Publications by authors named "Mark H Stoler"

160 Publications

The CERTAIN Study Results: Adjunctive p16 Immunohistochemistry Use in Cervical Biopsies According to LAST Criteria.

Am J Surg Pathol 2021 Apr 1. Epub 2021 Apr 1.

*Department of Pathology, Columbia University, New York City, NY †Department of Pathology, University of Virginia Health System, Charlottesville, VA ‡Department of Pathology, McGill University Health Center, Montreal, QC, Canada §Ventana Medical Systems Inc/Roche Tissue Diagnostics, Tucson, AZ.

The Lower Anogenital Squamous Terminology (LAST) Project recommends the use of p16 immunohistochemistry as an adjunct to morphologic assessment of cervical biopsies according to a specific set of criteria. We analyzed the effect of adjunctive p16 according to LAST criteria in a US-based diagnostic utility study involving 70 surgical pathologists providing a total of 38,500 reads on cervical biopsies. Compared with the results obtained using hematoxylin and eosin-stained slides only, including p16-stained slides per LAST criteria increased sensitivity and specificity for diagnosing histologic high-grade squamous intraepithelial lesions across all cases by 8.1% (95% confidence interval [95% CI], 6.5-9.7; P<0.0001) and 3.5% (95% CI, 2.8-4.2; P<0.0001), respectively, using expert consensus diagnoses on hematoxylin and eosin+p16 as reference. Within the subset of cases classified by the pathologists as fulfilling the LAST criteria, adding p16 significantly increased both sensitivity (+11.8%; 95% CI, 9.5-14.0; P<0.0001) and specificity (+9.7%; 95% CI, 7.8-11.5; P<0.0001). However, a comparable improvement in sensitivity (+11.0%; 95% CI, 7.8-14.1; P<0.0001) was found when p16 was used in cases for which p16 staining was not ordered per LAST by the pathologists, whereas specificity decreased by -0.8% (95% CI, -1.1 to -0.5; P<0.0001). The study demonstrates a clinically and statistically significant increase in sensitivity and specificity for high-grade squamous intraepithelial lesion when p16 is used according to LAST criteria. Expanding the use of p16 into non-LAST cases would lead to a comparable improvement in sensitivity within this subgroup of biopsies, at the cost of a minimal, but statistically significant difference in specificity.
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http://dx.doi.org/10.1097/PAS.0000000000001709DOI Listing
April 2021

The IMproving Primary Screening And Colposcopy Triage trial: human papillomavirus, cervical cytology, and histopathologic results from the baseline and 1-year follow-up phase.

Am J Obstet Gynecol 2021 Apr 20. Epub 2021 Apr 20.

Department of Medical Scientific Affairs, Ventana Medical Systems Inc./Roche Tissue Diagnostics, Tucson, AZ.

Background: An increase in human papillomavirus test volumes is expected in the near future because human papillomavirus-based screening protocols are expected to become more widely adopted.

Objective: The IMproving Primary Screening And Colposcopy Triage trial, a prospective, multicenter, US-based cervical cancer screening trial, was conducted to obtain US Food and Drug Administration approvals for the new, high-throughput cobas human papillomavirus (cobas HPV) test for use on the cobas 6800/8800 Systems (cobas HPV) for detecting cervical precancerous and cancerous cells (cervical intraepithelial neoplasia of grade 2 or worse and grade 3 or worse). Here, the baseline demographics, human papillomavirus test results, cervical cytology, and histopathologic results are presented. In addition, the baseline and 1-year risks of cervical intraepithelial neoplasia grade 2 or worse and grade 3 or worse associated with the human papillomavirus results are reported.

Study Design: In total, 35,263 women aged between 25 and 65 years undergoing routine screening were enrolled; liquid-based cytology and 2 polymerase chain reaction-based tests for high-risk human papillomavirus were performed. Women with abnormal Papanicolaou cytology, women positive for high-risk human papillomavirus by either of the 2 human papillomavirus tests, and a random subset of women negative according to the Papanicolaou cytology and the 2 human papillomavirus tests were referred for a colposcopy and cervical biopsy. Women who did not meet the study endpoint were eligible for the 1-year follow-up study phase. Verification bias-adjusted cervical disease prevalence and risks and 95% confidence intervals were computed.

Results: The prevalence of atypical squamous cells of undetermined significance and worse than atypical squamous cells of undetermined significance cytology were 6.5% and 3.2%, respectively. Prevalence of high-risk human papillomavirus, human papillomavirus 16, and human papillomavirus 18 based on the new cobas HPV test were 15.1%, 3.1%, and 1.4%, respectively. Both cytologic abnormalities and human papillomavirus positivity declined with increasing age. Among women who had a colposcopy and biopsy, the prevalence of cervical intraepithelial neoplasia grade 2 or worse and grade 3 or worse were 8.8% and 3.6%, respectively. The baseline and 1-year cumulative risks for cervical intraepithelial neoplasia grade 3 or worse were 13.6% and 16.9%, respectively, among women who tested positive for human papillomavirus 16. Women who tested negative for human papillomavirus had the lowest 1-year cumulative risk for cervical intraepithelial neoplasia grade 3 or worse (0.06%).

Conclusion: The contemporary, age-specific prevalence of human papillomaviruses (including human papillomavirus 16 and 18), cytologic abnormalities, and cervical intraepithelial neoplasia in a large, US-based cervical cancer screening population provides benchmarks for healthcare policies, screening programs, and for laboratories and clinicians.
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http://dx.doi.org/10.1016/j.ajog.2021.03.047DOI Listing
April 2021

Two Hours of In Vivo Lung Perfusion Improves Lung Function in Sepsis-Induced Acute Respiratory Distress Syndrome.

Semin Thorac Cardiovasc Surg 2021 Mar 11. Epub 2021 Mar 11.

Department of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Sepsis is the leading cause of acute respiratory distress syndrome (ARDS) in adults and carries a high mortality. Utilizing a previously validated porcine model of sepsis-induced ARDS, we sought to refine our novel therapeutic technique of in vivo lung perfusion (IVLP). We hypothesized that 2 hours of IVLP would provide non-inferior lung rehabilitation compared to 4 hours of treatment. Adult swine (n = 8) received lipopolysaccharide to develop ARDS and were placed on central venoarterial extracorporeal membrane oxygenation. Animals were randomized to 2 vs 4 hours of IVLP. The left pulmonary vessels were cannulated to IVLP using antegrade Steen solution. After IVLP treatment, the left lung was decannulated and reperfused for 4 hours. Total lung compliance and pulmonary venous gases from the right lung (control) and left lung (treatment) were sampled hourly. Biochemical analysis of tissue and bronchioalveolar lavage was performed along with tissue histologic assessment. Throughout IVLP and reperfusion, treated left lung PaO/FiO ratio was significantly higher than the right lung control in the 2-hour group (332.2 ± 58.9 vs 264.4 ± 46.5, P = 0.01). In the 4-hour group, there was no difference between treatment and control lung PaO/FiO ratio (258.5 ± 72.4 vs 253.2 ± 90.3, P = 0.58). Wet-to-dry weight ratios demonstrated reduced edema in the treated left lungs of the 2-hour group (6.23 ± 0.73 vs 7.28 ± 0.61, P = 0.03). Total lung compliance was also significantly improved in the 2-hour group. Two hours of IVLP demonstrated superior lung function in this preclinical model of sepsis-induced ARDS. Clinical translation of IVLP may shorten duration of mechanical support and improve outcomes.
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http://dx.doi.org/10.1053/j.semtcvs.2021.02.034DOI Listing
March 2021

PD-L1 and Mismatch Repair Status in Uterine Carcinosarcomas.

Int J Gynecol Pathol 2020 Dec 14. Epub 2020 Dec 14.

Departments of Pathology (T.M.J., M.H.S., A.M.M.) Obstetrics and Gynecology (L.A.C.), University of Virginia Health System, Charlottesville, Virgina.

Uterine carcinosarcomas have few adjuvant treatment options. Programmed cell death ligand-1 (PD-L1) expression in these tumors may predict response to checkpoint inhibitor therapies. An increase in PD-L1 expression has been shown in endometrial carcinomas with mismatch repair (MMR) deficiencies; however, few studies have evaluated PD-L1 expression in uterine carcinosarcomas. We examined PD-L1 expression in 41 cases of uterine carcinosarcoma using combined positive scores (CPS) and tumor proportion scores (TPS), and correlated with MMR status, p53 expression, and epithelial histotype. In addition to confirming the diagnosis of carcinosarcoma, the epithelial components were stratified based on endometrioid versus serous histology. Thirty-three cases (80%) were positive for PD-L1, defined as a CPS score of ≥1 or a TPS score of ≥1%. Twelve cases (29%) showed high expression of PD-L1, defined as a CPS score of ≥10 or a TPS score of ≥10%. The majority of the morphologically adjudicated carcinosarcomas had a serous epithelial component (83%) rather than endometrioid (17%), which was reinforced by aberrant p53 staining predominantly within cases with serous morphology. The majority of carcinosarcomas showed at least focal PD-L1 expression, predominantly in tumor-associated immune cells. Carcinosarcomas with endometrioid morphology were significantly more likely to have high-level PD-L1 (5/7 vs. 7/34; P=0.015). MMR-deficient carcinosarcomas were also more likely to have high-level PD-L1 (2/3 vs. 10/28); however, this did not reach statistical significance (P=0.2) and overall MMR-deficiency was uncommon (3 cases, 7%). These findings suggest that PD-L1 may be additive to MMR testing as a predictive biomarker for checkpoint inhibitor vulnerability in carcinosarcomas.
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http://dx.doi.org/10.1097/PGP.0000000000000752DOI Listing
December 2020

Efficacy of the bivalent HPV vaccine against HPV 16/18-associated precancer: long-term follow-up results from the Costa Rica Vaccine Trial.

Lancet Oncol 2020 12;21(12):1643-1652

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

Background: Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+).

Methods: Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464.

Findings: 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine.

Interpretation: The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable.

Funding: US National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30524-6DOI Listing
December 2020

Analysis of Ugandan cervical carcinomas identifies human papillomavirus clade-specific epigenome and transcriptome landscapes.

Nat Genet 2020 08 3;52(8):800-810. Epub 2020 Aug 3.

Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.
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http://dx.doi.org/10.1038/s41588-020-0673-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498180PMC
August 2020

Loss of MHC Class I Expression in HPV-associated Cervical and Vulvar Neoplasia: A Potential Mechanism of Resistance to Checkpoint Inhibition.

Am J Surg Pathol 2020 09;44(9):1184-1191

Department of Pathology, Division of Anatomic Pathology.

Tumor cell expression of major histocompatibility complex (MHC) class I is required for antigen presentation and adaptive immune recognition. Absent or diminished MHC class I expression is thought to contribute to immunotherapeutic resistance in some epithelial tumors but has not been previously studied in cervical and vulvar carcinoma. Given that anti-programmed cell death 1 (PD-1) checkpoint inhibition is deployed for programmed cell death ligand 1 (PD-L1)-positive recurrent and metastatic cervical squamous carcinomas, identifying tumors with loss of MHC class I is of clinical interest to optimize the selection of immunotherapeutic candidates. Immunohistochemistry for PD-L1 and MHC class I combined A, B, and C heavy chains (MHC class I) was assessed in 58 human papillomavirus-associated cervical and vulvar lesions, including 27 squamous intraepithelial lesions (SILs) and 31 invasive squamous cell carcinoma (SCC). Although 84% of SCC and 22% of SIL were PD-L1-positive, 35.5% (11/31) of SCC and 18.5% (5/27) of SIL also showed clonal or complete loss of MHC class I. Loss of MHC class I expression was more common in PD-L1-positive (10/26, 38%) versus PD-L1-negative SCC (1/5, 20%). In summary, over one third of human papillomavirus-associated cervical and vulvar SCC show clonal or complete loss of MHC class I expression, including many PD-L1-positive cases. This suggests that the efficacy of checkpoint inhibitors targeting the PD-1/PD-L1 axis may be limited in a subset of cervical and vulvar squamous neoplasms due to an impaired ability to engage with the adaptive immune system related to loss of MHC class I expression.
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http://dx.doi.org/10.1097/PAS.0000000000001506DOI Listing
September 2020

Mismatch Repair Deficiency in Uterine Carcinosarcoma: A Multi-institution Retrospective Review.

Am J Surg Pathol 2020 06;44(6):782-792

Departments of Pathology.

Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is recommended in endometrial carcinomas as a screening test for Lynch syndrome, and mismatch repair deficiency (MMRd) is reported in ∼30% of cases. However, few studies have evaluated the rate of MMR loss in uterine carcinosarcomas. A 5-year retrospective database search of uterine carcinosarcomas was performed at 3 academic institutions. The histologic diagnoses, type of carcinoma present, and MMR IHC interpretations were confirmed by a gynecologic pathologist. One hundred three cases of uterine carcinosarcomas with available MMR IHC results were identified. Ninety-nine cases (96%) showed intact expression and 4 cases (4%) showed loss of MLH1/PMS2. All MMRd carcinosarcomas identified in this series had an endometrioid carcinomatous component and wild-type p53 expression. In contrast, the majority of MMR intact carcinosarcomas had a serous morphology and aberrant p53 expression. Three additional cases initially diagnosed as carcinosarcoma also revealed MMRd; however, given the lack of clear mesenchymal differentiation, these cases were reclassified as dedifferentiated endometrial carcinomas and were subsequently excluded from the carcinosarcoma category. No cases of Lynch syndrome were identified among carcinosarcoma patients, as all 4 MMRd cases were due to somatic MLH1 hypermethylation. In summary, we found that the rate of MMRd is markedly lower in uterine carcinosarcoma when compared with endometrial carcinoma. In the setting of MMR loss, a diagnosis of dedifferentiated carcinoma should be considered as almost half of the MMRd tumors which were called carcinosarcomas initially were reclassified as dedifferentiated on review. However, given the interobserver variability in the classification of carcinosarcoma versus dedifferentiated carcinoma a universal screening approach that includes uterine carcinosarcoma is still recommended.
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http://dx.doi.org/10.1097/PAS.0000000000001434DOI Listing
June 2020

Reduced-flow ex vivo lung perfusion to rehabilitate lungs donated after circulatory death.

J Heart Lung Transplant 2020 01 18;39(1):74-82. Epub 2019 Sep 18.

Departments of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Background: Current ex vivo lung perfusion (EVLP) protocols aim to achieve perfusion flows of 40% of cardiac output or more. We hypothesized that a lower target flow rate during EVLP would improve graft function and decrease inflammation of donation after circulatory death (DCD) lungs.

Methods: A porcine DCD and EVLP model was utilized. Two groups (n = 4 per group) of DCD lungs were randomized to target EVLP flows of 40% (high-flow) or 20% (low-flow) predicted cardiac output based on 100 ml/min/kg. At the completion of 4 hours of normothermic EVLP using Steen solution, left lung transplantation was performed, and lungs were monitored during 4 hours of reperfusion.

Results: After transplant, left lung-specific pulmonary vein partial pressure of oxygen was significantly higher in the low-flow group at 3 and 4 hours of reperfusion (3-hour: 496.0 ± 87.7 mm Hg vs. 252.7 ± 166.0 mm Hg, p = 0.017; 4-hour: 429.7 ± 93.6 mm Hg vs. 231.5 ± 178 mm Hg, p = 0.048). Compliance was significantly improved at 1 hour of reperfusion (20.8 ± 9.4 ml/cm HO vs. 10.2 ± 3.5 ml/cm HO, p = 0.022) and throughout all subsequent time points in the low-flow group. After reperfusion, lung wet-to-dry weight ratio (7.1 ± 0.7 vs. 8.8 ± 1.1, p = 0.040) and interleukin-1β expression (927 ± 300 pg/ng protein vs. 2,070 ± 874 pg/ng protein, p = 0.048) were significantly reduced in the low-flow group.

Conclusions: EVLP of DCD lungs with low-flow targets of 20% predicted cardiac output improves lung function, reduces edema, and attenuates inflammation after transplant. Therefore, EVLP for lung rehabilitation should use reduced flow rates of 20% predicted cardiac output.
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http://dx.doi.org/10.1016/j.healun.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001159PMC
January 2020

Relationships of p16 Immunohistochemistry and Other Biomarkers With Diagnoses of Cervical Abnormalities: Implications for LAST Terminology.

Arch Pathol Lab Med 2020 06 13;144(6):725-734. Epub 2019 Nov 13.

From Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York (Dr Castle); Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom (Ms Adcock and Dr Cuzick); Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland (Drs Wentzensen and Schiffman); the Department of Pathology, University of New Mexico Cancer Center, Albuquerque (Ms Torrez-Martinez, Dr Torres, Dr Joste, Dr Gravitt, Mr Hunt, and Dr Wheeler); the Department of Pathology, University of Virginia Health System, Charlottesville (Dr Stoler); the Department of Pathology, Johns Hopkins University, Baltimore, Maryland (Dr Ronnett); the Department of Pathology, University of California, San Francisco (Dr Darragh); and Sacramento, California (Dr Kinney).

Context.—: Lower Anogenital Squamous Terminology (LAST) standardization recommended p16 immunohistochemistry (p16 IHC) for biopsies diagnosed morphologically as cervical intraepithelial neoplasia (CIN) grade 2 (CIN2) to classify them as low-grade or high-grade squamous intraepithelial lesions (HSILs).

Objective.—: To describe the relationships of p16 IHC and other biomarkers associated with cervical cancer risk with biopsy diagnoses.

Design.—: A statewide, stratified sample of cervical biopsies diagnosed by community pathologists (CPs), including 1512 CIN2, underwent a consensus, expert pathologist panel (EP) review (without p16 IHC results), p16 IHC interpretation by a third pathology group, and human papillomavirus (HPV) genotyping, results of which were grouped hierarchically according to cancer risk. Antecedent cytologic interpretations were also available.

Results.—: Biopsies were more likely to test p16 IHC positive with increasing severity of CP diagnoses, overall ( ≤ .001) and within each HPV risk group ( ≤ .001 except for low-risk HPV [ < .010]). All abnormal grades of CP-diagnosed biopsies were more likely to test p16 IHC positive with a higher HPV risk group ( < .001), and testing p16 IHC positive was associated with higher HPV risk group than testing p16 IHC negative for each grade of CP-diagnosed biopsies ( < .001). p16 IHC-positive, CP-diagnosed CIN2 biopsies were less likely than CP-diagnosed CIN3 biopsies to test HPV16 positive, have an antecedent HSIL cytology, or to be diagnosed as CIN3 by the EP ( .001 for all). p16 IHC-positive, CP-diagnosed CIN1 biopsies had lower HPV risk groups than p16 IHC-negative, CP-diagnosed CIN2 biopsies ( < .001).

Conclusions.—: p16 IHC-positive, CP-diagnosed CIN2 appears to be lower cancer risk than CP-diagnosed CIN3. LAST classification of "HSIL" diagnosis, which includes p16 IHC-positive CIN2, should annotate the morphologic diagnosis (CIN2 or CIN3) to inform all management decisions, which is especially important for young (<30 years) women diagnosed with CIN2 for whom surveillance rather than treatment is recommended.
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http://dx.doi.org/10.5858/arpa.2019-0241-OADOI Listing
June 2020

Lymphocyte-specific kinase expression is a prognostic indicator in ovarian cancer and correlates with a prominent B cell transcriptional signature.

Cancer Immunol Immunother 2019 Sep 12;68(9):1515-1526. Epub 2019 Sep 12.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Pressler St, Houston, TX, 77030, USA.

Objective: To investigate the prognostic and biologic significance of immune-related gene expression in high grade serous ovarian cancer (HGSOC).

Methods: Gene expression dependent survival analyses for a panel of immune related genes were evaluated in HGSOC utilizing The Cancer Genome Atlas (TCGA). Prognostic value of LCK was validated using IHC in an independent set of 72 HGSOC. Prognostic performance of LCK was compared to cytolytic score (CYT) using RNAseq across multiple tumor types. Differentially expressed genes in LCK high samples and gene ontology enrichment were analyzed.

Results: High pre-treatment LCK mRNA expression was found to be a strong predictor of survival in a set of 535 ovarian cancers. Patients with high LCK mRNA expression had a longer median progression free survival (PFS) of 29.4 months compared to 16.9 months in those without LCK high expression (p = 0.003), and longer median overall survival (OS) of 95.1 months versus 44.5 months (p = 0.001), which was confirmed in an independent cohort by IHC (p = 0.04). LCK expression was compared to CYT across tumor types available in the TCGA and was a significant predictor of prognosis in HGSOC where CYT was not predictive. Unexpectedly, LCK high samples also were enriched in numerous immunoglobulin-related and other B cell transcripts.

Conclusions: LCK is a better prognostic factor than CYT in ovarian cancer. In HGSOC, LCK high samples were characterized by higher expression of immunoglobulin and B-cell related genes suggesting that a cooperative interaction between tumor infiltrating T and B cells may correlate with better survival in this disease.
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http://dx.doi.org/10.1007/s00262-019-02385-xDOI Listing
September 2019

Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki-67 dual-stained cytology-Retrospective insights from ATHENA.

Int J Cancer 2020 05 6;146(9):2599-2607. Epub 2019 Oct 6.

Department of Pathology, Columbia University, New York City, NY.

The objective of our study was to assess the performance of different triage strategies for high-risk human papillomavirus (hrHPV)-positive results utilizing either extended genotyping or a p16/Ki-67 dual-stained cytology (DS) approach, with or without partial genotyping. A subset of women with hrHPV infections participating in the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study were analyzed to determine the number of cervical intraepithelial neoplasia grade 3 or worse (≥CIN3) cases detected, and the absolute risk for ≥CIN3 of each genotype. A clinical utility table was constructed to compare the impact of different triage strategies. In all, 2,339 women with single-genotype hrHPV infections were identified. Among these were 171 ≥CIN3 cases. The U.S. Food and Drug Administration (FDA)-approved algorithm (HPV16/18 positive, or 12-other hrHPV positive and Pap positive, i.e., ≥ atypical squamous cells of undetermined significance) for primary HPV screening detected 132/171 (77.2%) ≥CIN3 cases and required 964 colposcopies (colposcopies per ≥CIN3 ratio: 7.3). An approach that uses DS instead of cytology in the FDA-approved algorithm detected 147/171 (86.0%) ≥CIN3 cases, requiring 1,012 colposcopies (ratio: 6.9). Utilizing DS for triage of all hrHPV-positive women identified 126/171 (73.7%) ≥CIN3 cases, requiring 640 colposcopies (ratio: 5.1). A strategy that detected HPV16/18/31/33/35+ captured 130/171 (76.0%) ≥CIN3 cases, requiring 1,025 colposcopies (ratio: 7.9). Inclusion of additional genotypes resulted in greater disease detection at the expense of higher colposcopy ratios. Substituting cytology with a DS triage approach improved disease detection and the colposcopy detection rate. Further reduction of colposcopy rates can be achieved by using DS without partial genotyping. Extended genotyping strategies can identify a comparable number of cases but requires an increased number of colposcopies.
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http://dx.doi.org/10.1002/ijc.32669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078939PMC
May 2020

Vendor-specific microbiome controls both acute and chronic murine lung allograft rejection by altering CD4 Foxp3 regulatory T cell levels.

Am J Transplant 2019 10 2;19(10):2705-2718. Epub 2019 Aug 2.

Department of Surgery, University of Virginia, Charlottesville, Virginia.

Despite standardized postoperative care, some lung transplant patients suffer multiple episodes of acute and chronic rejection while others avoid graft problems for reasons that are poorly understood. Using an established model of C57BL/10 to C57BL/6 minor antigen mismatched single lung transplantation, we now demonstrate that the recipient microbiota contributes to variability in the alloimmune response. Specifically, mice from the Envigo facility in Frederick, Maryland contain nearly double the number of CD4 Foxp3 regulatory T cells (T ) than mice from the Jackson facility in Bar Harbor, Maine or the Envigo facility in Indianapolis, Indiana (18 vs 9 vs 7%). Lung graft recipients from the Maryland facility thus do not develop acute or chronic rejection. Treatment with broad-spectrum antibiotics decreases T and increases both acute and chronic graft rejection in otherwise tolerant strains of mice. Constitutive depletion of regulatory T cells, using Foxp3-driven expression of diphtheria toxin receptor, leads to the development of chronic rejection and supports the role of T in both acute and chronic alloimmunity. Taken together, our data demonstrate that the microbiota of certain individuals may contribute to tolerance through T -dependent mechanisms and challenges the practice of indiscriminate broad-spectrum antibiotic use in the perioperative period.
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http://dx.doi.org/10.1111/ajt.15523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919421PMC
October 2019

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction.

JCI Insight 2019 06 6;4(11). Epub 2019 Jun 6.

Department of Surgery, Carter Center for Immunology, and.

Despite the accepted notion that granulocytes play a universally destructive role in organ and tissue grafts, it has been recently described that eosinophils can facilitate immunosuppression-mediated acceptance of murine lung allografts. The mechanism of eosinophil-mediated tolerance, or their role in regulating alloimmune responses in the absence of immunosuppression, remains unknown. Using lung transplants in a fully MHC-mismatched BALB/c (H2d) to C57BL/6 (H2b) strain combination, we demonstrate that eosinophils downregulate T cell-mediated immune responses and play a tolerogenic role even in the absence of immunosuppression. We further show that such downregulation depends on PD-L1/PD-1-mediated synapse formation between eosinophils and T cells. We also demonstrate that eosinophils suppress T lymphocyte responses through the inhibition of T cell receptor/CD3 (TCR/CD3) subunit association and signal transduction in an inducible NOS-dependent manner. Increasing local eosinophil concentration, through administration of intratracheal eotaxin and IL-5, can ameliorate alloimmune responses in the lung allograft. Thus, our data indicate that eosinophil mobilization may be utilized as a novel means of lung allograft-specific immunosuppression.
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http://dx.doi.org/10.1172/jci.insight.128241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629120PMC
June 2019

Risk detection for high-grade cervical disease using Onclarity HPV extended genotyping in women, ≥21 years of age, with ASC-US or LSIL cytology.

Gynecol Oncol 2019 08 31;154(2):360-367. Epub 2019 May 31.

Becton, Dickinson and Company, BD Life Sciences - Diagnostic Systems, 7 Loveton Circle, Sparks, MD 21152, USA.

Objectives: There is growing interest in using human papillomavirus (HPV) genotyping as a risk-based triage approach for women with atypical squamous cells-undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL) cytology.

Methods: This analysis includes 2807 subjects with ASC-US or LSIL cytology, ≥21 years, from the baseline phase of the Onclarity HPV trial. All women were referred to colposcopy/biopsy. Hierarchical-ranked prevalence and risk values, associated with high-grade cervical disease, were calculated based on extended genotyping.

Results: HPV 16 carried the highest risk for cervical intraepithelial neoplasia grade 2 or worse (≥CIN2) in both the ASC-US and LSIL populations. Risk of ≥CIN3 and ≥CIN2 associated with the other 13 genotypes varied somewhat for women with ASC-US and LSIL, however, HPV 31, 18, 33/58, 51 and 52 appear to comprise an intermediate risk band. Risk associated with HPV 35/39/68, 45, and 56/59/66, in either cytology population, was relatively low and beneath the benchmark threshold risk for immediate colposcopy. Restricting the analysis to women 21-24 years, ≥25 years, or ≥30 years produced similar results.

Conclusions: HPV genotyping identified multiple risk bands for ≥CIN3 and ≥CIN2 in the ≥21 year-old ASC-US and LSIL populations. These results support a 1-year follow-up period to preclude immediate colposcopy for ASC-US or LSIL women positive for the lowest-risk HPV genotypes.
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http://dx.doi.org/10.1016/j.ygyno.2019.05.012DOI Listing
August 2019

Nine-valent HPV vaccine efficacy against related diseases and definitive therapy: comparison with historic placebo population.

Gynecol Oncol 2019 07 11;154(1):110-117. Epub 2019 Apr 11.

Merck & Co., Inc., Kenilworth, NJ, United States. Electronic address:

Objective: Nine-valent human papillomavirus (9vHPV) vaccine efficacy against disease and cervical surgeries related to all nine vaccine components was assessed compared with a historic placebo population. This was not assessed in the 9vHPV vaccine efficacy trial since the trial was quadrivalent HPV (qHPV) vaccine-controlled, efficacy was measured for the five HPV types covered only by 9vHPV vaccine (HPV31/33/45/52/58), but not the four types covered by both vaccines (HPV6/11/16/18).

Methods: Three international, randomized, double-blind studies were conducted using the same methodology. In the 9vHPV vaccine study (NCT00543543), 7106 and 7109 women received 9vHPV or qHPV vaccine, respectively. In the historic qHPV vaccine studies (FUTURE I [NCT00092521] and II [NCT00092534]), 8810 and 8812 women received qHPV vaccine or placebo, respectively, based on the same eligibility criteria. Cervical cytological testing was performed regularly. Biopsy or definitive therapy specimens were assessed for HPV DNA.

Results: Among women negative for 14 HPV types prior to vaccination, incidence of high-grade cervical disease (9vHPV, n = 2 cases; placebo, n = 141 cases) and cervical surgery (9vHPV, n = 3 cases; placebo, n = 170 cases) related to the nine HPV types was reduced by 98.2% (95% confidence interval [CI], 93.6-99.7) and 97.8% (95% CI, 93.4-99.4), respectively. The 9vHPV vaccine did not prevent disease related to vaccine HPV types detected at baseline, but significantly reduced cervical, vulvar, and vaginal diseases related to other vaccine HPV types.

Conclusions: Effective implementation of the 9vHPV vaccine may substantially reduce the burden of HPV-related diseases and related medical procedures.

Trial Registrations: clinicaltrials.gov: NCT00543543, NCT00092521, NCT00092534.
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http://dx.doi.org/10.1016/j.ygyno.2019.03.253DOI Listing
July 2019

The efficacy and safety of Tipapkinogen Sovacivec therapeutic HPV vaccine in cervical intraepithelial neoplasia grades 2 and 3: Randomized controlled phase II trial with 2.5 years of follow-up.

Gynecol Oncol 2019 06 4;153(3):521-529. Epub 2019 Apr 4.

Roche Pharmaceutical Research & Early Development, Roche Innovation Center New York, 430 E. 29th Street New York City, New York 10016, USA. Electronic address:

Background: While prophylactic human papillomavirus (HPV) vaccination exists, women are still developing cervical intraepithelial neoplasia (CIN) grade 2 or 3 for which an immunotherapeutic, non-surgical, approach may be effective. The primary aim was to assess the efficacy of tipapkinogen sovacivec (TS) vaccine in achieving histologic resolution of CIN2/3 associated with high risk (HR) HPV types.

Methods: Women 18 years and older who had confirmed CIN2/3 were enrolled in a randomized, double blind, placebo-controlled phase II trial and assigned to drug in a 2:1 ratio (vaccine:placebo). The primary endpoint occurred at month 6 when the excisional therapy was performed; cytology and HR HPV typing were performed at months 3, 6 and every six months through month 30. The safety population included all patients who received at least one dose of study drug.

Results: Of the 129 women randomized to vaccine and 63 to placebo, complete resolution was significantly higher in the vaccine group than placebo for CIN 2/3 regardless of the 13 HR HPV types assayed (24% vs. 10%, p < 0.05); as well as for only CIN 3 also regardless of HR HPV type (21% vs. 0%, p < 0.01). Irrespective of baseline HPV infection, viral DNA clearance was higher in the vaccine group compared to placebo (p < 0.01). The vaccine was well tolerated with the most common adverse events being injection site reactions.

Conclusions: The TS vaccine provides histologic clearance of CIN 2/3 irrespective of HR HPV type in one third of subjects and is generally safe through 30 months.
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http://dx.doi.org/10.1016/j.ygyno.2019.03.250DOI Listing
June 2019

Sporadic Obliterative Bronchiolitis: Case Series and Systematic Review of the Literature.

Mayo Clin Proc Innov Qual Outcomes 2019 Mar 17;3(1):86-93. Epub 2019 Jan 17.

Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, FL.

Objective: To describe the clinical characteristics and outcomes of patients diagnosed with obliterative bronchiolitis (OB) not associated with transplantation or point-source exposures to inhaled toxins.

Patients And Methods: We compiled all confirmed diagnoses of OB at our institution and analyzed their demographic characteristics, treatments, and outcomes as defined by pulmonary function tests (PFTs) and transplant-free mortality. The study period ranged from July 2007 to August 2017. Histological diagnosis was confirmed by a pathologist, and high-resolution chest computed tomography (CT) scans were reviewed and scored by chest radiologists. We also performed a systematic literature review of sporadic OB series.

Results: We identified 19 confirmed cases at our institution and 9 publications in the literature containing 104 patients. In both our series and the literature, patients were disproportionately middle-aged Caucasian women. The disease was idiopathic in 42% and was associated with connective tissue diseases and inhalational exposures in 31% and 15%, respectively. Chest CT showed expiratory air trapping in all patients. Patients were treated with corticosteroids, steroid-sparing agents, and macrolides in 77%, 46%, and 22%, respectively. Over a median follow-up in our series of 1703 days (range, 11-3206 days), PFTs did not change significantly. In all series combined, mortality incidence from any cause was 82/1000 patient-years (95% CI, 65-102). Of 14 patients who died, 3 deaths were due to respiratory failure and 5 were potentially related to complications of immunosuppressive therapy.

Conclusion: Sporadic OB is a rare disease that is uniformly associated with air trapping on high-resolution chest CT. The diagnosis should be established with surgical biopsy if possible. The illness is not typically progressive.
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http://dx.doi.org/10.1016/j.mayocpiqo.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410330PMC
March 2019

HPV infections and cytologic abnormalities in vaccinated women 21-34 years of age: Results from the baseline phase of the Onclarity trial.

Gynecol Oncol 2019 05 7;153(2):259-265. Epub 2019 Mar 7.

Becton, Dickinson and Company, BD Life Sciences - Diagnostic Systems, 7 Loveton Circle, Sparks, MD 21152, USA.

Objectives: Countries with school-based human papillomavirus (HPV) vaccination have seen significant reductions in vaccine-targeted HPV infections, cytologic abnormalities, and high-grade cervical intraepithelial neoplasia (≥CIN2). However, the impact of HPV vaccination in the United States (where vaccination is largely opportunistic) may be less due to lower coverage rates and vaccination in patients at ages beyond the recommended routine vaccination age.

Methods: The Onclarity trial enrolled 33,858 subjects ≥21 years who were screened with cytology and the BD Onclarity HPV Assay. HPV positive women or those with cytologic abnormalities underwent colposcopy and biopsy. The prevalence of HPV, cytologic abnormalities, and ≥CIN2 was compared in a subset of 14,153, vaccinated and unvaccinated women, 21-34 years. Results were compared by vaccination status; Mantel-Haenszel analysis was performed to determine the association between vaccination status and prevalence, adjusting for age.

Results: The prevalence of overall HPV, HPV16, 18, 31, and 33/58 were all lower in vaccinated women for each age group; a significant difference (p < 0.001) was observed in vaccinated women for all ages combined. Cytologic low-grade squamous intraepithelial lesion (LSIL) or worse was lower in vaccinated women (p = 0.021), as was ≥CIN2 prevalence associated with HPV 16 or 18 (p = 0.011).

Conclusions: Women with a prior history of HPV vaccination have a lower prevalence of any high-risk HPV, HPV 16, 18, 31, and 33/58; a cytology result of ≥LSIL, and ≥CIN2 associated with HPV 16/18 compared to unvaccinated women. A lower HPV prevalence in older, vaccinated women suggests that "catch-up" vaccination provides benefit.
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http://dx.doi.org/10.1016/j.ygyno.2019.02.016DOI Listing
May 2019

A mobile-phone based high-resolution microendoscope to image cervical precancer.

PLoS One 2019 6;14(2):e0211045. Epub 2019 Feb 6.

Department of Bioengineering, Rice University, Houston, Texas, United States of America.

Nearly 90% of cervical cancer cases and deaths occur in low- and middle-income countries that lack comprehensive national HPV immunization and cervical cancer screening programs. In these settings, it is difficult to implement screening programs due to a lack of infrastructure and shortage of trained personnel. Screening programs based on visual inspection with acetic acid (VIA) have been successfully implemented in some low-resource settings. However, VIA has poor specificity and up to 90% of patients receiving treatment based on a positive VIA exam are over-treated. A number of studies have suggested that high-resolution cervical imaging to visualize nuclear morphology in vivo can improve specificity by better distinguishing precancerous and benign lesions. To enable high-resolution imaging in low-resource settings, we developed a portable, low-cost, high-resolution microendoscope that uses a mobile phone to detect and display images of cervical epithelium in vivo with subcellular resolution. The device was fabricated for less than $2,000 using commercially available optical components including filters, an LED and triplet lenses assembled in a 3D-printed opto-mechanical mount. We show that the mobile high-resolution microendoscope achieves similar resolution and signal-to-background ratio as previously reported high-resolution microendoscope systems using traditional cameras and computers to detect and display images. Finally, we demonstrate the ability of the mobile high-resolution microendoscope to image normal and precancerous squamous epithelium of the cervix in vivo in a gynecological referral clinic in Barretos, Brazil.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211045PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364962PMC
November 2019

HPV Testing With 16, 18, and 45 Genotyping Stratifies Cancer Risk for Women With Normal Cytology.

Am J Clin Pathol 2019 03;151(4):433-442

Becton, Dickinson and Company, BD Life Sciences-Diagnostic Systems, Sparks, MD.

Objectives: To determine the BD Onclarity human papillomavirus (HPV) assay performance and risk values for cervical intraepithelial neoplasia grade 2 (CIN2) or higher and cervical intraepithelial neoplasia grade 3 (CIN3) or higher during Papanicolaou/HPV cotesting in a negative for intraepithelial lesions or malignancies (NILM) population.

Methods: In total, 22,383 of the 33,858 enrolled women were 30 years or older with NILM cytology. HPV+ and a subset of HPV- patients (3,219/33,858 combined; 9.5%) were referred to colposcopy/biopsy.

Results: Overall, 7.9% of women were Onclarity positive; HPV 16 had the highest prevalence (1.5%). Verification bias-adjusted (VBA) CIN2 or higher and CIN3 or higher prevalences were 0.9% and 0.3%, respectively. Onclarity had VBA CIN2 or higher (44.1%) and CIN3 or higher (69.5%) sensitivities, as well as CIN2 or higher (92.4%) and CIN3 or higher (92.3%) specificities-all similar to Hybrid Capture 2. HPV 16, 18, 45, and the other 11 genotypes had CIN3 or higher risks of 6.9%, 2.6%, 1.1%, and 2.2%, respectively.

Conclusions: Onclarity is clinically validated for cotesting in NILM women. Genotyping actionably stratifies women at greater CIN3 or higher risk.
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http://dx.doi.org/10.1093/ajcp/aqy169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396747PMC
March 2019

Stratified risk of high-grade cervical disease using onclarity HPV extended genotyping in women, ≥25 years of age, with NILM cytology.

Gynecol Oncol 2019 04 10;153(1):26-33. Epub 2019 Jan 10.

Becton, Dickinson and Company, BD Life Sciences, - Diagnostic Systems, 7 Loveton Circle, Sparks, MD 21152, USA. Electronic address:

Objectives: Increasing evidence suggests that extended human papillomavirus (HPV) genotyping (beyond 16/18) is effective for risk stratification in women with normal cytology. This report provides extended genotyping results, using the BD Onclarity HPV Assay, for individual genotypes HPV16, 18, 31, 45, 51, and 52 ̶ and three pooled genotype results for HPV33/58, 35/39/68, and 56/59/66.

Methods: 27,037 women with normal cytology, ≥25 years, were enrolled into the Onclarity HPV trial during routine screening. Women positive for any HPV genotype were referred to colposcopy/biopsy. Hierarchical-ranked prevalence and risk values, associated with cervical intraepithelial neoplasia, grade 2 or worse (≥CIN2) or ≥CIN3, were calculated based on extended genotyping results.

Results: HPV 16 and 31 carried the highest risk for ≥CIN2 (11.6% and 12.1%, respectively) and ≥CIN3 (8.1% and 7.5%, respectively); these genotypes were the most prevalent in both ≥CIN2 (29.6% and 19.3%, respectively) and ≥CIN3 (43.7% and 22.5%, respectively). Of the other 12 genotypes, HPV 18, 33/58, and 52 comprised an intermediate risk band (≥CIN2 risk range: 4.9-6.8%; ≥CIN3 risk range: 3.9-5.0%). Genotypes 45, 51, 35/39/68, and 56/59/66 constituted the lowest risk band for both disease grades (≥CIN2 value risk range: 1.7-3.0%; ≥CIN3 value risk range: 1.2-3.6%).

Conclusions: Extended genotyping stratifies risk for ≥CIN2/3 in the ≥25 year-old, normal cytology population. While baseline HPV 16/31 values exceeded the risk threshold for colposcopy referral, the management of women with normal cytology who were positive for the intermediate- or lower-risk genotypes may evolve based on refined risk estimates as well as clinical factors.
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http://dx.doi.org/10.1016/j.ygyno.2018.12.024DOI Listing
April 2019

Ex Vivo Assessment of Porcine Donation After Circulatory Death Lungs That Undergo Increasing Warm Ischemia Times.

Transplant Direct 2018 Dec 12;4(12):e405. Epub 2018 Nov 12.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.

Background: Increased utilization of donation after circulatory death (DCD) lungs may help alleviate the supply/demand mismatch between available donor organs and lung transplant candidates. Using an established porcine DCD model, we sought to determine the effect of increasing warm ischemia time (WIT) after circulatory arrest on lung function during ex vivo lung perfusion (EVLP).

Methods: Porcine donors (n = 15) underwent hypoxic cardiac arrest, followed by 60, 90, or 120 minutes of WIT before procurement and 4 hours of normothermic EVLP. Oxygenation, pulmonary artery pressure, airway pressure, and compliance were measured hourly. Lung injury scores were assessed histologically after 4 hours of EVLP.

Results: After EVLP, all 3 groups met all the criteria for transplantation, except for 90-minute WIT lungs, which had a mean pulmonary artery pressure increase greater than 15%. There were no significant differences between groups as assessed by final oxygenation capacity, as well as changes in pulmonary artery pressure, airway pressure, or lung compliance. Histologic lung injury scores as well as lung wet-to-dry weight ratios did not significantly differ between groups.

Conclusions: These results suggest that longer WIT alone (up to 120 minutes) does not predict worse lung function at the conclusion of EVLP. Expanding acceptable WIT after circulatory death may eventually allow for increased utilization of DCD lungs in procurement protocols.
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http://dx.doi.org/10.1097/TXD.0000000000000845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283086PMC
December 2018

Detection of Cervical Neoplasia by Human Papillomavirus Testing in an Atypical Squamous Cells-Undetermined Significance Population: Results of the Becton Dickinson Onclarity Trial.

Am J Clin Pathol 2019 01;151(1):53-62

Becton, Dickinson and Company, BD Life Sciences-Diagnostic Systems, Sparks, MD.

Objectives: To determine clinical utility of Onclarity human papillomavirus (HPV) assay for atypical squamous cells-undetermined significance (ASC-US) triage, and the value of HPV genotyping within ASC-US.

Methods: Women (n = 33,858; 21 years or older) had HPV testing using Onclarity and Hybrid Capture 2 (HC2). ASC-US individuals (n = 1,960, 5.8%) were referred to colposcopy.

Results: Of ASC-US, 39.1% were HPV positive by Onclarity; HPV 16 was the most prevalent genotype (7.4%). Cervical intraepithelial neoplasia grade 2 (CIN 2) and CIN 3+ prevalences were 4.4% and 2.2%, respectively. Onclarity had sensitivity for CIN 2+ (85.7%) and CIN 3+ (91.4%), and specificities for CIN 2+ (64.1%) and CIN 3+ (62.0%), similar to HC2. Risks for CIN 3+ were 16.1%, 2.8%, 2.5%, and 2.7% with HPV 16, 18, 45, and 11 other genotypes, respectively.

Conclusions: Onclarity is clinically validated for ASC-US triage. Through risk stratification, genotyping could help identify women at highest risk for CIN 3+.
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http://dx.doi.org/10.1093/ajcp/aqy084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287654PMC
January 2019

Necrobiotic Pulmonary Nodules of Crohn's Disease in a Patient Receiving Vedolizumab.

Am J Respir Crit Care Med 2019 01;199(1):e1-e2

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.

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http://dx.doi.org/10.1164/rccm.201806-1056IMDOI Listing
January 2019

PD-L1 and IDO expression in cervical and vulvar invasive and intraepithelial squamous neoplasias: implications for combination immunotherapy.

Histopathology 2019 Jan 29;74(2):256-268. Epub 2018 Oct 29.

Department of Pathology, University of Virginia, Charlottesville, VA, USA.

Aims: The immunoregulatory enzyme indoleamine dioxygenase 2,3 (IDO) has been implicated in cervical and vulvar squamous carcinomas (SCC) and may represent a mechanism of resistance to anti-PD-1/anti-PD-L1 therapy. However, the relationship between IDO and PD-L1 has not been well-investigated.

Methods And Results: Sixty-five cases of cervical and vulvar intraepithelial neoplasia and SCC were assessed for IDO and PD-L1 expression. Overall, tumoral PD-L1 expression was seen in 72% of SCC, while 50% expressed IDO; co-expression was seen in 42%. Using the combined positive score (CPS) threshold of 1 to account for both tumoral and immune staining, 83% of SCC expressed PD-L1, 61% expressed IDO and 53% showed co-expression. Cervical SCCs were significantly more likely than human papillomavirus (HPV)-related vulvar SCCs to express tumoral IDO (75% versus 13%, P < 0.001) and demonstrate an IDO CPS ≥ 1 (88% versus 25%, P < 0.001); no significant differences were seen for PD-L1. Additionally, there were no significant differences in IDO and PD-L1 expression in dVIN-associated versus HPV-associated vulvar SCC. In contrast to SCC, the majority of intraepithelial lesions were entirely negative for tumoral PD-L1 and IDO and had a CPS score of <1.

Conclusions: In summary, IDO and PD-L1 co-expression is common in cervical SCCs and, to a lesser extent, vulvar SCCs. These data suggest a role for combination immunotherapy in a subset of cervical SCCs as well as select vulvar SCCs. Expression for both markers is less common in intraepithelial lesions, providing no strong support for this form of immunotherapy in the absence of invasion.
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http://dx.doi.org/10.1111/his.13723DOI Listing
January 2019

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age.

Obstet Gynecol 2018 08;132(2):261-270

Department of Microbiology Infectious Diseases, the Royal Women's Hospital, Department of Microbiology, the Royal Children's Hospital, Infection and Immunity, Murdoch Children's Research Institute, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia; the Department of Gynecology and Obstetrics, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; the Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas; Institut Catala d'Oncologia, IDIBELL, CIBER-ESP, RTICC, L'Hospitalet de Llobregat, Barcelona, Spain; the Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; the Department of Pathology, SMBD Jewish General Hospital and McGill University, Montréal, Québec, Canada; the Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia; the Center for Infection Research in Cancer, Moffitt Cancer Center, Tampa, Florida; the National Institute of Public Health, Cuernavaca, Morelos, Mexico; the Division of Gynecologic Oncology, University of Alabama, Birmingham, Alabama; the Department of Clinical Science, University of Bergen/Haukeland University Hospital, Bergen, Norway; the Danish Cancer Society Research Center, Copenhagen, Denmark and Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Johns Hopkins University School of Medicine, Baltimore, Maryland; the Department of Obstetrics and Gynecology, Clinica Colsanitas, Fundacion Universitaria Sanitas, Bogota, Colombia; Institut du col, Paris, France; the National Institute of Cancer, Bogotá, Colombia; the Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland; the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Direction des Risques Biologiques et de la Santé au Travail, Institut National de Santé Publique du Québec, Montréal, Québec, Canada; Robert E. Fechner Laboratory of Surgical Pathology, University of Virginia Health System, Charlottesville, Virginia; the Departments of Pathology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; UCLA School of Nursing, Los Angeles, California; Merck & Co, Inc., Kenilworth, New Jersey; Universidad del Rosario, Bogota, Colombia; and Analytica LASÉR, Montréal, Québec, Canada.

Objective: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59).

Methods: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods.

Results: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs.

Conclusion: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs.

Clinical Trial Registration: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.
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http://dx.doi.org/10.1097/AOG.0000000000002736DOI Listing
August 2018

HPV RNA in situ hybridization can inform cervical cytology-histology correlation.

Cancer Cytopathol 2018 08 5;126(8):533-540. Epub 2018 Jul 5.

Department of Pathology, University of Virginia, Charlottesville, Virginia.

Background: In situ hybridization for human papillomavirus (HPV) messenger RNA (HPV RNA ISH) recently was introduced as an ancillary tool in the diagnosis of cervical squamous intraepithelial lesions, and can aid in the distinction between low-grade squamous intraepithelial lesions (LSILs) versus reactive/negative biopsies. Prior work has shown that up to one-half of cases originally diagnosed as LSIL are reclassified as negative/reactive by expert consensus review of morphology, and negative HPV RNA ISH results most often correlate with an expert diagnosis of negative/reactive. Given that LSIL overdiagnoses on biopsy may result in the erroneous clinical impression that a cervical lesion has been sampled appropriately, the authors proposed that HPV RNA ISH can inform cytology-histology correlation for challenging LSIL biopsies.

Methods: A total of 92 cervical biopsies originally diagnosed as LSIL were reviewed by 3 gynecologic pathologists and reclassified based on consensus opinion of morphology. ISH was performed for high-risk and low-risk HPV E6/E7 mRNA. Prior/concurrent cytology results were collected.

Results: Based on expert consensus morphologic review, 49% of biopsies (45 of 92 biopsies) originally diagnosed as LSIL were reclassified as negative, 6.5% (6 of 92 biopsies) were reclassified as high-grade squamous intraepithelial lesion, and 44.5% (41 of 92 biopsies) were maintained as LSIL. The majority of LSIL biopsies reclassified as negative (80%; 36 of 45 biopsies) were HPV RNA negative, whereas 93% of LSIL biopsies (39 of 41 biopsies) and 100% of high-grade squamous intraepithelial lesion biopsies were HPV RNA positive.

Conclusions: LSIL often is overdiagnosed by morphology on biopsy, potentially leading to the false impression that a lesion identified on cytology has been sampled. Performing RNA ISH on biopsies decreases histologic LSIL overdiagnosis, and potentially can prompt further sampling when there is cytology-histology discordance. Cancer (Cancer Cytopathol) 2018. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncy.22027DOI Listing
August 2018

Routine Use of Adjunctive p16 Immunohistochemistry Improves Diagnostic Agreement of Cervical Biopsy Interpretation: Results From the CERTAIN Study.

Am J Surg Pathol 2018 08;42(8):1001-1009

Ventana Medical Systems Inc., Roche Tissue Diagnostics, Tucson, AZ.

The diagnosis of squamous intraepithelial lesions in cervical tissue specimens is subject to substantial variability. Adjunctive immunohistochemical (IHC) staining for p16 has been shown to add objective biomarker information to morphologic interpretation of hematoxylin and eosin (H&E)-stained tissues. In the CERvical Tissue AdjunctIve aNalysis (CERTAIN) study, we systematically analyzed the impact of adjunctive p16 IHC on the accuracy (agreement with reference pathology results) of diagnosing cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) in the United States. Eleven hundred cervical biopsies were divided into 4 sets of 275 cases by stratified randomization. All H&E slides from each set were interpreted by 17 to 18 individual surgical pathologists, for a total of 19,250 reads by 70 surgical pathologists. After a wash-out period and blinding to original results, cases were re-read by the same pathologists using H&E+p16-stained slides. Using expert consensus diagnoses on H&E+p16 as reference, adjunctive p16 IHC use significantly improved diagnostic agreement of surgical pathologists by 4.7% (95% confidence interval [CI], 3.9, 5.4; P<0.0001). This improvement was driven by an increase of 11.5% (95% CI, 9.3, 13.5; P<0.0001) in sensitivity and an increase of 3.0% (95% CI, 2.2, 3.7; P<0.0001) in specificity. Diagnostic performance was significantly increased as well when expert consensus diagnoses established on H&E only was used as reference. Furthermore, interobserver reliability improved significantly from moderate (H&E: κ=0.58) to substantial (H&E+p16: κ=0.73; P<0.0001). Adjunctive use of p16 IHC provides more accurate and reproducible diagnostic results in the interpretation of cervical biopsies, ensuring that more patients are treated correctly without treating more patients.
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http://dx.doi.org/10.1097/PAS.0000000000001072DOI Listing
August 2018

The Onclarity Human Papillomavirus Trial: Design, methods, and baseline results.

Gynecol Oncol 2018 06 19;149(3):498-505. Epub 2018 Apr 19.

Becton, Dickinson and Company, BD Life Sciences - Diagnostic Systems, 7 Loveton Circle, Sparks, MD 21152, USA.

Objectives: The baseline phase of the Onclarity trial was conducted to determine the screening performance of the Onclarity human papillomavirus (HPV) assay for detecting cervical cancer and precancer (≥CIN2) during triage of women ≥21 years with ASC-US cytology, as an adjunct test in women ≥30 years with normal cytology and for primary screening (HPV alone) in women ≥25 years.

Methods: 33,858 women ≥21 years were enrolled during routine clinic visits. All women with abnormal cytology, women ≥25 years that were high-risk HPV positive, and a random subset of women ≥25 years, negative by cytology and for HPV, were referred for colposcopy and cervical biopsy. Verification bias adjustment with 95% confidence intervals was applied.

Results: ASC-US prevalence was 5.8%. The overall HPV prevalence was 14.7%; for HPV 16, 18, and the 12 other HPV types it was 2.7%, 0.8%, and 11.2%, respectively. The prevalence of ASC-US and HPV was inversely proportional with age. The verification bias adjusted prevalence of ≥CIN2 and ≥CIN3 was 1.8% and 0.8%, respectively. Overall, five cases of cervical cancer were identified (all were HPV positive). The odds ratios associated with any HPV positive genotype, or with individual genotypes HPV 16, HPV 18, and HPV 31, for ≥CIN3, were statistically significant when compared to negative histology (p < 0.0001 for all).

Conclusions: This report provides demographic information, cytology findings, HPV genotype information, and histopathology for participants in the baseline phase of this trial and offers further evidence to support genotype-specific screening for cervical cancer and precancer. Clinical Trial Registry URL:https://clinicaltrials.gov/ct2/show/NCT01944722.
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http://dx.doi.org/10.1016/j.ygyno.2018.04.007DOI Listing
June 2018