org/10.1007/s12105-019-01117-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235114PMC
June 2020

The role of Glial cell derived neurotrophic factor in head and neck cancer.

PLoS One 2020 21;15(2):e0229311. Epub 2020 Feb 21.

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, United States of America.

Glial cell-derived neurotrophic factor (GDNF) is reported to promote the survival of neurons and salivary gland regeneration after radiation damage. This study investigated the effect of GDNF on cell migration, growth, and response to radiation in preclinical models of head and neck squamous cell carcinoma (HNSCC) and correlated GDNF expression to treatment outcomes in HNSCC patients. Our ultimate goal is to determine whether systemic administration of GDNF at high dose is safe for the management of hyposalivation or xerostomia in HNSCC patients. Three HPV-positive and three HPV-negative cell lines were examined for cell migration, growth, and clonogenic survival in vitro and tumor growth assay in vivo. Immunohistochemical staining of GDNF, its receptors GFRα1 and its co-receptor RET was performed on two independent HNSCC tissue microarrays (TMA) and correlated to treatment outcomes. Results showed that GDNF only enhanced cell migration in two HPV-positive cells at supra-physiologic doses, but not in HPV-negative cells. GDNF did not increase cell survival in the tested cell lines post-irradiation. Likewise, GDNF treatment affected neither tumor growth in vitro nor response to radiation in xenografts in two HPV-positive and two HPV-negative HNSCC models. High stromal expression of GDNF protein was associated with worse overall survival in HPV-negative HNSCC on multivariate analysis in a combined cohort of patients from Stanford University (n = 82) and Washington University (n = 189); however, the association between GDNF gene expression and worse survival was not confirmed in a separate group of HPV-negative HNSCC patients identified from the Cancer Genome Atlas (TCGA) database. Based on these data, we do not believe that GNDF is a safe systemic treatment to prevent or treat xerostomia in HNSCC and a local delivery approach such as intraglandular injection needs to be explored.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229311PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034888PMC
May 2020

Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing Position Statements on Polymyxin B and Colistin Clinical Breakpoints.

Clin Infect Dis 2020 Dec;71(9):e523-e529

Adelaide Medical School, University of Adelaide, South Australia, Australia.

Recent data on polymyxin pharmacokinetics, pharmacodynamics, toxicity, and clinical outcomes suggest these agents have limited clinical utility. Pharmacokinetics-pharmacodynamics data show a steady-state concentration of 2 μg/mL is required for killing bacteria with colistin minimum inhibitory concentrations of 2 μg/mL. Less than 50% of patients with normal renal function achieve this exposure, and it is associated with high risk of nephrotoxicity. This exposure does not achieve bacterial stasis in pneumonia models. Randomized and observational studies consistently demonstrate increased mortality for polymyxins compared with alternative agents. The Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) are 2 global organizations that establish interpretive criteria for in vitro susceptibility data. CLSI has recently taken the step to eliminate the "susceptible" interpretive category for the polymyxins, whereas EUCAST maintains this interpretive category. This viewpoint describes the opinions of these organizations and the data that were used to inform their perspectives.
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http://dx.doi.org/10.1093/cid/ciaa121DOI Listing
December 2020

Histologic Classification and Molecular Signature of Polymorphous Adenocarcinoma (PAC) and Cribriform Adenocarcinoma of Salivary Gland (CASG): An International Interobserver Study.

Am J Surg Pathol 2020 04;44(4):545-552

Department of Pathology, Memorial Sloan-Kettering Cancer Center.

Polymorphous adenocarcinoma (PAC) shows histologic diversity with streaming and targetoid features whereas cribriform adenocarcinoma of salivary gland (CASG) demonstrates predominantly cribriform and solid patterns with glomeruloid structures and optically clear nuclei. Opinions diverge on whether CASG represents a separate entity or a variant of PAC. We aimed to assess the level of agreement among 25 expert Head and Neck pathologists in classifying these tumors. Digital slides of 48 cases were reviewed and classified as: PAC, CASG, tumors with ≥50% of papillary architecture (PAP), and tumors with indeterminate features (IND). The consensus diagnoses were correlated with a previously reported molecular alteration. The consensus diagnoses were PAC in 18/48, CASG in16/48, PAP in 3/48, and IND in 11/48. There was a fair interobserver agreement in classifying the tumors (κ=0.370). The full consensus was achieved in 3 (6%) cases, all of which were classified as PAC. A moderate agreement was reached for PAC (κ=0.504) and PAP (κ=0.561), and a fair agreement was reached for CASG (κ=0.390). IND had only slight diagnostic concordance (κ=0.091). PAC predominantly harbored PRKD1 hotspot mutation, whereas CASG was associated with fusion involving PRKD1, PRKD2, or PRKD3. However, such molecular events were not exclusive as 7% of PAC had fusion and 13% of CASG had mutation. In conclusion, a fair to moderate interobserver agreement can be achieved in classifying PAC and CASG. However, a subset (23%) showed indeterminate features and was difficult to place along the morphologic spectrum of PAC/CASG among expert pathologists. This may explain the controversy in classifying these tumors.
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http://dx.doi.org/10.1097/PAS.0000000000001431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437128PMC
April 2020

The Clinical and Laboratory Standards Institute Subcommittee on Antimicrobial Susceptibility Testing: Background, Organization, Functions, and Processes.

J Clin Microbiol 2020 02 24;58(3). Epub 2020 Feb 24.

Departments of Pharmacy and Infectious Diseases, Oregon Health and Science University, Portland, Oregon, USA.

The Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing (AST SC) is a volunteer-led, multidisciplinary consensus body that develops and publishes standards and guidelines (among other products) for antimicrobial susceptibility testing (AST) methods and results interpretation in the United States and internationally. The Subcommittee (SC) meets face-to-face twice yearly, and its working groups (WGs) are active throughout the year via teleconferences. All meetings are open to the public. Participants include clinical microbiologists, infectious disease (ID) pharmacists, and infectious disease physicians representing the health care professions, government, and industry. Individuals who work for a company with a primary financial dependency on drug sales cannot serve as voting members, and well-defined conflict of interest polices are in place. In addition to developing and updating susceptibility breakpoints, the SC develops and validates new testing methods, provides guidance on how results should be interpreted and applied, sets quality control ranges, and educates users through seminars, symposia, and webinars. Based on its work, the SC publishes print and electronic standards and guidelines, including an annual update, the Performance Standards for Antimicrobial Susceptibility Testing (M100). This commentary will describe the background, organization, functions, and operational processes of the AST SC.
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http://dx.doi.org/10.1128/JCM.01864-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041576PMC
February 2020

Two for the price of one: Prevalence, demographics and treatment implications of multiple HPV mediated Head and Neck Cancers.

Oral Oncol 2020 01 22;100:104475. Epub 2019 Nov 22.

Massachusetts Eye and Ear, Boston, MA, United States; Harvard Medical School, Boston, MA, United States. Electronic address:

Objectives: HPV mediated head and neck squamous cell carcinoma (HPVmHNSCC) is increasing in prevalence in the United States, as are reports of patients with multiple HPVmHNSCCs. The prevalence, demographics, and treatment implications of this emerging clinical entity are poorly understood.

Materials And Methods: We performed a multitiered assessment of patients with multiple HPVmHNSCC including: 1. systematic review of the literature, 2. query of the 2017 Surveillance, Epidemiology and End Results (SEER) database and 3. institutional level reporting at two high volume academic centers.

Results: Systematic literature review: 13 articles met inclusion criteria (48 patients with multiple HPVmHNSCC). Pooled prevalence rate of multiple HPVmHNSCC was 2.64%. SEER database: 60(0.95%) patients with HPVmHNSCC had two tumors. Patients with multiple HPVmHNSCC were more likely to be younger and present with a lower T and N stage (p < 0.025 for all). The second identified tumor was more likely to be contralateral, found synchronously, of smaller size, and to occur in the tonsil (p < 0.05 for all). Institutional reporting: 17(1.69%) patients with HPVmHNSCC had two primary tumors. Similar to the SEER database, patients with multiple HPVmHNSCC were more likely to present with a low T stage and tonsil location (p < 0.007 for both).

Conclusion: Multiple HPVmHNSCCs occur in a subset of HPVmHNSCC cases with distinct characteristics. Thorough interrogation of all oropharyngeal subsites should be performed as part of the initial workup for HPVmHNSCC, with consideration given to contralateral tonsillectomy at the time of surgical resection for HPV mediated tonsil cancers due to the prevalence of contralateral tonsil primaries.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017724PMC
January 2020

Transcriptionally Active HPV and Targetable EGFR Mutations in Sinonasal Inverted Papilloma: An Association Between Low-risk HPV, Condylomatous Morphology, and Cancer Risk?

Am J Surg Pathol 2020 03;44(3):340-346

Departments of Pathology, Microbiology, and Immunology.

Sinonasal inverted papillomas (IPs) commonly recur, and transform to malignancy in 5% to 10% of patients. It has long been debated whether IPs are caused by high-risk or low-risk (lr) human papillomavirus (HPV) and whether the HPV is transcriptionally active. EGFR mutations have also been recently implicated in the pathogenesis of IP with an unclear relationship to HPV status. IP cases over a 10-year period were tested for p16 by immunohistochemistry and for transcriptionally active hrHPV and lrHPV by reverse-transcriptase real-time polymerase chain reaction and RNA in situ hybridization, respectively. EGFR tyrosine kinase domain Sanger sequencing was performed on all lrHPV RNA positive and 15 randomly selected lrHPV RNA negative IPs. Seven sinonasal nonkeratinizing squamous cell carcinomas (SCCs) without associated IP were included as controls. Of the 44 IPs, 5 (11.4%) were associated with SCC, all keratinizing type. All IPs and associated SCCs were negative for p16 and hrHPV. lrHPV RNA was detected in 5/42 (12%) cases, including 3/5 (60%) with associated SCC (P=0.009). All 5 lrHPV RNA positive IPs involved the nasal cavity, had a distinct, condylomatous morphology, and were EGFR wild-type. In contrast, 11/15 (73.3%) lrHPV RNA negative IPs that were sequenced had EGFR exon 19 or 20 mutations. All control nonkeratinizing SCCs were lrHPV RNA negative, but 5/7 (71.4%) were p16 and high-risk HPV RNA positive. This study shows that a subset of IPs involving the nasal cavity have transcriptionally active lrHPV, condylomatous morphology, and possibly increased risk of malignancy. Furthermore, lrHPV positivity is mutually exclusive with EGFR mutations, which suggests alternate mechanisms of pathogenesis.
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http://dx.doi.org/10.1097/PAS.0000000000001411DOI Listing
March 2020

EPHB2 carried on small extracellular vesicles induces tumor angiogenesis via activation of ephrin reverse signaling.

JCI Insight 2019 12 5;4(23). Epub 2019 Dec 5.

Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Angiogenesis is a key process that allows nutrient uptake and cellular trafficking and is coopted in cancer to enable tumor growth and metastasis. Recently, extracellular vesicles (EVs) have been shown to promote angiogenesis; however, it is unclear what unique features EVs contribute to the process. Here, we studied the role of EVs derived from head and neck squamous cell carcinoma (HNSCC) in driving tumor angiogenesis. Small EVs (SEVs), in the size range of exosomes (50-150 nm), induced angiogenesis both in vitro and in vivo. Proteomic analysis of HNSCC SEVs revealed the cell-to-cell signaling receptor ephrin type B receptor 2 (EPHB2) as a promising candidate cargo to promote angiogenesis. Analysis of patient data further identified EPHB2 overexpression in HNSCC tumors to be associated with poor patient prognosis and tumor angiogenesis, especially in the context of overexpression of the exosome secretion regulator cortactin. Functional experiments revealed that EPHB2 expression in SEVs regulated angiogenesis both in vitro and in vivo and that EPHB2 carried by SEVs stimulates ephrin-B reverse signaling, inducing STAT3 phosphorylation. A STAT3 inhibitor greatly reduced SEV-induced angiogenesis. These data suggest a model in which EVs uniquely promote angiogenesis by transporting Eph transmembrane receptors to nonadjacent endothelial cells to induce ephrin reverse signaling.
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http://dx.doi.org/10.1172/jci.insight.132447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962030PMC
December 2019

Tissue Fixation Conditions for p16 Immunohistochemistry and Human Papillomavirus RNA In Situ Hybridization in Oropharyngeal Squamous Cell Carcinoma.

Head Neck Pathol 2020 Sep 18;14(3):637-644. Epub 2019 Oct 18.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 3020D Vanderbilt University Hospital, Nashville, TN, 37232-7415, USA.

Human papillomavirus (HPV) has become a critical prognostic biomarker in oropharyngeal squamous cell carcinoma (OPSCC). While retrospective studies suggest that p16 immunohistochemistry and even HPV RNA in situ hybridization work well on tissues and tumors from a variety of labs and various fixation conditions, no formal study of fixation conditions has been performed to date. We took surgically resected specimens from three p16 and HPV RNA in situ hybridization positive OPSCC patients, divided their fresh tumors into small pieces, and varied the time to formalin fixation as 1, 3, 6, 24, and 48 h. Tumors were either held moistened at room temperature or were refrigerated. After fixation and processing, routine hematoxylin and eosin slides were generated and p16 immunohistochemistry and RNA in situ hybridization performed. All three tumors were nonkeratinizing and had strong and diffuse p16 expression at immediate fixation, which, surprisingly, remained positive for all fixation times and conditions and despite significant degeneration at the later points for two of the patients while for one, the nuclear signal dropped out of most cells at early and mid time points, particularly at room temperature, causing false negatives. HPV RNA in situ hybridization stayed positive in all specimens up to 48 h of cold ischemic time refrigerated and even at room temperature, except for overtly autolyzed tumor regions. These findings help to establish that, at least for standard nonkeratinizing, p16 and HPV RNA strongly positive OPSCC patients, and using the most common tests in clinical practice, relatively lenient time to fixation may be acceptable if it cannot be avoided. However, for some patients, p16 immunohistochemistry may be sensitive to signal loss with autolysis. HPV RNA in situ hybridization, in particular, seems remarkably resistant to pretest cold ischemic times.
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http://dx.doi.org/10.1007/s12105-019-01090-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413959PMC
September 2020

Comparative Performance of High-Risk Human Papillomavirus RNA and DNA In Situ Hybridization on College of American Pathologists Proficiency Tests.

Arch Pathol Lab Med 2020 03 4;144(3):344-349. Epub 2019 Sep 4.

From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur).

Context.—: Detection of high-risk human papillomavirus (HR-HPV) in squamous cell carcinoma is important for classification and prognostication. In situ hybridization (ISH) is a commonly used HR-HPV-specific test that targets viral RNA or DNA. The College of American Pathologists (CAP) provides proficiency testing for laboratories performing HR-HPV ISH.

Objective.—: To compare the analytical performance of RNA- and DNA-based ISH methods on CAP HR-HPV proficiency tests.

Design.—: Data from the 2016-2018 CAP HPV ISH proficiency testing surveys were reviewed. These surveys consist of well-characterized samples with known status for HR-HPV, including 1 to 2 copies, 50 to 100 copies, 300 to 500 copies, and no copies of HR-HPV per cell.

Results.—: Ninety-five participants submitted 1268 survey results from 20 cores. Overall, RNA ISH had a significantly higher percentage of correct responses than DNA ISH: 97.4% (450 of 462) versus 80.6% (650 of 806) ( < .001). This disparity appears to be the consequence of a superior sensitivity of RNA ISH compared to DNA ISH for samples with 1 to 2 and with 50 to 100 copies of HR-HPV per cell: 95.2% (120 of 126) versus 53.8% (129 of 240), < .001, respectively, and 100% (89 of 89) versus 76.3% (119 of 156), < .001, respectively.

Conclusions.—: An assessment of CAP HR-HPV proficiency test performance indicates that RNA ISH shows significantly higher accuracy than DNA ISH owing to higher analytical sensitivity of RNA ISH in tumors with low (1-2 copies per cell) to intermediate (50-100 copies per cell) HR-HPV viral copy numbers. These data support the use of RNA over DNA ISH in clinical laboratories that perform HR-HPV testing as part of their testing algorithms.
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http://dx.doi.org/10.5858/arpa.2019-0093-CPDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422928PMC
March 2020

Don't stop the champions of research now: a brief history of head and neck pathology developments.

Hum Pathol 2020 01 23;95:1-23. Epub 2019 Aug 23.

Department of Pathology, University of Texas Southwestern Medical Center, Clements University Hospital, Dallas, TX 75390, USA. Electronic address:

The field of head and neck pathology was just developing 50 years ago but has certainly come a long way in a relatively short time. Thousands of developments in diagnostic criteria, tumor classification, malignancy staging, immunohistochemistry application, and molecular testing have been made during this time, with an exponential increase in literature on the topics over the past few decades: There were 3506 articles published on head and neck topics in the decade between 1969 and 1978 (PubMed source), with a staggering 89266 manuscripts published in the most recent decade. It is daunting and impossible to narrow the more than 162000 publications in this field and suggest only a few topics of significance. However, the breakthrough in this anatomic discipline has been achieved in 3 major sites: oropharyngeal carcinoma, salivary gland neoplasms, and sinonasal tract tumors. This review will highlight selected topics in these anatomic sites in which the most profound changes in diagnosis have occurred, focusing on the information that helps to guide daily routine practice of surgical pathology.
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http://dx.doi.org/10.1016/j.humpath.2019.08.017DOI Listing
January 2020

Dalbavancin use in an academic medical centre and associated cost savings.

Int J Antimicrob Agents 2019 Nov 6;54(5):652-654. Epub 2019 Aug 6.

Department of Pharmacy Services, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Department of Medicine, Division of Infectious Diseases, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.

Dalbavancin is a lipoglycopeptide antibiotic with unique weekly dosing active against Gram-positive organisms. This retrospective study included 37 patients receiving a mean of 2.7 weeks of dalbavancin. Nine patients (24%) were re-admitted to the hospital within 30 days. A total of 617 hospital days were saved, estimated to result in US$1 495 336 in savings and a mean cost avoidance of US$40 414 per patient. Dalbavancin provides a valuable antibiotic option that may minimise healthcare expenditure.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.08.007DOI Listing
November 2019

Isavuconazole to prevent invasive fungal infection in immunocompromised adults: Initial experience at an academic medical centre.

Mycoses 2019 Aug 23;62(8):665-672. Epub 2019 May 23.

Department of Pharmacy Services, Oregon Health & Science University Hospital and Clinics, Portland, Oregon.

Objective: To evaluate clinical and economic outcomes associated with the use of isavuconazole as antifungal prophylaxis in high-risk immunocompromised patients.

Patients/methods: Retrospective, single-centre cohort study of patients who received isavuconazole prophylaxis. Outcomes assessed included breakthrough IFI, early discontinuation of isavuconazole for any reason and antifungal prophylaxis prescribed at discharge. The impact on inpatient drug expenditure was evaluated using current isavuconazole and posaconazole drug costs per observed isavuconazole days of therapy (DOT) during the study period.

Results: One hundred thirty-eight courses of isavuconazole prophylaxis were administered to 98 inpatients (2193 DOT). Relapsed/refractory acute myelogenous leukaemia was the indication for prophylaxis in over half (59.4%) of patients. Breakthrough IFI occurred in 8 (5.8%) courses. Suspected drug-related toxicities led to early discontinuation in 6 (4.3%) courses (five hepatotoxicity, one drug rash). At discharge, 24 (17.4%) courses lacked insurance coverage for isavuconazole. The formulary switch to isavuconazole prophylaxis resulted in an estimated mean drug cost savings of $128.25 per DOT relative to estimated posaconazole costs (P < 0.001).

Conclusion: Isavuconazole may be an option for antifungal prophylaxis in high-risk immunocompromised adults and has the potential to produce significant inpatient drug cost savings. Further studies are needed to confirm the clinical efficacy and cost-effectiveness of isavuconazole in this role.
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http://dx.doi.org/10.1111/myc.12924DOI Listing
August 2019

UV Signature Mutations Reclassify Salivary High-grade Neuroendocrine Carcinomas as Occult Metastatic Cutaneous Merkel Cell Carcinomas.

Am J Surg Pathol 2019 05;43(5):682-687

Departments of Pathology and Immunology.

Salivary high-grade neuroendocrine carcinomas (NECs) are rare, occur predominantly in the parotid gland, and are difficult to differentiate from metastatic cutaneous Merkel cell carcinomas (MCCs), which have overlapping morphologic, immunophenotypic, and molecular profiles. Oncogenic Merkel cell polyomavirus (MCPyV), found in 70% to 80% of MCCs, has also been reported in a few salivary NECs, but this is controversial. A promising biomarker to distinguish the 2 tumor types are UV signature mutations. UV signature mutations indicate a sun damage-induced mechanism of pathogenesis and recently have been found to be highly prevalent in MCPyV-negative MCCs but would be inconsistent with salivary origin. Here, we examine UV signature mutations as a molecular marker to distinguish primary salivary high-grade NEC from MCC. Whole exome DNA sequencing was performed on matched tumor-normal tissue from 4 MCPyV-negative high-grade salivary NECs with no other primary source identified, as well as 3 melanomas and 3 lung NECs as positive and negative controls, respectively. UV signature mutations were found in all salivary NECs, when defined as ≥60% of total mutations being C-to-T transitions at dipyrimidine sites, and when compared with known human cancer-related mutational signatures. The presence of UV signature mutations in salivary high-grade NECs strongly favors these to be occult metastatic MCCs. True salivary primary NECs are likely exceedingly rare. When a high-grade NEC is encountered in the salivary gland, the presence of UV signature mutations or MCPyV may be useful to exclude occult unknown primary MCC.
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http://dx.doi.org/10.1097/PAS.0000000000001231DOI Listing
May 2019

Inter-observer Variability in the Diagnosis of Proliferative Verrucous Leukoplakia: Clinical Implications for Oral and Maxillofacial Surgeon Understanding: A Collaborative Pilot Study.

Head Neck Pathol 2020 Mar 10;14(1):156-165. Epub 2019 Apr 10.

Southern California Permanente Medical Group, Woodland Hills Medical Center, Woodland Hills, CA, USA.

The use of diverse terminology may lead to inconsistent diagnosis and subsequent mistreatment of lesions within the proliferative verrucous leukoplakia (PVL) spectrum. The objectives of this study were: (a) to measure inter-observer variability between a variety of pathologists diagnosing PVL lesions; and (b) to evaluate the impact of diverse terminologies on understanding, interpretation, and subsequent treatment planning by oral and maxillofacial surgeons (OMFS). Six oral pathologists (OP) and six head and neck pathologists (HNP) reviewed 40 digitally scanned slides of PVL-type lesions. Inter-observer agreement on diagnoses was evaluated by Fleiss' kappa analysis. The most commonly used diagnostic terminologies were sent to ten OMFS to evaluate their resulting interpretations and potential follow-up treatment approaches. The overall means of the surgeons' responses were compared by Student t test. There was poor inter-observer agreement between pathologists on the diagnosis of PVL lesions (κ = 0.270), although there was good agreement (κ = 0.650) when diagnosing frankly malignant lesions. The lowest agreement was in diagnosing verrucous hyperplasia (VH) with/without dysplasia, atypical epithelial proliferation (AEP), and verrucous carcinoma (VC). The OMFS showed the lowest agreement on identical categories of non-malignant diagnoses, specifically VH and AEP. This study demonstrates a lack of standardized terminology and diagnostic criteria for the spectrum of PVL lesions. We recommend adopting standardized criteria and terminology, proposed and established by an expert panel white paper, to assist pathologists and clinicians in uniformly diagnosing and managing PVL spectrum lesions.
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http://dx.doi.org/10.1007/s12105-019-01035-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021885PMC
March 2020

Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients.

Clin Infect Dis 2020 02;70(5):723-730

Division of Infectious Diseases, Oregon Health and Science University, Portland.

Background: Isavuconazole (ISA) is an attractive candidate for primary mold-active prophylaxis in high-risk patients with hematologic malignancies or hematopoietic cell transplant (HCT) recipients. However, data supporting the use of ISA for primary prophylaxis in these patients are lacking.

Methods: We conducted a retrospective review of breakthrough invasive fungal infections (bIFIs) among adult hematologic malignancy patients and HCT recipients who received ≥7 days of ISA primary prophylaxis between 1 September 2016 and 30 September 2018. The incidence of bIFIs in patients receiving ISA was compared to those receiving posaconazole (POS) and voriconazole (VOR) during the same time period.

Results: One hundred forty-five patients received 197 courses of ISA prophylaxis. Twelve bIFIs (Aspergillus fumigatus [5], Aspergillus species [2], Mucorales [2], Fusarium species [2], and Candida glabrata [1]) occurred, representing 8.3% of patients and 6.1% of courses, after a median duration of 14 days of ISA prophylaxis. All bIFIs occurred during periods of neutropenia. Seven patients (58.3%) died within 42 days of onset of bIFI. In addition, bIFIs complicated 10.2% of ISA, 4.1% of POS, and 1.1% of VOR courses among patients with de novo or relapsed/refractory acute myeloid leukemia during the study period, with invasive pulmonary aspergillosis (IPA) complicating 6.8% of ISA, 1.3% of POS, and zero VOR courses.

Conclusions: Although ISA has been approved for treatment of invasive Aspergillus and mucormycosis, we observed an increased rate of bIFI, notably IPA, using ISA for primary prophylaxis. These results support the need for further study to determine the role of ISA as primary prophylaxis.
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http://dx.doi.org/10.1093/cid/ciz282DOI Listing
February 2020