Single and Multiple High-Risk Human Papillomavirus Infections in Histopathologically Confirmed Cervical Squamous Lesions: Incidences, Distribution, and Associated Detection Rates for Precancerous and Cancerous Lesions.

Coinfection with multiple high-risk human papillomavirus (hrHPV) is frequently observed in cervical specimens; however, the clinical significance of concomitant multiple hrHPV infections is poorly understood, and the published results remain inconsistent. A retrospective study at a tertiary care institution was performed, evaluating Tellgenplex human papillomavirus (HPV) 27 genotyping or YanengBio HPV 23 genotyping results and immediate cervical histologic diagnosis (within 6 months after HPV genotyping), between November 2015 and October 2022. Among 49,299 cases with hrHPV genotyping and histologic diagnosis, 24,361 cases were diagnosed as cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma. Among women with cervical squamous lesions, 86.5% (21,070/24,361) had hrHPV infections, and concomitant multiple hrHPV infections accounted for 24.7% of hrHPV-positive cases (5210/21,070). The hrHPV-positive rates in these cervical squamous lesions increased progressively with disease severity; however, the percentages of concomitant multiple hrHPV infection rates among hrHPV-positive cases decreased significantly with increasing degree of squamous abnormalities. There was no increased detection rate of CIN3+ (CIN3 and squamous cell carcinoma) in cases with concomitant 2 or 3 hrHPV genotype infections when compared with those with corresponding single hrHPV infections. Conversely, some combinations of multiple hrHPV infections demonstrated a decrease in the detection rates of CIN3+ lesions. In this large cohort, our results demonstrated that multiple hrHPV infections do not carry an increased risk for developing CIN3+ lesions when compared to the corresponding single-genotype infection. The reduced risk of CIN3+ in women infected with some combinations of hrHPV genotypes compared to those with single-genotype infections supports the concept of intergenotypic competition of hrHPV genotypes in cervical squamous lesions.

Extended human papillomavirus genotype distribution in cervical intraepithelial neoplasia and cancer: Analysis of 40 352 cases from a large academic gynecologic center in China.

Our aim was to conduct a large epidemiologic analysis of the distribution of human papilloma virus (HPV) genotypes associated with cervical neoplasias and cancers at a major Chinese gynecologic center. The pathologic database was searched for cervical histopathologic diagnoses with prior HPV genotyping from liquid cervical cytology specimens obtained ≤6 months before biopsy. HPV testing was performed by using the Tellgenplex HPV27 or YanengBio HPV23 genotyping assays. A total of 40 352 cases meeting study criteria were identified. High risk human papillomavirus (hrHPV) was detected in 94.1% of squamous cancers compared to in only 83.3% of cervical adenocarcinomas. The prevalence of multiple HPV infections was highest in cervical intraepithelial neoplasia 1 (CIN1) (33.8%) and decreased with increasing severity of squamous lesions. The distribution of HPV genotypes was similar between CIN1 and histopathologic-negative cases. HPV16 was one of the three most common hrHPV genotypes before all histopathologic abnormalities, ranging from 72.0% for cervical cancers, 38.7% for CIN2/3/AIS, 13.1% for CIN1, and 9.1% for biopsy-negative cases. HPV16 and HPV18 accounted for over 87.2% of detected hrHPV genotypes for all glandular intraepithelial neoplastic lesions and cancers, whereas squamous lesions did not show this pattern. 80.3% of cervical cancers were associated with genotypes covered by HPV16/18 vaccines and 89.6% with genotypes covered by 9-valent vaccination.

The Potential Prognostic and Therapeutic Implications of Prolactin Receptor and Growth Hormone-releasing Hormone Receptor Expression in Uterine Leiomyosarcomas.

The management of uterine leiomyosarcomas (uLMS) remains challenging. The rate of recurrence and metastasis is high, with 5-yr survival reaching only 40% to 50% in patients with tumor confined to the uterus (FIGO stage I or II). Prolactin receptor (PRLR) and growth hormone-releasing hormone receptor (GHRHR) have been implicated in the carcinogenesis of malignant tumors of the breast, endometrium, ovary, liver, and prostate. GHRHR antagonists inhibit in vitro growth of many human tumors and the expression of PRLR is associated with resistance to chemotherapy. The immunohistochemical expression of PRLR and GHRH in 24 primary and 2 recurrent uLMS was evaluated. Representative sections were stained with PRLR and GHRHR antibodies and immunoreactivity was calculated using H -score. The results were correlated with clinicopathologic data using Kaplan-Meier survival and multivariable Cox proportion hazard regression analyses. All tumors were positive for both markers with predominantly moderate to strong expression of PRLR (89%) and GHRHR (82%). Patients with tumors showing moderate to strong expression of PRLR were significantly less likely to achieve disease-free survival ( P =0.004) and significantly more likely to have a poor overall survival ( P =0.049). No significant difference in mean PRLR expression was found between tumors with higher mitotic counts (>20/10 hpf) and lower mitotic counts (20 or less/10 hpf). Furthermore, in 2 patients where the primary and recurrent tumors were tested, there was stronger expression of PRLR in the recurrence compared with the primary. This correlation was not found with GHRHR. Both PRLR and GHRHR may play a role in carcinogenesis in uLMS, as they do in other malignant neoplasms. To our knowledge, this study is the first evaluating the expression of these receptors in uLMS. Moderate or high expression of PRLR may serve as a prognostic marker associated with recurrences and increased mortality in uLMS patients.

Reliably making the primary diagnosis of mesothelioma utilizing serous fluid cytology specimens: an institutional experience.

INTRODUCTION: The diagnosis of mesothelioma has historically been challenging, especially on serous fluid cytology (SFC). Distinguishing between reactive and neoplastic mesothelial cells can be difficult on cytomorphology alone. However, additional ancillary tests, such as BRCA1 associated protein-1 immunohistochemistry and fluorescence in situ hybridization for cyclin-dependent kinase inhibitor 2A deletion, can provide a sensitive and highly specific method of proving malignancy. MATERIALS AND METHODS: SFC specimens diagnosed as mesothelioma, suspicious for mesothelioma (SM), and atypical mesothelial cells (AMCs) since 2012 were identified by querying the laboratory information system. Clinical data and pathologic parameters were gathered. RESULTS: One hundred ten cases of mesothelioma, SM, and AMC were identified. Of these, 61 cases had a definitive diagnosis of mesothelioma on SFC. Average age at SFC diagnosis was 67 years (26-87 years), with most patients being male (67%). Out of the 61 cases, 11 cases (18%) had an initial diagnosis of mesothelioma made on SFC specimens, with 5 of these 11 cases being in patients that never received a histologic diagnosis of mesothelioma. Ancillary studies were utilized in all 11 cases. An initial diagnosis of metastatic mesothelioma was made on SFC in 9 cases (15%). For 6 of these 9 cases, the SFC diagnosis was the sole diagnosis of metastatic mesothelioma without a companion histologic diagnosis. In addition, 15 cases were diagnosed as SM, with 11 of these cases following a definitive mesothelioma diagnosis. Thirty-four cases were diagnosed as AMC, with 27 cases following a definitive mesothelioma diagnosis. CONCLUSIONS: The diagnosis of mesothelioma can be reliably made on SFC with the appropriate cytomorphology criteria and/or confirmatory ancillary testing.

The Immunohistochemical Profile of Mammary Tissue in Women With Macromastia and Its Potential Clinical Implications.

Macromastia is an excessive, rapid, or slow growth of breast tissue in 1 or both breasts. While macromastia represents a benign lesion, it may cause breast, shoulder, back, and neck pain, poor posture, infections, and loss of nipple sensation. The pathogenesis of macromastia or hypertrophy of mammary tissue remains poorly understood. The purpose of this study is to investigate the immunohistochemical expression of several hormone receptors that may potentially influence the growth of breast tissue in women with macromastia. Immunohistochemical studies performed on representative sections of breast tissue from 63 patients diagnosed with macromastia included estrogen receptor, progesterone receptor, androgen receptor (AR), prolactin receptor, growth hormone receptor, and vascular endothelial growth factor. The expression of each stain was evaluated separately in the glandular epithelium and adipose tissue and calculated as an H-score. We observed that AR expression in breast glandular and adipose tissue in women with macromastia was significantly lower than benign, nonhypertrophic breast tissue of a control group. Although the analyses were controlled for the age, the fact the mean age and hormonal status differed between the patients and the controls could have affected the results. Additional large studies will be required to further verify this finding and increase the knowledge about the etiology of this condition and then guide pharmacological treatment of juvenile and/or idiopathic gigantomastia.

A comprehensive analysis of SOX17 expression by immunohistochemistry in human epithelial tumors, with an emphasis on gynecologic tumors.

OBJECTIVES: The objective of this study was to evaluate SOX17, a transcription factor from the Sry high-mobility group-related box superfamily, as a diagnostic marker to determine site of origin using both whole-tissue sections and tissue microarrays (TMAs). METHODS: SOX17 immunohistochemistry was performed on gynecologic and nongynecologic tissues (N = 1004) using whole-tissue sections and both internally constructed and commercially available TMAs. SOX17 nuclear reactivity was scored as positive or negative on the whole-tissue sections and using the semiquantitative H score method on TMAs. RESULTS: Using both whole-tissue sections and TMAs, SOX17 was positive in 94% (n = 155) of endometrial tumors and 96% (n = 242) of ovarian tumors. All breast cases (n = 241) and vulvar/cervical squamous cell carcinomas (n = 150) were negative. Among 1004 tumors from 20 sites, the only organs with positive tumors were ovary, uterus, and testis. CONCLUSIONS: SOX17 is a sensitive and specific marker for gynecologic origin in the tissues tested and may be a valuable adjunct to PAX8 and other commonly used markers to confirm endometrial or ovarian origin. SOX17 expression is lower in mucinous tumors, endocervical adenocarcinoma, high-grade neuroendocrine tumors, and undifferentiated/dedifferentiated endometrial carcinoma.

Changes over time in papanicolaou cytology test and HPV test in a large women's academic center laboratory.

INTRODUCTION: In the past 2 decades, cervical cancer screening guidelines in the United States have undergone numerous revisions with recent greater emphasis on primary high-risk human papillomavirus (hrHPV) testing. MATERIALS AND METHODS: We examine the trends of Papanicolaou test and hrHPV testing at our large academic center across 4 years (2006, 2011, 2016, and 2021) over a 15-year period. The number of ThinPrep Papanicolaou and hrHPV tests, as well as the triggers for HPV testing, were retrospectively analyzed. RESULTS: A total of 308,355 Papanicolaou tests and 117,477 hrHPV tests were reported across the 4 years. The number of Papanicolaou tests performed decreased nearly 3-fold over the study period, with only 43,230 Papanicolaou tests performed in 2021. The HPV test to Papanicolaou test ratio increased: 17% of Papanicolaou tests had an associated HPV test in 2006, whereas 72% of Papanicolaou tests ordered in 2021 had a companion hrHPV. The use of co-testing also increased. Overall, 73% were co-tests and 27% were reflexively ordered in the 4 one-year time periods. Co-tests constituted only 46% of HPV tests in 2006, but this increased to 93% in 2021. The percentage of positive hrHPV results decreased; in 2006, 18.3% of cases were positive, dropping to 8.6% in 2021 due to the marked increase in co-testing. Stratifying by diagnostic category, hrHPV results have remained relatively constant. CONCLUSION: With the numerous recent revisions of cervical screening guidelines, screening strategies at our institution reflected these changes in clinical practice. Papanicolaou and HPV co-testing became the most common screening method for women 30 to 65 years of age in our cohort.

High-fidelity simulation for continuing education in nurse anesthesia.

Simulation represents a true paradigm shift in teaching and learning that has revolutionized healthcare education. However, few continuing education opportunities for anesthesia providers exist using simulation of any type. This article explores the usefulness of high-fidelity simulation (HFS) as a valuable tool for continuing education and reports the results of a needs assessment conducted among 22 practicing nurse anesthetists. The questions related to their exposure to HFS and asked them to rank their experience with 11 anesthesia events. Next, respondents were asked to rank a similar list of anesthesia events that would be useful for continuing education using simulation. Of participants, 71% ranked advanced cardiac life support scenarios, anesthesia machine mishaps, and malignant hyperthermia as highly effective choices for using HFS. Eighty-one percent of participants identified that they envision simulation as a valuable tool to assess competency, but respondents had mixed written responses when asked if simulation should be used for recertification. This needs assessment represents a beginning, grassroots attempt to establish nurse anesthetists' perceptions related to using HFS as a tool for continuing education.

Change of Practice Patterns Following an Educational Comment on Reports of Benign-Appearing Endometrial Cells in Papanicolaou Tests.

OBJECTIVES: Since the publication of our study demonstrating high negative predictive values (>99% for women in their 40s) of benign-appearing endometrial cells (nEMCs), we have begun to include an educational comment in Papanicolaou (Pap) test reports with nEMCs that recommends routine periodic screening for asymptomatic premenopausal women (APW). The current study evaluated how the inclusion of this comment has affected clinical practice patterns at our institution. METHODS: The 2017 to 2019 database identified 175 reports containing the educational comment in women aged 45 to 54 years with a follow-up time of 11 to 37 months. Data, including age, menopause status, symptoms, imaging, and outcome, were collected. The procedure rate and the impact of clinical modifiers were assessed. RESULTS: Thirty-seven (20.6%) patients had biopsies within 6 months, which decreased from 48.1% as we previously reported. All nine (5%) APW with biopsies triggered only by nEMCs had benign histopathology. The remaining 28 biopsied patients had abnormal bleeding or a thickened endometrium, or they were postmenopausal, including a 53-year-old patient with complex atypical hyperplasia. None of the 138 patients with conservative follow-up developed atypical/malignant lesions. CONCLUSIONS: A qualifying educational note included in Pap reports significantly reduced follow-up biopsies in APW. Optimal follow-up of nEMCs should be based on relevant clinical modifiers.

The effects of high-fidelity simulation on salivary cortisol levels in SRNA students: a pilot study.

The use of clinical simulation in graduate level nursing education provides the opportunity for students to learn and apply theoretical practices of nursing care in a safe and controlled environment. It was postulated that laboratory simulation would mimic the stress levels of a real clinical situation as measured by the stress hormone cortisol. The purpose of this study was to determine whether high-fidelity simulation approximates the stress experienced by nurse anesthesia students in the operating room. Participants (n = 21) were recruited from an accredited nurse anesthesia program in the southern U.S. Saliva was collected for 3 days under controlled conditions for baseline data. Next, saliva was collected for 3 days: the day before, the day of, and the day after simulation. The same process was repeated for the first clinical day in the operating room. The participants acted as their own control. There was a significant (p < 0.05) increase in cortisol levels during laboratory simulation as compared to baseline values. Although levels of cortisol were higher during clinical time than baseline, this increase was not significant (p > 0.05), and levels were lower than levels during simulation. Laboratory simulation of patient scenarios raised the stress hormone cortisol level threefold above baseline levels in nurse anesthesia students, while actual clinical experience did not.

Personalized Medicine and Cervical Screening: Development of Individualized Quantitative Risk Assessments for Cervical Adenocarcinoma and Adenocarcinoma in situ.

INTRODUCTION: Cervical screening has decreased the incidence of cervical carcinoma around the world primarily by preventing cervical squamous carcinoma, with significantly less measurable protective benefits in prevention of cervical adenocarcinoma. In this study, we apply Bayesian modeling of cervical clinical, screening, and biopsy data from a large integrated health system to explore the feasibility of calculating personalized risk assessments on screened system patients for subsequent histopathologic diagnoses of invasive cervical adenocarcinoma (AdCa) or cervical adenocarcinoma in situ (AIS). MATERIALS AND METHODS: Diagnoses of cervical AIS or AdCa rendered between 2005 and 2018 were identified in our large health system database with 1,053,713 cytology results, 354,843 high-risk (hr) human papillomavirus (HPV) test results, and 99,012 cervical histopathologic results. Using our continuously updated Bayesian cervical cancer screening model which includes clinical data, cervical screening results, and cervical biopsy results, we projected quantitative estimates of patients' 5-year cumulative risk for cervical AIS or AdCa. RESULTS: 161 patients were identified with AIS (ages 17-75, mean 37 years), and 99 patients had diagnoses of cervical AdCa (ages 26-91, mean 48 years). Quantitative Bayesian 5-year cumulative risk projections for diagnoses of cervical AdCa or AIS in patients with different cervical screening test and biopsy histories were determined. The highest patient risk projections for subsequent cervical AdCa and/or AIS histopathologic diagnoses were associated with prior cervical screening test results of HPV-positive atypical glandular cells. Prior squamous cytologic abnormalities were associated with lower risk estimates. Prior histopathologic diagnoses of squamous abnormalities also influenced quantitative risk. A prior histopathologic diagnosis of AIS was associated with a very low risk of subsequent AdCa, consistent with effective excisional treatment. AdCa risk was greatest in women aged 30-65 years with prior CIN3 biopsy results, whereas AIS risk was greatest in women <30. CONCLUSION: Prevention of cervical AdCa in screened patients remains a major challenge for cervical screening. Individualized risk projections for cervical glandular neoplasia reflecting patient age, prior cervical screening test results, and prior cervical biopsy history are feasible using Bayesian modeling of health system data.

Evaluating a web-based test results system at an urban STI clinic.

BACKGROUND: Notifying patients of gonorrhea and chlamydia test results using online services may improve clinic efficiency and increase receipt of test results. This study evaluated the implementation of an online results system in an urban sexually transmitted infections clinic. METHODS: Using the clinic's electronic medical records system to assess if and how gonorrhea and chlamydia test results were obtained, 3 time periods were examined between December 2007 and April 2009: period 1, six months before initiation of the online results system; Period 2, six months when patients could opt in for online results by creating their own access codes; and Period 3, four months when access codes were assigned. In addition, a survey was conducted to assess reasons for accepting or declining the online results system. RESULTS: A total of 9056 new patient visits were evaluated. During periods 1, 2, and 3, respectively 67%, 67%, and 70% patients received results either online or by telephone (NS). The proportion of patients calling the clinic for results decreased from 67% in period 1, to 51% in period 2, and 36% in period 3 (P < 0.0001). Survey results indicated that patients accepted online results primarily because of the ability to check results anytime of day. Reasons for not accepting results online included lack of Internet access or a preference to receive results via the telephone. CONCLUSIONS: The online results system decreased the number of phone calls to the clinic pertaining to STI test results, but had no effect on the overall proportion of patients receiving results.

CRNA-physician collaboration in anesthesia.

The benefits of collaboration in healthcare have been linked positively with higher patient satisfaction, improved patient outcomes, enhanced nursing staff satisfaction, and decreased hospital costs. A sample of nurse anesthetists and anesthesiologists affiliated with postgraduate training programs in the state of Texas responded to a survey designed to gather attitudes toward physician-nurse collaboration using an adaptation of the Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration. Two-hundred seventy surveys were completed by 62 anesthesiologists and 208 nurse anesthetists. The mean for the total scores on attitudes toward collaboration for anesthesiologists was 44.4 (+/- SD 8.7) and 51.8 (+/- SD 2.7) for nurse anesthetists. Mean scores were consistently higher in the 4 subscales (showed stronger agreement) for nurse anesthetists than for anesthesiologists. No significant differences in attitudes were found between men and women for the total sample. However, the health discipline showed a statistically significant difference. These findings suggest that Certified Registered Nurse Anesthetists who deal with role conflict or unclear expectations as well as limited scope of practice may have increased job stress and dissatisfaction.

Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance.

As a critical signaling node, ERK1/2 are attractive drug targets, particularly in tumors driven by activation of the MAPK pathway. Utility of targeting the MAPK pathway has been demonstrated by clinical responses to inhibitors of MEK1/2 or RAF kinases in some mutant BRAF-activated malignancies. Unlike tumors with mutations in BRAF, those with mutations in KRAS (>30% of all cancers and >90% of certain cancer types) are generally not responsive to inhibitors of MEK1/2 or RAF. Here, a covalent ERK1/2 inhibitor, CC-90003, was characterized and shown to be active in preclinical models of KRAS-mutant tumors. A unique occupancy assay was used to understand the mechanism of resistance in a KRAS-mutant patient-derived xenograft (PDX) model of colorectal cancer. Finally, combination of CC-90003 with docetaxel achieved full tumor regression and prevented tumor regrowth after cessation of treatment in a PDX model of lung cancer. This effect corresponded to changes in a stemness gene network, revealing a potential effect on tumor stem cell reprograming. IMPLICATIONS: Here, a covalent ERK1/2 inhibitor (CC-90003) is demonstrated to have preclinical efficacy in models of KRAS-mutant tumors, which present a therapeutic challenge for currently available therapies.

Correction: Unique CDR3 epitope targeting by CAR-T cells is a viable approach for treating T-cell malignancies.

In the original version of this article the author name Xiaolei Chen was published incorrectly. This has been corrected to Xiao Lei Chen.

The efficacy of spinosad against the western flower thrips, Frankliniella occidentalis, and its impact on associated biological control agents on greenhouse cucumbers in southern Ontario.

Insecticides are the most commonly used tactic to control western flower thrips (WFT), Frankliniella occidentalis Pergande (Thysanoptera: Thripidae), on greenhouse cucumber. However, WFT has developed resistance to several of the insecticides presently in use. In addition, some of these insecticides adversely affect greenhouse biological control agents used to control WFT, resulting in subsequent pest resurgence. Therefore, there is a need to identify novel insecticides with unique modes of action for use in integrated pest management (IPM) programs to effectively control WFT with minimal impact on associated biological control agents. In laboratory bioassays conducted in 2001, immature and adult WFT and three associated greenhouse biological control agents: Amblyseius cucumeris Oudemans (Acarina: Phytoseiidae), Orius insidiosus Say (Hemiptera: Anthocoridae) and Encarsia formosa Gahan (Hymenoptera: Aphelinidae) were exposed to direct, direct/residual, and residual contact applications of the novel biopesticide, spinosad (Conserve 120 SC), and the industry standard for whitefly control, endosulfan (Thiodan 50 WP). In all three types of assay, spinosad was effective against immature and adult WFT life stages. It showed low toxicity to A. cucumeris, moderate toxicity to O. insidiosus and high toxicity to E formosa. Greenhouse studies involving exposure of immature and adult WFT and adult biological control agents to cucumber leaves sprayed previously with spinosad supported the laboratory data. Spinosad showed low toxicity to A. cucumeris exposed to leaves 1 day after treatment (DAT), moderate toxicity to O. insidiosus 1 and 8 DAT, and high toxicity to E. formosa up to 28 DAT. These data, along with spinosad's unique mode of action, suggest it would be a valuable reduced-risk control agent for greenhouse cucumber IPM programs.