Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

NCCN Guidelines® Insights: Cervical Cancer, Version 1.2024.

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

Identification of Three Human POLH Germline Variants Defective in Complementing the UV- and Cisplatin-Sensitivity of POLH-Deficient Cells.

DNA polymerase (pol) η is responsible for error-free translesion DNA synthesis (TLS) opposite ultraviolet light (UV)-induced cis-syn cyclobutane thymine dimers (CTDs) and cisplatin-induced intrastrand guanine crosslinks. POLH deficiency causes one form of the skin cancer-prone disease xeroderma pigmentosum variant (XPV) and cisplatin sensitivity, but the functional impacts of its germline variants remain unclear. We evaluated the functional properties of eight human POLH germline in silico-predicted deleterious missense variants, using biochemical and cell-based assays. In enzymatic assays, utilizing recombinant pol η (residues 1-432) proteins, the C34W, I147N, and R167Q variants showed 4- to 14-fold and 3- to 5-fold decreases in specificity constants (kcat/Km) for dATP insertion opposite the 3'-T and 5'-T of a CTD, respectively, compared to the wild-type, while the other variants displayed 2- to 4-fold increases. A CRISPR/Cas9-mediated POLH knockout increased the sensitivity of human embryonic kidney 293 cells to UV and cisplatin, which was fully reversed by ectopic expression of wild-type pol η, but not by that of an inactive (D115A/E116A) or either of two XPV-pathogenic (R93P and G263V) mutants. Ectopic expression of the C34W, I147N, and R167Q variants, unlike the other variants, did not rescue the UV- and cisplatin-sensitivity in POLH-knockout cells. Our results indicate that the C34W, I147N, and R167Q variants-substantially reduced in TLS activity-failed to rescue the UV- and cisplatin-sensitive phenotype of POLH-deficient cells, which also raises the possibility that such hypoactive germline POLH variants may increase the individual susceptibility to UV irradiation and cisplatin chemotherapy.

Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org.

Timing and magnitude of net methylmercury effects on waterbird reproductive output are dependent on food availability.

Mercury (Hg) is a globally distributed pollutant. Its sub-lethal effects on reproduction of birds have been used as indicators of contamination and of potential demographic effects. However, studies typically used single endpoints that might not be representative of entire reproductive cycle. To estimate timing and net cumulative effects of Hg exposure under field conditions, we used observational data over 11 years from >1200 nests of great egrets breeding under temporally and spatially varying food availability and Hg exposures in the Florida Everglades. We collected measures of fish biomass and availability (>100 locations annually) and used four avian reproductive endpoints that represented the entire breeding cycle. We calculated net reproductive loss by adding estimated Hg effects on failures prior to egg laying, clutch size, hatching success and nestling survival in response to food availability and Hg exposure. To validate and assess results of the observational egret study, we ran the same analyses with data of captive breeding white ibises experimentally exposed to Hg with ad libitum food over 3 years. We found large (>50 %) reductions in great egret offspring with high Hg exposure (18 µg/g dw THg nestling feather, ~0.7 µg/g ww whole egg THg) and high food availability, and even larger reductions (up to 100 %) with high Hg exposure and low food. Timing and the relative contribution of different endpoints to overall reproductive failure varied with food availability. Failures prior to egg laying were relevant at all food availabilities and proportionally most important during high food availability (~70 % of total losses). Under high food, post-hatching failures increased moderately with increasing exposure (~10 % of total losses), and under low food, hatching failures became dominant (~50 % of total losses). Patterns of failure of captive white ibis fed ad libitum resembled those of great egrets under high food availability but differed in total magnitude. We suggest that, a) net reproductive effects of Hg in free-ranging animals are probably much higher than generally reported in studies using single endpoints, b) Hg effect sizes vary considerably among different endpoints and c) food availability is a strong driver of timing and net effects of Hg exposure.

Carboplatin enhances lymphocyte-endothelial interactions to promote CD8+ T cell trafficking into the ovarian tumor microenvironment.

OBJECTIVES: Standard chemotherapy agents, including carboplatin, have known immunogenic properties. We sought to determine how carboplatin may influence lymphocyte trafficking to tumor sites. METHODS: Murine models of ovarian cancer were utilized to examine lymphocyte trafficking with common clinically used agents including carboplatin, anti-PD-1 antibody, or anti-VEGFR-2 antibody. Adhesion interactions of lymphocytes with tumor vasculature were measured using intravital microscopy, lymphocyte homing with immunohistochemistry, and treatment groups followed for overall survival. RESULTS: Carboplatin chemotherapy profoundly alters the tumor microenvironment to promote lymphocyte adhesive interactions with tumor vasculature and resultant improvement in lymphocyte trafficking. The measured results seen with carboplatin in the tumor microenvironment were superior to anti-PD-1 treatment or anti-VEGFR-2 which may have contributed to increased overall survival in carboplatin treated groups. CONCLUSIONS: These novel findings suggest a role for chemotherapeutic agents to broadly influence anti-tumor immune responses beyond the induction of immunogenic tumor cell death.

A general deep learning model for bird detection in high-resolution airborne imagery.

Advances in artificial intelligence for computer vision hold great promise for increasing the scales at which ecological systems can be studied. The distribution and behavior of individuals is central to ecology, and computer vision using deep neural networks can learn to detect individual objects in imagery. However, developing supervised models for ecological monitoring is challenging because it requires large amounts of human-labeled training data, requires advanced technical expertise and computational infrastructure, and is prone to overfitting. This limits application across space and time. One solution is developing generalized models that can be applied across species and ecosystems. Using over 250,000 annotations from 13 projects from around the world, we develop a general bird detection model that achieves over 65% recall and 50% precision on novel aerial data without any local training despite differences in species, habitat, and imaging methodology. Fine-tuning this model with only 1000 local annotations increases these values to an average of 84% recall and 69% precision by building on the general features learned from other data sources. Retraining from the general model improves local predictions even when moderately large annotation sets are available and makes model training faster and more stable. Our results demonstrate that general models for detecting broad classes of organisms using airborne imagery are achievable. These models can reduce the effort, expertise, and computational resources necessary for automating the detection of individual organisms across large scales, helping to transform the scale of data collection in ecology and the questions that can be addressed.

Accounting for food availability reveals contaminant-induced breeding impairment, food-modulated contaminant effects, and endpoint-specificity of exposure indicators in free ranging avian populations.

It remains unclear how sub-lethal effects of contaminants play out in relation to other stressors encountered by free-ranging populations. Effects may be masked or influenced by interactions with field stressors such as food availability. We predicted that (1) including food availability, and particularly its interaction with Hg, would reveal or enhance associations between Hg and breeding endpoints. We further predicted that (2) breeding impairment associated with Hg would be higher under food stress conditions. We monitored Hg and nest success of great egrets (Ardea alba) in eight breeding colonies in the Florida Everglades over 11 years. We characterized variation in local food availability among colonies and years using fish biomass and recession range -a proxy to fish vulnerability. We used two Hg exposure indicators (egg albumen Hg and nestling feather Hg) and six breeding endpoints (clutch-size, brood-size, fledged-size, hatching success, post-hatching success and fledglings per egg) to assess whether variation in food availability influenced associations between Hg and these endpoints. Accounting for interactions between Hg and food availability, we identified statistically significant associations in all 12 indicator-endpoint combinations, while only three were detectable without food. Further, 10 combinations showed interactions between Hg and components of food availability. Our results also indicated an endpoint-specific affinity, with albumen [Hg] explaining more variation in hatching success while nestling feather [Hg] explained more variation in post-hatching survival. Both Hg indicators accounted for relevant (6-10%) amounts of variation in fledglings produced per egg laid, an integrative endpoint. Increased Hg exposure resulted in overall reduced reproductive success when food availability was low, but our models predicted low or no effects of increasing Hg exposure when food availability was high. Our results indicate that Hg induced impairment is strongly driven by food availability, providing a framework that accommodates previously contradictory results in the literature.

NCCN Guidelines® Insights: Uterine Neoplasms, Version 3.2021.

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer or uterine sarcoma. These NCCN Guidelines Insights focus on the recent addition of molecular profiling information to aid in accurate diagnosis, classification, and treatment of uterine sarcomas.

Alligator presence influences colony site selection of long-legged wading birds through large scale facilitative nest protector relationship.

Positive ecological relationships, such as facilitation, are an important force in community organization. The effects of facilitative relationships can be strong enough to cause changes in the distributions of species and in many cases have evolved as a response to predation pressure, however, very little is known about this potential trend in vertebrate facilitative relationships. Predation is an important selective pressure that may strongly influence breeding site selection by nesting birds. The American Alligator (Alligator mississippiensis) facilitates a safer nesting location for wading birds (Ciconiiformes and Pelecaniformes) by deterring mammalian nest predators from breeding sites. However, alligators do not occur throughout the breeding range of most wading birds, and it is unclear whether alligator presence affects colony site selection. We predicted that nesting wading birds change colony site preferences when alligators are not present to serve as nest protectors. Within the northern fringe of alligator distribution we compared colony characteristics in locations where alligator presence was either likely or unlikely while controlling for availability of habitat. Wading birds preferred islands that were farther from the mainland and farther from landmasses > 5 ha when alligator presence was unlikely compared to when alligators were likely. These findings indicate that wading birds are seeking nesting locations that are less accessible to mammalian predators when alligators are not present, and that this requirement is relaxed when alligators are present. This study illustrates how a landscape-scale difference between realized and fundamental niche can result from a facilitative relationship in vertebrates.

Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer: A Phase 2 Nonrandomized Clinical Trial.

IMPORTANCE: Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies. OBJECTIVE: To assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020. INTERVENTIONS: Patients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent. MAIN OUTCOMES AND MEASURES: Primary outcomes were objective response rate (ORR) and progression-free survival (PFS). RESULTS: Of the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]). CONCLUSIONS AND RELEVANCE: In this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02853318.

Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters.

BACKGROUND: In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients. METHODS: Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/) and the ADME database (https://life-science.kyushu.fujitsu.com/admedb/). RESULTS: Chloroquine and hydroxychloroquine are metabolized by P450 1A2, 2C8, 2C19, 2D6, and 3A4/5 in vitro and by P450s 2C8 and 3A4/5 in vivo by N-deethylation. Chloroquine effectively inhibited P450 2D6 in vitro; however, in vivo inhibition was not apparent except in individuals with limited P450 2D6 activity. Chloroquine is both an inhibitor and inducer of the transporter MRP1 and is also a substrate of the Mate and MRP1 transport systems. Hydroxychloroquine also inhibited P450 2D6 and the transporter OATP1A2. CONCLUSIONS: Chloroquine caused a statistically significant decrease in P450 2D6 activity in vitro and in vivo, also inhibiting its own metabolism by the enzyme. The inhibition indicates a potential for clinical drug-drug interactions when taken with other drugs that are predominant substrates of the P450 2D6. When chloroquine and hydroxychloroquine are used clinically with other drugs, substrates of P450 2D6 enzyme, attention should be given to substrate-specific metabolism by P450 2D6 alleles present in individuals taking the drugs.

Early Breeding Failure in Birds Due to Environmental Toxins: A Potentially Powerful but Hidden Effect of Contamination.

Toxin emissions and legacies are major global issues affecting many species through, among other effects, endocrine disruption and reproductive impairment. Assessment of toxin risk to wildlife focuses mostly on offspring-related metrics, while the lack of breeding initiation or early breeding failure has received less attention. We tested whether exposure to methyl mercury (MeHg) results in early breeding failure and reduced number of breeding birds using observational and experimental data. We used 21 years of numbers of breeding pairs of colonially breeding wild Great Egrets (Ardea alba) in response to annual and geographical variation upon exposure to environmental MeHg. After controlling for food availability, we found a strong negative association between MeHg exposure and the number of breeding Great Egrets. We report reductions of >50% in breeding numbers under exposure levels otherwise associated with <20% reduction in post-egg-laying breeding success. Experimental exposure of White Ibises (Eudocimus albus) to MeHg also caused early breeding failure and a ∼20% reduction in breeding numbers at environmentally relevant exposures. The demographic consequences of reductions in breeding pairs are additive to known and typically studied impairments in postlaying reproductive success. Net demographic effects of exposure to endocrine disruptors may often be strongly underestimated if early breeding failure is not measured.

Community-Engaged Approach to the Development and Implementation of a Student-Centered Return to Learn Care Plan After Concussion.

BACKGROUND: Current return to learn (RTL) after concussion guidelines lack specificity for individualized student care, limiting potential for adoption and implementation. We used a community-engaged research framework to develop and evaluate the implementation of a student-centered care plan that assists school personnel in facilitating RTL. METHODS: We used best-practice RTL guidelines and input from administrators and medical experts to iteratively develop a flexible student-centered care plan. Thirteen schools participated. Coding completion of care plans indicated feasibility and fidelity; interviews with RTL coordinators indicated acceptability. RESULTS: The care plan includes educational materials, symptom checklists, and guidelines for classroom adjustments linked to student symptoms. Care plans were initiated for 24 (70.6%) of 34 students with concussions, indicating feasibility. Fidelity was high, with the following subsections completed: Action Checklist (90%), Symptom Evaluation (91%), Temporary Adjustment Recommendations (95%). Qualitative analysis of interviews suggested care plans were acceptable and facilitate consistent communication, prioritization of individual needs of students, and increased ability to delegate tasks to other school staff. CONCLUSIONS: Implementation of a student-centered, individually tailored care plan for RTL is feasible and acceptable in public high schools. Future research should examine how to expediently initiate student-centered concussion care plans after diagnosis to optimize recovery.

NCCN Guidelines Insights: Cervical Cancer, Version 1.2020.

The NCCN Guidelines for Cervical Cancer provide recommendations for diagnostic workup, staging, and treatment of patients with the disease. These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to first- and second-line systemic therapy recommendations for patients with recurrent or metastatic disease, and emerging evidence on a new histopathologic classification system for HPV-related endocervical adenocarcinoma.

Analysis of movement recursions to detect reproductive events and estimate their fate in central place foragers.

BACKGROUND: Recursive movement patterns have been used to detect behavioral structure within individual movement trajectories in the context of foraging ecology, home-ranging behavior, and predator avoidance. Some animals exhibit movement recursions to locations that are tied to reproductive functions, including nests and dens; while existing literature recognizes that, no method is currently available to explicitly target different types of revisited locations. Moreover, the temporal persistence of recursive movements to a breeding location can carry information regarding the fate of breeding attempts, but it has never been used as a metric to quantify recursive movement patterns. Here, we introduce a method to locate breeding attempts and estimate their fate from GPS-tracking data of central place foragers. We tested the performance of our method in three bird species differing in breeding ecology (wood stork (Mycteria americana), lesser kestrel (Falco naumanni), Mediterranean gull (Ichthyaetus melanocephalus)) and implemented it in the R package 'nestR'. METHODS: We identified breeding sites based on the analysis of recursive movements within individual tracks. Using trajectories with known breeding attempts, we estimated a set of species-specific criteria for the identification of nest sites, which we further validated using non-reproductive individuals as controls. We then estimated individual nest survival as a binary measure of reproductive fate (success, corresponding to fledging of at least one chick, or failure) from nest-site revisitation histories during breeding attempts, using a Bayesian hierarchical modeling approach that accounted for temporally variable revisitation patterns, probability of visit detection, and missing data. RESULTS: Across the three species, positive predictive value of the nest-site detection algorithm varied between 87 and 100% and sensitivity between 88 and 92%, and we correctly estimated the fate of 86-100% breeding attempts. CONCLUSIONS: By providing a method to formally distinguish among revisited locations that serve different ecological functions and introducing a probabilistic framework to quantify temporal persistence of movement recursions, we demonstrated how the analysis of recursive movement patterns can be applied to estimate reproduction in central place foragers. Beyond avian species, the principles of our method can be applied to other central place foraging breeders such as denning mammals. Our method estimates a component of individual fitness from movement data and will help bridge the gap between movement behavior, environmental factors, and their fitness consequences.

Mercury bioaccumulation in tropical bats from a region of active artisanal and small-scale gold mining.

Mercury negatively affects human and animal health. Artisanal and small-scale gold mining can be a major local source of mercury contamination, especially into aquatic systems in tropical areas. Animals associated with mercury-contaminated aquatic systems are at high risk of experiencing effects of this heavy metal, but it is not clear how far the effects may extend into nearby terrestrial systems. We report mercury contamination levels in bats in agricultural areas at increasing distances from gold mining (~3-89 km of distance). We hypothesized that bat mercury concentrations would differ between feeding guilds, land use types, and be higher at sites closer to gold mining areas. We collected 112 fur samples from 30 bat species and eight guilds, and provide the first reports of concentrations in 12 species. All mercury concentrations were below the level at which health is likely to be affected (10 ppm). We found guild-influenced differences among mercury concentration levels, with the highest concentrations in aerial insectivores and carnivores, and the lowest in canopy frugivores. Our results suggest insectivorous and carnivorous bats may still be at some risk even at sites distant from aquatic mercury contamination. We did not find an effect of agricultural land-use type on mercury concentrations within species or guilds, suggesting mercury contamination did not extend to agricultural sites from areas of gold mining activities, and that these agricultural activities themselves were not an important source of mercury. We conclude bats did not demonstrate a signature of mercury risk either as a result of proximity of gold mining, or as a result of agricultural activities.

Gestational Trophoblastic Neoplasia, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Gestational trophoblastic neoplasia (GTN), a subset of gestational trophoblastic disease (GTD), occurs when tumors develop in the cells that would normally form the placenta during pregnancy. The NCCN Guidelines for Gestational Trophoblastic Neoplasia provides treatment recommendations for various types of GTD including hydatidiform mole, persistent post-molar GTN, low-risk GTN, high-risk GTN, and intermediate trophoblastic tumor.

Nestling carcasses from colonially breeding wading birds: patterns of access and energetic relevance for a vertebrate scavenger community.

Energy transfer is fundamental to ecosystem processes, affecting productivity and community structure. Large aggregations of colonially breeding birds are known as nutrient sources through deposition of feces, but also may deposit large quantities of energy in the form of dead nestlings. The magnitude and ecological relevance of this process to the scavenger community is poorly understood. We used trail cameras to monitor the fates of size-appropriate chicken carcasses in heron colonies in order to quantify the proportion of available fallen nestlings that were consumed by scavengers in the Everglades of Florida, USA. Overall, 85% of 160 carcasses were consumed, with Turkey Vultures (Cathartes aura, 47%) and American Alligators (Alligator mississippiensis, 29%) being the primary consumers. Probability of consumption by alligators or vultures was related to distance from nest to water, local nesting density, and colony type. Consumption probabilities of both scavengers in relation to habitat covariates suggested clear resource partitioning promoting coexistence. We estimate fallen nestlings throughout this ecosystem could support 16% of the alligator population and 147 adult Turkey Vultures during a nesting season. This work indicates that fallen nestlings can serve as an important source of energy for scavengers at colonial breeding aggregations, particularly in oligotrophic systems.