Re-evaluation of the methodology for estimating the US specialty physician workforce.

Increasing pursuit of subspecialized training has quietly revolutionized physician training, but the potential impact on physician workforce estimates has not previously been recognized. The Physicians Specialty Data Reports of the Association of American Medical Colleges, derived from specialty designations in the American Medical Association (AMA) Physician Professional Data (PPD), are the reference source for US physician workforce estimates; by 2020, the report for pathologists was an undercount of 39% when compared with the PPD. Most of the difference was due to the omission of pathology subspecialty designations. The rest resulted from reliance on only the first of the AMA PPD's 2 specialty data fields. Placement of specialty designation in these 2 fields is sensitive to sequence of training and is thus affected by multiple or intercalated (between years of residency training) fellowships. Both these phenomena have become progressively more common and are not unique to pathology. Our findings demonstrate the need to update definitions and methodology underlying estimates of the US physician workforce for pathology and suggest a like need in other specialties affected by similar trends.

Prediction of Pelvic Organ Prolapse Postsurgical Outcome Using Biomaterial-Induced Blood Cytokine Levels: Machine Learning Approach.

BACKGROUND: Pelvic organ prolapse (POP) refers to symptomatic descent of the vaginal wall. To reduce surgical failure rates, surgical correction can be augmented with the insertion of polypropylene mesh. This benefit is offset by the risk of mesh complication, predominantly mesh exposure through the vaginal wall. If mesh placement is under consideration as part of prolapse repair, patient selection and counseling would benefit from the prediction of mesh exposure; yet, no such reliable preoperative method currently exists. Past studies indicate that inflammation and associated cytokine release is correlated with mesh complication. While some degree of mesh-induced cytokine response accompanies implantation, excessive or persistent cytokine responses may elicit inflammation and implant rejection. OBJECTIVE: Here, we explore the levels of biomaterial-induced blood cytokines from patients who have undergone POP repair surgery to (1) identify correlations among cytokine expression and (2) predict postsurgical mesh exposure through the vaginal wall. METHODS: Blood samples from 20 female patients who previously underwent surgical intervention with transvaginal placement of polypropylene mesh to correct POP were collected for the study. These included 10 who experienced postsurgical mesh exposure through the vaginal wall and 10 who did not. Blood samples incubated with inflammatory agent lipopolysaccharide, with sterile polypropylene mesh, or alone were analyzed for plasma levels of 13 proinflammatory and anti-inflammatory cytokines using multiplex assay. Data were analyzed by principal component analysis (PCA) to uncover associations among cytokines and identify cytokine patterns that correlate with postsurgical mesh exposure through the vaginal wall. Supervised machine learning models were created to predict the presence or absence of mesh exposure and probe the number of cytokine measurements required for effective predictions. RESULTS: PCA revealed that proinflammatory cytokines interferon gamma, interleukin 12p70, and interleukin 2 are the largest contributors to the variance explained in PC 1, while anti-inflammatory cytokines interleukins 10, 4, and 6 are the largest contributors to the variance explained in PC 2. Additionally, PCA distinguished cytokine correlations that implicate prospective therapies to improve postsurgical outcomes. Among machine learning models trained with all 13 cytokines, the artificial neural network, the highest performing model, predicted POP surgical outcomes with 83% (15/18) accuracy; the same model predicted POP surgical outcomes with 78% (14/18) accuracy when trained with just 7 cytokines, demonstrating retention of predictive capability using a smaller cytokine group. CONCLUSIONS: This preliminary study, incorporating a sample size of just 20 participants, identified correlations among cytokines and demonstrated the potential of this novel approach to predict mesh exposure through the vaginal wall following transvaginal POP repair surgery. Further study with a larger sample size will be pursued to confirm these results. If corroborated, this method could provide a personalized medicine approach to assist surgeons in their recommendation of POP repair surgeries with minimal potential for adverse outcomes.

Strong Job Market for Pathologists: Results From the 2021 College of American Pathologists Practice Leader Survey.

CONTEXT.­: There has long been debate about whether and when there may be a shortage of pathologists in the United States. One way to assess this is to survey the hiring experiences of pathology practices. A 2018 survey revealed a strong demand for pathologists, with expectations of continued strength. This study updates that prior analysis using data from a 2021 survey of pathology practice leaders. OBJECTIVE.­: To assess the US pathologist job market and examine implications. DESIGN.­: We analyzed data from the 2021 College of American Pathologists Practice Leader Survey. This survey queried practice leaders, including regarding the hiring of pathologists, the level of experience being sought, success in filling positions, and expectations for hiring in the next 3 years. RESULTS.­: Among the 375 surveyed practice leaders (about one-third of all US pathology practices), 282 provided information about pathologist hiring in 2021. A total of 157 of these 282 practices (55.7%) sought to hire at least 1 pathologist in 2021, up from 116 of 256 practices (45.3%) in 2017; the mean number of pathologists hired per practice also increased. In 2021, a total of 175 of 385 positions (45.5%) were to fill new positions, compared with 95 of 249 positions (38.2%) in 2017. Most practice leaders were comfortable hiring pathologists with less than 2 years of posttraining experience. Practice leaders anticipated continued strong demand for hiring pathologists during the next 3 years. CONCLUSIONS.­: Our analysis confirms that the demand in pathologist hiring is strong and much increased from 2017. We believe, in combination with other job market indicators, that demand may outstrip the supply of pathologists, which is limited by the number of trainees and has remained constant during the past 20 years.

Features of burnout amongst pathologists: A reassessment.

There has been little rigorous assessment of burnout among pathologists and pathology trainees. Given this relative dearth of relevant literature on pathologist burnout, this report aims to raise awareness of the issue among those working in and around this specialty. Our results are based on a survey given in conjunction with the American Board of Pathology's (ABPath) biennial Continuing Certification (CC) reporting of activities required of diplomates to maintain certification. The survey was voluntary, open to all diplomates participating in CC, and conducted over two consecutive years (2019 and 2020), with alternate years comprising different sets of diplomates. The data are based on 1256 respondents (820 from 2019 to 436 from 2020). The three highest aggregate reported rates of burnout (reported as experienced nearly all of the time, most of the time, or part of the time) occurred when respondents were in their first year of residency training (41.1%) and when they were in (47.6%) and beyond (46.6%) their first three years of practice. We considered this high-low-high, or U-shaped distribution in recollected burnout over time among pathologists a notable finding and investigated its distribution among respondents. Conversely at every point in their training and practice, from half to three-quarters of respondents reported never or infrequently experiencing burnout. This study represents the largest pathologist cohort survey to date about pathologists' burnout. Importantly, especially for those considering pathology as a career, these data are on the low end of the distribution of burnout among specialties for those in practice.

Therapeutic Targeting of Macrophage Plasticity Remodels the Tumor-Immune Microenvironment.

SIGNIFICANCE: Comprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy. See related commentary by Lee et al., p. 2515.

Development and validation of a quantitative reactive stroma biomarker (qRS) for prostate cancer prognosis.

To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor. We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens. In the developmental cohort (Baylor College of Medicine, n = 482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p = 0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n = 332; HR 2.64; p = 0.02) and also biochemical recurrence (Canary; n = 988; HR 1.51; p = 0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA. qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements.

Diagnosis of "cribriform" prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations.

Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number of lumina), number of attachments with gland border by tumor cells forming a "glomeruloid-like" pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a "glomeruloid-like" pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4.

ISUP Consensus Definition of Cribriform Pattern Prostate Cancer.

The presence of a cribriform pattern is now recognized as a clinically important, independent adverse prognostic indicator for prostate cancer. For this reason the International Society of Urological Pathology (ISUP) recently recommended its inclusion in standard reporting. In order to improve interobserver agreement as to the diagnosis of cribriform patterns, the ISUP assembled an international panel of 12 expert urogenital pathologists for the purpose of drafting a consensus definition of cribriform pattern in prostate cancer, and provide their opinions on a set of 32 images and on potential diagnostic criteria. These images were selected by the 2 nonvoting convenors of the study and included the main categories where disagreement was anticipated. The Delphi method was applied to promote consensus among the 12 panelists in their review of the images during 2 initial rounds of the study. Following a virtual meeting, convened to discuss selected images and diagnostic criteria, the following definition for cribriform pattern in prostate cancer was approved: "A confluent sheet of contiguous malignant epithelial cells with multiple glandular lumina that are easily visible at low power (objective magnification ×10). There should be no intervening stroma or mucin separating individual or fused glandular structures" together with a set of explanatory notes. We believe this consensus definition to be practical and that it will facilitate reproducible recognition and reporting of this clinically important pattern commonly seen in prostate cancer. The images and the results of the final Delphi round are available at the ISUP website as an educational slide set (https://isupweb.org/isup/blog/slideshow/cribriform-slide-deck/).

Aspiration fluid cytology during single operator cholangioscopy with targeted biopsy to improves the diagnostic yield in indeterminate biliary strictures.

INTRODUCTION: Sensitivities of various sampling methods to detect malignant biliary strictures remain suboptimal. Irrigation during digital single operator cholangioscopy (dSOC) is done routinely for visualization of the duct. The aim of this study was to evaluate improvement of the sensitivity for detecting malignant biliary strictures when adding aspiration fluid cytology (AFC) from the irrigated fluid during cholangioscopy to cholangioscopic biopsy (CBx). METHODS: We conducted a retrospective analysis of patients at a tertiary medical center who underwent CBx for evaluation of their biliary strictures. We included patients who had aspiration of fluid from the bile duct after CBx and were sent for cytology from January 2017 to October 2017. Diagnosis was made on the basis of final pathology or follow-up over 9 months. RESULTS: Fifty-six patients had CBx obtained, out of which 35 patients had AFC in conjunction. Twenty-two (62%) patients were male and the average age was 65 years. Considering atypical cells as benign, the sensitivity, specificity, positive and negative predictive values (PPV, NPV) for CBx were 62.5%, 100%, 100%, and 76% respectively. When CBx combined with AFC, the above statistics went up to 81.25%, 100%, 100%, and 86.36% respectively. When atypical cells were considered malignant, the sensitivity, specificity, PPV and NPV for CBx were 81.25%, 84.21%, 81.25%, 84.21% and increased to 93.75%, 78.94%, 78.94%, and 93.75% respectively after adding AFC results. CONCLUSION: For patients with biliary stricture, addition of AFC dSOC guided biopsies, significantly improves the sensitivity for detecting malignancy.

Aquaculture Production of the Brown Seaweeds Laminaria digitata and Macrocystis pyrifera: Applications in Food and Pharmaceuticals.

Seaweeds have a long history of use as food, as flavouring agents, and find use in traditional folk medicine. Seaweed products range from food, feed, and dietary supplements to pharmaceuticals, and from bioenergy intermediates to materials. At present, 98% of the seaweed required by the seaweed industry is provided by five genera and only ten species. The two brown kelp seaweeds Laminaria digitata, a native Irish species, and Macrocystis pyrifera, a native New Zealand species, are not included in these eleven species, although they have been used as dietary supplements and as animal and fish feed. The properties associated with the polysaccharides and proteins from these two species have resulted in increased interest in them, enabling their use as functional foods. Improvements and optimisations in aquaculture methods and bioproduct extractions are essential to realise the commercial potential of these seaweeds. Recent advances in optimising these processes are outlined in this review, as well as potential future applications of L. digitata and, to a greater extent, M. pyrifera which, to date, has been predominately only wild-harvested. These include bio-refinery processing to produce ingredients for nutricosmetics, functional foods, cosmeceuticals, and bioplastics. Areas that currently limit the commercial potential of these two species are highlighted.

Recommended standardized anatomic terminology of the posterior female pelvis and vulva based on a structured medical literature review.

BACKGROUND: Anatomic terminology in both written and verbal forms has been shown to be inaccurate and imprecise. OBJECTIVE: Here, we aimed to (1) review published anatomic terminology as it relates to the posterior female pelvis, posterior vagina, and vulva; (2) compare these terms to "Terminologia Anatomica," the internationally standardized terminology; and (3) compile standardized anatomic terms for improved communication and understanding. STUDY DESIGN: From inception of the study to April 6, 2018, MEDLINE database was used to search for 40 terms relevant to the posterior female pelvis and vulvar anatomy. Furthermore, 11 investigators reviewed identified abstracts and selected those reporting on posterior female pelvic and vulvar anatomy for full-text review. In addition, 11 textbook chapters were included in the study. Definitions of all pertinent anatomic terms were extracted for review. RESULTS: Overall, 486 anatomic terms were identified describing the vulva and posterior female pelvic anatomy, including the posterior vagina. "Terminologia Anatomica" has previously accepted 186 of these terms. Based on this literature review, we proposed the adoption of 11 new standardized anatomic terms, including 6 regional terms (anal sphincter complex, anorectum, genital-crural fold, interlabial sulcus, posterior vaginal compartment, and sacrospinous-coccygeus complex), 4 structural terms (greater vestibular duct, anal cushions, nerve to the levator ani, and labial fat pad), and 1 anatomic space (deep postanal space). In addition, the currently accepted term rectovaginal fascia or septum was identified as controversial and requires further research and definition before continued acceptance or rejection in medical communication. CONCLUSION: This study highlighted the variability in the anatomic nomenclature used in describing the posterior female pelvis and vulva. Therefore, we recommended the use of standardized terminology to improve communication and education across medical and anatomic disciplines.

Cribriform prostate cancer: Morphologic criteria enabling a diagnosis, based on survey of experts.

Among four sub-patterns of Gleason grade 4 prostate cancer, voluminous evidence supports that the cribriform pattern holds an unfavorable prognostic impact, as compared with poorly-formed, fused, or glomeruloid. The International Society of Urological Pathology (ISUP) recommends specifying whether invasive grade 4 cancer is cribriform. Recently, ISUP experts published a consensus definition of cribriform pattern highlighting criteria that distinguish it from mimickers. The current study aimed to analyze morphologic features separately to identify those that define the essence of the cribriform pattern. Thirty-two selected photomicrographs were classified by 12 urologic pathologists as: definitely cribriform cancer, probably cribriform, unsure, probably not cribriform, or definitely not cribriform. Consensus was defined as 9/12 agree or disagree, with ≤1 strongly supporting the opposite choice. Final consensus was achieved in 21 of 32 cases. Generalized estimating equation (GEE) model with logit link was fitted to estimate effect of multiple morphologic predictors. Fisher exact test was used for categorical findings. Presence of intervening stroma precluded calling cribriform cancer (p = 0.006). Mucin presence detracted (p = 0.003) from willingness to call cribriform cancer (only 3 cases had mucin). Lumen number was associated with cribriform consensus (p = 0.0006), and all consensus cases had ≥9 lumens. Predominant papillary pattern or an irregular outer boundary detracted (p = NS). Invasive cribriform carcinoma should have absence of intervening stroma, and usually neither papillary pattern, irregular outer boundary, nor very few lumens. Setting the criteria for cribriform will help prevent over- or undercalling this important finding.

Intraductal Carcinoma of the Prostate: Pathogenesis and Molecular Perspectives.

Intraductal carcinoma of the prostate (IDC-P), a clinicopathological entity characterized by malignant prostatic epithelial cells growing within ducts and/or acini, has a distinct architectural pattern, cytological features, and biological behavior. Whereas most IDC-P tumors could be derived from adjacent high-grade invasive cancer via retrograde spreading of cancer cells along benign ducts and acini, a small subset of IDC-P may arise from the transformation and intraductal proliferation of precancerous cells induced by various oncogenic events. These isolated IDC-P tumors possess a distinct mutational profile and may function as a carcinoma in situ lesion with de novo intraductal outgrowth of malignant cells. Further molecular characterization of these two types of IDC-P and better understanding of the mechanisms underlying IDC-P formation and progression could be translated into valuable biomarkers for differential diagnosis and actionable targets for therapeutic interventions. PATIENT SUMMARY: Intraductal carcinoma of the prostate is an aggressive type of prostate cancer associated with high risk for local recurrence and distant metastasis. In this review, we discussed pathogenesis, biomarkers, differential diagnoses, and therapeutic strategies for this tumor.

ORIGIN AND DEVELOPMENT OF AMERICAN SURGICAL PATHOLOGY.

Although the discipline of pathology had its very beginnings in the earliest development and evolution of what became "modern medicine," the subset of pathology known as "surgical pathology" had its origins only in the last two centuries. Surgical pathology began as a clinico-pathologic analysis of gross morphologic findings with clinical outcomes, beginning with findings at autopsy. With the advent of microscopy, which enabled a higher level of morphologic classification and disease understanding, along with advances in surgery (anesthesia, antisepsis, and then antibiotics), the need for accurate pathologic classification in the living patient became of paramount importance. This review chronicles the evolution of surgical pathology in the United States in the context of advances in the science and practice of medicine generally and surgery specifically.

Granular necrosis: a distinctive form of cell death in malignant tumours.

Foci of necrosis are frequently seen in malignant tumours and may be due to a variety of causes. Different types of necrosis are given various names based upon their morphological features and presumed pathogenesis, such as coagulative, liquefactive and fibrinoid necrosis. Here, we propose the term 'granular necrosis' (GN) for a specific form of tumour necrosis characterised by the presence of well-defined necrotic foci being sharply demarcated from adjacent viable tumour. A constant feature is loss of architecture resulting in an amorphous necrotic mass containing granular nuclear and cytoplasmic debris, without an associated neutrophilic infiltrate. There is usually extensive karyorrhexis, which in larger tumours is more prominent at the periphery. These foci are often microscopic but may range up to several millimetres or larger in size. This distinctive form of necrosis has been erroneously given a variety of names in the literature including coagulative necrosis and microscopic necrosis, which on the basis of the aforementioned gross and microscopic findings is inappropriate. It is apparent that this is a specific form of necrosis, hence the descriptive term 'granular necrosis' that differentiates this form of necrosis from other types. The presence of GN is recognised as occurring in a variety of tumour types, being commonly seen in renal cell carcinoma, where it has been shown to have independent prognostic significance. In some epithelial and stromal tumours of the uterus, the presence of GN also has prognostic significance and is a defining feature for the differentiation of uterine leiomyoma and leiomyosarcoma. The pathogenesis of GN is unresolved. It does not show the features of apoptosis and in recent studies has been shown to have some of the molecular changes associated with necroptosis.

The parotid secretory protein BPIFA2 is a salivary surfactant that affects lipopolysaccharide action.

NEW FINDINGS: What is the central question of this study? The salivary protein BPIFA2 binds lipopolysaccharide, but its physiological function is not known. This study uses a new knockout mouse model to explore the physiological role of BPIFA2 in the oral cavity and systemic physiology. What is the main finding and its importance? BPIFA2 is a crucial surfactant in mouse saliva. In its absence, saliva exhibits the surface tension of water. Depletion of BPIFA2 affects salivary and ingested lipopolysaccharide and leads to systemic sequelae that include increased insulin secretion and metabolomic changes. These results suggest that the lipopolysaccharide-binding activity of BPIFA2 affects the activity of ingested lipopolysaccharide in the intestine and that BPIFA2 depletion causes mild metabolic endotoxaemia. ABSTRACT: Saliva plays important roles in the mastication, swallowing and digestion of food, speech and lubrication of the oral mucosa, antimicrobial and anti-inflammatory activities, and the control of body temperature in grooming animals. The salivary protein BPIFA [BPI fold containing family A member 2; former names: parotid secretory protein (PSP), SPLUN2 and C20orf70] is related to lipid-binding and lipopolysaccharide (LPS)-binding proteins expressed in the mucosa. Indeed, BPIFA2 binds LPS, but the physiological role of BPIFA2 remains to be determined. To address this question, Bpifa2 knockout (Bpifa2tm1(KOMP)Vlcg ) (KO) mice were phenotyped, with emphasis on the saliva and salivary glands. Stimulated whole saliva collected from KO mice was less able to spread on a hydrophobic surface than wild-type saliva, and the surface tension of KO saliva was close to that of water. These data suggest that BPIFA2 is a salivary surfactant that is mainly responsible for the low surface tension of mouse saliva. The reduced surfactant activity of KO saliva did not affect consumption of dry food or grooming, but saliva from KO mice contained less LPS than wild-type saliva. Indeed, mice lacking BPIFA2 responded to ingested LPS with an increased stool frequency, suggesting that BPIFA2 plays a role in the solubilization and activity of ingested LPS. Consistent with these findings, BPIFA2-depleted mice also showed increased insulin secretion and metabolomic changes that were consistent with a mild endotoxaemia. These results support the distal physiological function of a salivary protein and reinforce the connection between oral biology and systemic disease.