Implementation of endometrial cancer molecular subtyping into a hybrid community-academic practice.

OBJECTIVES: We sought to confirm utility of our institution's modified Proactive Molecular Risk Classifier for Endometrial Cancer protocol in our daily practice, which includes mismatch repair (MMR), p53, and L1 cell adhesion molecule (L1CAM) immunohistochemistry with in-house next-generation sequencing for POLE, TP53, and CTNNB1. METHODS: We conducted a retrospective review of all patients in our institution who underwent primary endometrial carcinoma resection from the year prior to protocol implementation (PRE; October 1, 2020, to September 30, 2021) through first year of implementation (POST; October 1, 2021, to September 30, 2022) to compare the distribution of molecular and traditional staging factors using GOG-249 criteria to assign clinical risk. RESULTS: In total, 136 of 260 PRE patients were classified as clinically low risk (LR), of whom 31 were MMR deficient. Of the 157 LR POST patients with endometrioid-type carcinoma, 45 were MMR deficient, 5 were POLE mutant, 5 were TP53 mutant, 56 were of no specific molecular profile (NSMP), and 46 did not receive full protocol testing. Of all 79 POST NSMP endometrioid-type cases, 18 were CTNNB1 mutated and 8 showed L1CAM expression. CONCLUSIONS: Our protocol identified 22 (14%) of 157 LR tumors that harbored incipient intermediate- to high-risk molecular aberrations in TP53, CTNNB1, or L1CAM. Moving forward, results of ongoing trials assessing adjuvant therapy decisions based on molecular classification are necessary to confirm protocol utility and identify appropriate modifications.

Immunohistochemistry and immunofluorescence utilization audit by subspecialty in an academic setting: A step toward stewardship.

There are immunohistochemistry (IHC) and immunofluorescence (IF) panels described in the literature and established by personal and institutional experiences that are in common use by pathologists in their daily practice. Stewardship is a difficult discussion because IHC utilization is influenced by many factors including the pathologist's experience, background, practice setting, personal bias, and medicolegal culture. We developed the methodology to audit the IHC/IF utilization in our academic subspecialty practice. We aim to share this methodology and to provide our data that can be used for consideration by other subspecialized academic practices. This analysis included a total of 63,157 specimens that were accessioned during 2022, representing 38,612 cases. The likelihood of ordering IHC/IF ranged from 1 % (in genitourinary pathology) to 59 % (in renal pathology). The average percentage of specimens with IHC/IF was 21 % for the entire practice. In cases where IHC/IF was ordered, the number of stained slides averaged 4.9 per specimen for the entire practice. The number of IHC/IF slides per specimen ranged from 1.9 (in gastrointestinal pathology) to 12.2 (in renal pathology). The highest number of antibodies ordered for a single specimen by subspecialty ranged from 11 (in cardiac pathology) to 63 (in dermatopathology). Renal pathology was the only subspecialty that had an average number of IHC/IF slides that was statistically significantly different from all other subspecialties. We described the various patterns of utilization by subspecialty and rationalized their subtle differences. We also analyzed the types of cases that exceeded the reimbursement limits set by the Centers for Medicare and Medicaid Services (CMS).

Proton and Redox Couple Synergized Strategy for Aqueous Low Voltage-Driven WO3 Electrochromic Devices.

Aqueous electrolytes possess non-combustible and eco-friendly features compared to organic electrolytes, leading them to be more suitable for application in smart windows for daily use. However, limited by the narrow electrochemical window of water (1.23 V), its use in conventional electrochromic devices (ECDs) would result in irreversible performance loss, which arises from decomposition caused by high voltage. Here, we propose a synergistic scheme combining a redox couple-catalytic counter electrode (RC-CCE) strategy with protons as guest ions. With the help of the intelligent matching of the reaction potentials of the RC and amorphous WO3 electrochromic electrodes and the highly active and fast kinetic features of protons, it successfully reduces the working voltage range of the device to 1.1 V. The assembled HClO4-ECD can possess an overall modulation rate (350-1200 nm) of 0.43 and 0.94 at -0.1 and -0.7 V, respectively, and a modulation of 66.8% at 600 nm at -0.7 V. Moreover, compared with other guest ions, the proton-based ECD exhibits higher coloration efficiency, a broader color modulation capability, and better stability. In addition, the house model equipped with the proton-based ECD effectively blocks solar radiation, which provides a potential solution for the design of aqueous smart windows.

Long-Term Stable Complementary Electrochromic Device Based on WO3 Working Electrode and NiO-Pt Counter Electrode.

Complementary electrochromic devices (ECDs) composed of WO3 and NiO electrodes have wide applications in smart windows. However, they have poor cycling stability due to ion-trapping and charge mismatch between electrodes, which limits their practical application. In this work, we introduce a partially covered counter electrode (CE) composed of NiO and Pt to achieve good stability and overcome the charge mismatch based on our structure of electrochromic electrode/Redox/catalytic counter electrode (ECM/Redox/CCE). The device is assembled using a NiO-Pt counter electrode with WO3 as the working electrode, and PC/LiClO4 containing a tetramethylthiourea/tetramethylformaminium disulfide (TMTU/TMFDS2+) redox couple as the electrolyte. The partially covered NiO-Pt CE-based ECD exhibits excellent EC performance, including a large optical modulation of 68.2% at 603 nm, rapid switching times of 5.3 s (coloring) and 12.8 s (bleaching), and a high coloration efficiency of 89.6 cm2·C-1. In addition, the ECD achieves a good stability of 10,000 cycles, which is promising for practical application. These findings suggest that the structure of ECC/Redox/CCE could overcome the charge mismatch problem. Moreover, Pt could enhance the Redox couple's electrochemical activity for achieving high stability. This research provides a promising approach for the design of long-term stable complementary electrochromic devices.

Effective Nanocomposite Based on Bi2MoO6/MoS2/AuNRs for NIR-II Light-Boosted Photodynamic/Chemodynamic Therapy.

Bi2MoO6 (BMO) nanoparticles (NPs) have been widely used as a photocatalyst to decompose organic pollutants, but their potential for photodynamic therapy (PDT) is yet to be explored. Normally, the UV absorption property of BMO NPs is not suitable for clinical application because the penetration depth of the UV light is too small. To overcome this limitation, we rationally designed a novel nanocomposite based on Bi2MoO6/MoS2/AuNRs (BMO-MSA), which simultaneously possesses both the high photodynamic ability and POD-like activity under NIR-II light irradiation. Additionally, it has excellent photothermal stability with good photothermal conversion efficiency. The as-prepared BMO-MSA nanocomposite could induce the germline apoptosis of Caenorhabditis elegans (C. elegans) via the cep-1/p53 pathway after being illuminated by light with a wavelength of 1064 nm. The in vivo investigations confirmed the ability of the BMO-MSA nanocomposite for the induction of DNA damage in the worms, and the mechanism was approved by determining the egl-1 fold induction in the mutants that have a loss of function in the genes involved in DNA damage response mutants. Thus, this work has not only provided a novel PDT agent, which may be used for PDT in the NIR-II region, but also introduced a new approach to therapy, taking advantage of both PDT and CDT effects.

Mixed neuroendocrine/Non-neuroendocrine neoplasm (MiNEN) of gastrointestinal lineage arising in an ovarian mature cystic teratoma.

•Mixed neuroendocrine/non-neuroendocrine neoplasm (MiNEN) of gastrointestinal lineage arising in an ovarian mature cystic teratoma is extremely rare.•It is important to differentiate the gastrointestinal-type adenocarcinoma arising along with neuroendocrine tumor from a primary mucinous adenocarcinoma of the ovary. SATB2 and CDX2 Immunohistochemical stains play important role in differentiate these two.•This case highlights the careful morphologic evaluation and extensive sampling is crucial to make this rare diagnosis.

Microscopic Features of Vaginectomy Specimens from Transgender Patients.

OBJECTIVES: We aimed to better understand the histologic changes in vaginectomy specimens in transgender and gender-diverse (TGD) individuals after prolonged androgen administration. METHODS: After obtaining institutional review board approval, we reviewed clinical records for all TGD individuals who underwent vaginal tissue resection at our institution between January 2002 and July 2020. RESULTS: Ten transgender males who underwent vaginectomy for gender affirmation were identified. All patients had been assigned female gender at birth, and the median age at surgery was 41 years (range, 22-74 years). All 10 patients had received androgen for 2 to 10 years preoperatively. The corresponding pathology specimens were examined grossly and microscopically, including with immunohistochemical stains for NKX3.1, prostate-specific antigen (PSA), p501s, and androgen receptor (AR). No gross lesions were identified. Microscopically, prostate-like glands (8/10), urothelial metaplasia (4/10), and vaginal atrophy (8/10) were identified. Seven cases with prostate-like glands showed positive staining with PSA, NKX3.1, p501s, and AR in both squamous and glandular components. CONCLUSIONS: Recognition of these androgen-related changes enables pathologist to avoid the overdiagnosis of dysplasia. Long-term follow-up is needed to thoroughly understand any potential future implications of these androgen-related changes.

Green synthesis of broccoli-derived carbon quantum dots as effective photosensitizers for the PDT effect testified in the model of mutant Caenorhabditis elegans.

The clinical application of photodynamic therapy (PDT) is still limited because of the drawbacks of the traditional photosensitizers, such as low singlet oxygen (1O2) quantum yield and the problem of photobleaching. Herein, carbon quantum dots (CQDs) derived from broccoli natural biomass as a carbon source were fabricated via a simple hydrothermal method and showed outstanding PDT ability as an effective photodynamic agent tested in Caenorhabditis elegans (C. elegans) models. The as-prepared broccoli-derived CQDs (BCQDs) showed excellent water solubility and optical properties and could generate singlet oxygen (1O2) effectively under irradiated light with a wavelength of 660 nm. The in vivo experiment revealed that the PDT efficiency of the BCQDs was dependent on the induction of germline apoptosis through the cep-1/p53 pathway. Further investigation confirmed the DNA damage of the worm by the BCQDs after sufficient light irradiation, which was tested by measuring the egl-1-fold induction in hus-1(op244), and cep-1(w40) mutants that have a loss of function in the genes involved in DNA damage response such as hus-1 (DNA checkpoint gene) and cep-1/p53 (tumor suppressor). The lack of germline apoptosis in the loss of function mutants egl-1(n487), hus-1(op244), and cep-1(w40) exposed to light irradiation compared with the control proved the necessity of these genes in DNA damage-induced germline apoptosis. Therefore, this work has not only provided a new photodynamic agent but also introduced C. elegans as an easy and high-throughput model for the rapid evaluation of the efficiency of PDT.

Nonhormone-Related Histologic Findings in Postsurgical Pathology Specimens From Transgender Persons.

OBJECTIVES: The objective of this review is to characterize the literature addressing postprocedural complications in persons undergoing gender-affirming surgeries. METHODS: A literature search using the OVID MEDLINE and PubMed databases was performed to identify all studies describing histologic findings in surgical pathology specimens from transgender persons from 1946 to April 2021. The studies describing postsurgical complications were categorized based on anatomic site, type of complication, study design, publication region, and date. RESULTS: Thirty-nine studies describing postsurgical complications in transgender women were identified. The most common sites of postprocedural pathology included the breasts and neovagina, with additional studies including buttocks and thighs, cutaneous sites, and the pulmonary system. Most of the literature comprised case reports, followed by case series and comparative studies. The search did not identify any studies of complications secondary to masculinizing surgeries. CONCLUSIONS: This body of literature is small but growing. Most studies are case reports. There are significant gaps in the literature. The literature in this area is not yet mature enough to support a meta-analysis.

Histologic Findings in Surgical Pathology Specimens From Individuals Taking Masculinizing Hormone Therapy for the Purpose of Gender Transition.

CONTEXT.­: Transgender men and transmasculine persons experience a discordance between the female sex they were assigned at birth and their gender. They may choose to take hormone therapy and/or undergo surgery to masculinize the body. Understanding the common (and less common) histologic changes present in patients taking masculinizing hormones will empower pathologists to better serve this unique patient population. OBJECTIVE.­: To summarize histologic findings in surgical pathology specimens from persons taking masculinizing hormones as a part of gender transition. DATA SOURCES.­: A systematic review of the OVID Medline and PubMed databases was performed to identify all studies describing histologic findings in surgical pathology specimens from transgender men from January 1946 to January 2021. CONCLUSIONS.­: Publication in this area has markedly increased in the last 2 decades. However, most of the studies identified were descriptive and case reports describing changes seen in specimens removed as a part of masculinizing surgical procedures. Benign histologic findings include stromal hyalinization and epithelial atrophy in the breast, polycystic ovarian syndrome-like changes in the ovary, and transitional cell metaplasia in the cervix. The most commonly reported neoplastic finding was adenocarcinoma of the breast, with rare cases of ovarian, endometrial, cervical, vaginal, pituitary, pancreatic, and cardiovascular neoplasia also reported. Ongoing research in this area is needed to better characterize the histologic findings in persons taking masculinizing hormones to provide a deeper understanding of the effect of these treatments on different tissues and facilitate better patient management.

Impact of Screening Modality on the Detection of Cervical Adenocarcinoma In Situ and Adenocarcinoma.

OBJECTIVE: The aim of the study was to determine the impact of screening modality on the detection of cervical adenocarcinoma in situ (AIS) and adenocarcinoma. MATERIALS AND METHODS: This was a cross-sectional study of patients with AIS or adenocarcinoma who had undergone routine screening with cytology and high-risk human papillomavirus (HPV) cotesting between January 2007 and December 2017. Patients were stratified into 3 groups by screening test results: (1) HPV positive with abnormal cytology (HPV+/Pap+), (2) HPV negative with abnormal cytology (HPV-/Pap+), and (3) HPV positive with normal cytology (HPV+/Pap-). Demographic and clinical characteristics were collected. Data were analyzed with χ2, Fisher exact tests, and t tests as appropriate. RESULTS: Of the 118 patients diagnosed with AIS (n = 97) or adenocarcinoma (n = 21) after abnormal screening tests, 92 (78%) were detected by HPV+/Pap+, 15 (12.7%) were HPV+/Pap-, and 11 (9.3%) were HPV-/Pap+. Demographics were similar between groups, although the HPV+/Pap- patients had higher body mass indices. Rates of definitive hysterectomy were similar between groups (53.3%-80.0%, p = .11). CONCLUSIONS: In our cohort, a significant proportion of AIS and adenocarcinoma was detected by both HPV alone (with normal cytology) and cytology alone (with negative HPV), suggesting that cotesting with both HPV and cytology may be a more sensitive method of detection of AIS and adenocarcinoma.

Sentinel Nodal Metastasis Detection in Endometrial Carcinoma With Microcystic, Elongated, and Fragmented (MELF) Pattern by Cytokeratin Immunostaining.

OBJECTIVES: The microcystic, elongated, and fragmented (MELF) pattern of myoinvasion in endometrial carcinoma (EC) is associated with an increased risk of lymph node metastasis. Our aim is to assess the role of cytokeratin immunohistochemical (IHC) stains in detecting sentinel nodal metastasis in MELF pattern tumors. METHODS: We recovered 19 MELF pattern EC hysterectomies with lymphadenectomy from our files. Negative nodes were subjected to cytokeratin AE1/AE3 IHC. Ten additional cases with sentinel lymph node (SLN) biopsies primarily assessed by IHC were also analyzed. RESULTS: Of the 19 cases of EC, 6 had positive lymph nodes based on H&E-stained sections at the time of their initial diagnosis. With the addition of IHC stains, 8 previously negative cases were found to have node metastases, and 3 of these were SLNs. Among the 10 cases primarily assessed by IHC, 5 had malignant cells in their SLNs. CONCLUSIONS: Cytokeratin IHC staining detected malignant cells in 9 of 16 cases with SLNs in our sample of women with MELF pattern of myoinvasion. Immunohistochemical stains should be routinely performed on SLNs from all MELF-positive cases to detect occult lymph node metastases and isolated tumor cells.

Boosting light harvesting and charge separation of WO3 via coupling with Cu2O/CuO towards highly efficient tandem photoanodes.

Photoanodes based on semiconductor WO3 have been attractive due to its good electron mobility, long hole-diffusion length, and suitable valence band potential for water oxidation. However, the semiconductor displays disadvantages including a relatively wide bandgap, poor charge separation and transfer, and quick electron-hole recombination at the interface with the electrolyte. Here we present a significantly improved photoanode with a tandem structure of ITO/WO3/Cu2O/CuO, which is prepared first by hydrothermally growing a layer of WO3 on the ITO surface, then by electrodepositing an additional layer of Cu2O, and finally by heat-treating in the air to form an exterior layer of CuO. Photocurrent measurements reveal that the prepared photoanode produces a maximum current density of 4.7 mA cm-2, which is, in comparison, about 1.4 and 5.5 times the measured values for ITO/WO3/Cu2O and ITO/WO3 ones, respectively. These enhancements are attributed to (1) harvested UV, visible, and NIR light of the solar spectrum, (2) accelerated charge separation at the heterojunction between WO3 and Cu2O/CuO, (3) better electrocatalytic activity of formed Cu x O than pure Cu2O, (4) formation of a protective layer of CuO. This study thus may lead to a promising way to make high-performance and low-cost photoanodes for solar energy harvesting.

Incisional carcinoma of Mullerian Origin: A case report and review of literature.

Primary incisional carcinoma (PIC) is a rare, delayed complication of surgery, usually attributed to the malignant transformation of endometriosis. We report a case of incisional carcinoma with nodal metastases in a 55-year-old woman, 18 years after cesarean section. She underwent extirpative surgery, including hysterectomy and bilateral salpingo-oophorectomy, without intraperitoneal disease identifed. Adjuvant treatment included sandwiched platinum-based chemotherapy (carboplatin and paclitaxel) and radiation. She remains disease-free 8 months after completing therapy. We identified 46 additional reported cases. Of these, >90% had undergone an "endometrium-exposing" surgery, most commonly cesarean section; while no cases followed adnexal-only surgery. The median time between antecedent surgery and presentation was 18 years. At presentation, tumors were often large (median 8 cm), and symptomatic with pain (63%) and/or mass (26%). Serum CA125 levels were commonly, albeit slightly, elevated (median 57U/ml (IQR 22-96, Range 6-1690)). Lymph node metastases were common (35%), with most following a vulvar-type spread pattern (inguinal first). Most patients (63%) were treated with chemotherapy +/- radiation. Approximately 50% of patients recurred promptly (median < 6 months), but long-term survival was reported following combined chemotherapy/radiation. Lymph node metastases portended a shorter disease-free interval, with 73% of cases recurring (median 5 months) despite chemotherapy-based treatment. These data suggest that some incisional carcinomas may result from displacement of healthy endometrium followed by delayed malignant transformation. Chemotherapy-only and radiation-only treatments are attended by modest prognosis. Taken together, these data suggest there is both need and potential avenues for improved prevention, detection, and treatment of this condition.

Real-Time Intraoperative Consultation Reporting in the Electronic Health Record.

OBJECTIVES: We sought to make pathologists' intraoperative consultation (IOC) results immediately available to the surgical team, other clinicians, and laboratory medicine colleagues to improve communication and decrease postanalytic errors. METHODS: We created an IOC report in our stand-alone laboratory information system that could be signed out prior to, and independent of, the final report, and transfer immediately to the electronic health record (EHR) as a preliminary diagnosis. We evaluated two metrics: preliminary (IOC) result review in the EHR by clinicians and postanalytic errors. RESULTS: We assessed 2,886 IOC orders from the first 22 months after implementation. Clinicians reviewed 1,956 (68%) of the IOC results while in preliminary status, including 1,399 (48%) within the first 24 hours. We evaluated 150 cases preimplementation and 300 cases postimplementation for discrepancies between the pathologist's IOC result and the IOC result recorded by the surgeon in the operative note. Discrepancies dropped from 12 of 150 preimplementation to 6 of 150 and 7 of 150 in postimplementation years 1 and 2. One of the 25 discrepancies had a major clinical impact. CONCLUSIONS: Real-time reporting of IOC results to the EHR reliably transmits results immediately to clinical teams. This strategy reduces but does not eliminate postanalytic interpretive errors by clinical teams.

The interaction between microRNA-152 and DNA methyltransferase-1 as an epigenetic prognostic biomarker in HCV-induced liver cirrhosis and HCC patients.

The necessity for early detection and hence improving the outcome of treatment of hepatocellular carcinoma (HCC) is critical especially in Hepatitis C virus (HCV)-Genotype 4 induced cases. In our current work, we examined the miRNA-152 and DNMT-1 expression in chronic liver disease (CLD) due to HCV genotype 4 infection with/without cirrhosis and HCC patients as an attempt to evaluate the potential benefits of these new circulating, noninvasive, prognostic, epigenetic markers for liver cirrhosis and carcinogenesis of Egyptian patients. Eighty subjects were included in this study, divided into two groups; group I (40 patients) were classified into subgroup Ia (CLD without cirrhosis, n = 18) and subgroup Ib (CLD with cirrhosis, n = 22), group II (CLD patients with HCC, n = 20), and control (Healthy volunteer, n = 20). The expression of miRNA-152 and DNMT-1 genes were analyzed using Real-Time PCR. MiRNA-152 showed a persistent and significant downregulation in all diseased groups, which was in consistence with the progression of the disease toward the HCC stage. DNMT-1 showed upregulation in all diseased groups when compared to control and subgroup Ia. The miRNA-152 was shown to correlate inversely with DNMT-1 in subgroup Ia, Ib and group II (r = -0.557, p < 0.01), (r = -0.850, p < 0.001) and (r = -0.544, p < 0.02) respectively. In addition, miRNA-152 and DNMT-1 showed a diagnostic ability to discriminate between cases of cirrhosis and HCC against CLD without cirrhosis (p < 0.01), while DNMT-1 did not, except between HCC and cirrhotic cases. Furthermore, both genes can be considered as predictor and prognostic parameters for cirrhosis (OR = 1.041, p = 0.043) and (OR = 1.039, p = 0.04) respectively, while miRNA-152 alone is proved as a prognostic marker for HCC (OR = 1.003, p = 0.044). Finally, the persistent reverse correlation between miRNA-152 with DNMT-1 prompts their use as noninvasive prognostic biomarkers for HCV induced liver cirrhosis and HCC in HCV Genotype 4 patients.

Health Care Provider Adherence to Surgical Guidelines for Risk-Reducing Salpingo-Oophorectomy.

OBJECTIVE: To evaluate health care provider adherence to the surgical protocol endorsed by the National Comprehensive Cancer Network and the American College of Obstetricians and Gynecologists at the time of risk-reducing salpingo-oophorectomy and compare adherence between gynecologic oncologists and obstetrician-gynecologists (ob-gyns). METHODS: In this multicenter retrospective cohort study, women were included if they had a pathogenic BRCA mutation and underwent risk-reducing salpingo-oophorectomy between 2011 and 2017. Adherence was defined as completing all of the following: collection of washings, complete resection of the fallopian tube, and performing the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) pathologic protocol. RESULTS: Of 290 patients who met inclusion criteria, 160 patients were treated by 18 gynecologic oncologists and 130 patients by 75 ob-gyns. Surgery was performed at 10 different hospitals throughout a single metropolitan area. Demographic and clinical characteristics were similar between groups. Overall, 199 cases (69%) were adherent to the surgical protocol. Gynecologic oncologists were more than twice as likely to fully adhere to the full surgical protocol as ob-gyns (91% vs 41%, P<.01). Specifically, gynecologic oncologists were more likely to resect the entire tube (99% vs 95%, P=.03), to have followed the SEE-FIM protocol (98% vs 82%, P<.01), and collect washings (94% vs 49%, P<.01). Complication rates did not differ between groups. Occult neoplasia was diagnosed in 11 patients (3.8%). The incidence of occult neoplasia was 6.3% in gynecologic oncology patients and 0.8% in obstetrics and gynecology patients (P=.03). CONCLUSION: Despite clear surgical guidelines, only two thirds of all health care providers were fully adherent to guidelines. Gynecologic oncologists were more likely to follow surgical guidelines compared with general ob-gyns and more likely to diagnose occult neoplasia despite similar patient populations. Rates of risk-reducing surgery will likely continue to increase as genetic testing becomes more widespread, highlighting the importance of health care provider education for this procedure. Centralized care or referral to subspecialists for risk-reducing salpingo-oophorectomy may be warranted.