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Purpose. To compare radiographic and clinical outcomes after anterior cervical discectomy in patients with cervical degenerative disc disease using PEEK cages or PMMA spacers with a minimum 1-year follow-up. Methods. Anterior cervical discectomy was performed in 107 patients in one or two levels using empty PEEK cages (51 levels), Sulcem PMMA spacers (49 levels) or Palacos PMMA spacers (41 levels) between January, 2005 and February, 2009. Bony fusion, subsidence, and sagittal alignment were retrospectively assessed in CT scans and radiographs at follow-up. Clinical outcome was measured using the VAS, NDI, and SF-36. Results. Bony fusion was assessed in 65% (PEEK cage), 57% (Sulcem), and 46% (Palacos) after a mean follow-up of 2.5 years. Mean subsidence was 2.3–2.6 mm without significant differences between the groups. The most pronounced loss of lordosis was found in PEEK cages (−4.1°). VAS was 3.1 (PEEK cage), 3.6 (Sulcem), and 2.7 (Palacos) without significant differences. Functional outcome in the PEEK cage and Palacos group was superior to the Sulcem group. Conclusions. The substitute groups showed differing fusion rates. Clinical outcome, however, appears to be generally not correlated with fusion status or subsidence. We could not specify a superior disc substitute for anterior cervical discectomy. This trial is registered with DRKS00003591.

The visual system continually adjusts its sensitivity to the statistical properties of the environment through an adaptation process that starts in the retina. Colour perception and processing is commonly thought to occur mainly in high visual areas, and indeed most evidence for chromatic colour contrast adaptation comes from cortical studies. We show that colour contrast adaptation starts in the retina where ganglion cells adjust their responses to the spectral properties of the environment. We demonstrate that the ganglion cells match their responses to red-blue stimulus combinations according to the relative contrast of each of the input channels by rotating their functional response properties in colour space. Using measurements of the chromatic statistics of natural environments, we show that the retina balances inputs from the two (red and blue) stimulated colour channels, as would be expected from theoretical optimal behaviour. Our results suggest that colour is encoded in the retina based on the efficient processing of spectral information that matches spectral combinations in natural scenes on the colour processing level.

Many biological systems perform computations on inputs that have very large dimensionality. Determining the relevant input combinations for a particular computation is often key to understanding its function. A common way to find the relevant input dimensions is to examine the difference in variance between the input distribution and the distribution of inputs associated with certain outputs. In systems neuroscience, the corresponding method is known as spike-triggered covariance (STC). This method has been highly successful in characterizing relevant input dimensions for neurons in a variety of sensory systems. So far, most studies used the STC method with weakly correlated Gaussian inputs. However, it is also important to use this method with inputs that have long range correlations typical of the natural sensory environment. In such cases, the stimulus covariance matrix has one (or more) outstanding eigenvalues that cannot be easily equalized because of sampling variability. Such outstanding modes interfere with analyses of statistical significance of candidate input dimensions that modulate neuronal outputs. In many cases, these modes obscure the significant dimensions. We show that the sensitivity of the STC method in the regime of strongly correlated inputs can be improved by an order of magnitude or more. This can be done by evaluating the significance of dimensions in the subspace orthogonal to the outstanding mode(s). Analyzing the responses of retinal ganglion cells probed with [Formula: see text] Gaussian noise, we find that taking into account outstanding modes is crucial for recovering relevant input dimensions for these neurons.

Rapid repair of epithelial wounds is essential for intestinal homeostasis, and involves cell proliferation and migration, which in turn are mediated by multiple cellular signaling events including PKC activation. PKC isoforms have been implicated in regulating cell proliferation and migration, however, the role of PKCs in intestinal epithelial cell (IEC) wound healing is still not completely understood. In the current work we used phorbol 12-myristate 13-acetate (PMA), a well recognized agonist of classical and non-conventional PKC subfamilies to investigate the effect of PKC activation on IEC wound healing. We found that PMA treatment of wounded IEC monolayers resulted in 5.8±0.7-fold increase in wound closure after 24 hours. The PMA effect was specifically mediated by PKCβII, as its inhibition significantly diminished the PMA-induced increase in wound closure. Furthermore, we show that the PKCβII-mediated increase in IEC wound closure after PMA stimulation was mediated by increased cell spreading/cell migration but not proliferation. Cell migration was mediated by PKCβII dependent actin cytoskeleton reorganization, enhanced formation of lamellipodial extrusions at the leading edge and increased activation of the focal adhesion protein, paxillin. These findings support a role for PKCβII in IEC wound repair and further demonstrate the ability of epithelial cells to migrate as a sheet thereby efficiently covering denuded surfaces to recover the intestinal epithelial barrier.

Neural populations encode information about their stimulus in a collective fashion, by joint activity patterns of spiking and silence. A full account of this mapping from stimulus to neural activity is given by the conditional probability distribution over neural codewords given the sensory input. For large populations, direct sampling of these distributions is impossible, and so we must rely on constructing appropriate models. We show here that in a population of 100 retinal ganglion cells in the salamander retina responding to temporal white-noise stimuli, dependencies between cells play an important encoding role. We introduce the stimulus-dependent maximum entropy (SDME) model-a minimal extension of the canonical linear-nonlinear model of a single neuron, to a pairwise-coupled neural population. We find that the SDME model gives a more accurate account of single cell responses and in particular significantly outperforms uncoupled models in reproducing the distributions of population codewords emitted in response to a stimulus. We show how the SDME model, in conjunction with static maximum entropy models of population vocabulary, can be used to estimate information-theoretic quantities like average surprise and information transmission in a neural population.

The way information is represented by sequences of action potentials of spiking neurons is determined by the input each neuron receives, but also by its biophysics, and the specifics of the circuit in which it is embedded. Even the "code" of identified neurons can vary considerably from individual to individual. Here we compared the neural codes of the identified H1 neuron in the visual systems of two families of flies, blow flies and flesh flies, and explored the effect of the sensory environment that the flies were exposed to during development on the H1 code. We found that the two families differed considerably in the temporal structure of the code, its content and energetic efficiency, as well as the temporal delay of neural response. The differences in the environmental conditions during the flies' development had no significant effect. Our results may thus reflect an instance of a family-specific design of the neural code. They may also suggest that individual variability in information processing by this specific neuron, in terms of both form and content, is regulated genetically.

Traditionally, the information content of the neural response is quantified using statistics of the responses relative to stimulus onset time with the assumption that the brain uses onset time to infer stimulus identity. However, stimulus onset time must also be estimated by the brain, making the utility of such an approach questionable. How can stimulus onset be estimated from the neural responses with sufficient accuracy to ensure reliable stimulus identification? We address this question using the framework of colour coding by the archer fish retinal ganglion cell. We found that stimulus identity, "what", can be estimated from the responses of best single cells with an accuracy comparable to that of the animal's psychophysical estimation. However, to extract this information, an accurate estimation of stimulus onset is essential. We show that stimulus onset time, "when", can be estimated using a linear-nonlinear readout mechanism that requires the response of a population of 100 cells. Thus, stimulus onset time can be estimated using a relatively simple readout. However, large nerve cell populations are required to achieve sufficient accuracy.

Abstract Background Rats treated chronically with the D2–3 dopamine agonist quinpirole were previously proposed as an animal model of obsessive-compulsive disorder (OCD) since their behavior is based on repeated, compulsive-like persistent traveling between a few places in the open field. The aim of the present study was to determine properties of the physical environment that shape such behavior. For this, quinpirole-treated rats were first exposed to an arena with an array of objects (landmarks) and after the development of compulsive-like behavior, the arena was manipulated by multiplying the number of objects, changing their spacing, relocating object array, or removing the objects. Results When the number of objects was retained but they were spaced further apart, rat routes converged at 1–2 of the objects and at the corner at which the rats had been introduced into the arena (start corner). When object spacing was retained but their number was increased, the rats traveled between the objects with the routes converging only at the start corner. Finally, when object array was relocated to different places within the arena, the rats extended their routes from the start corner to the object array, regardless of array location. Conclusion Quinpirole-treated rats organized and updated their progression primarily according to the proximal layout of landmarks, but did so with excessive repetitions compared with saline-treated rats. The behavior of quinpirole-treated rats paralleled human OCD rituals that are linked to the immediate physical environment, featuring an excessive rate of performance. Finally, when only a few objects were present, they were perceived by the rats as positional cues (beacons) that routes converged at them. In contrast, in the presence of many objects, the routes passed between the objects as if using them as directional cues.

Superficial malignant peripheral nerve sheath tumors (SF-MPNSTs) are rare cancers and can be difficult to distinguish from spindle cell (SCM) or desmoplastic (DM) melanomas. Their biology is poorly understood. We performed whole-exome sequencing and RNA sequencing (RNA-seq) on SF-MPNST (n = 8) and compared them with cases of SCM (n = 7), DM (n = 8), and deep MPNST (D-MPNST, n = 8). Immunohistochemical staining for H3K27me3 and PRAME was also performed. SF-MPNST demonstrated intermediate features between D-MPNST and melanoma. Patients were younger than those with melanoma and older than those with D-MPNST; the outcome was worse and better, respectively. SF-MPNST tumor mutational burden (TMB) was higher than D-MPNST and lower than melanoma; differences were significant only between SF-MPNST and SCM (P = .0454) and between D-MPNST and SCM (P = .001, Dunn's Kruskal-Wallis post hoc test). Despite having an overlapping mutational profile in some common cancer-associated genes, the COSMIC mutational signatures clustered DM and SCM together with UV light exposure signatures (SBS7a, 7b), and SF- and D-MPNST together with defective DNA base excision repair (SBS30, 36). RNA-seq revealed differentially expressed genes between SF-MPNST and SCM (1670 genes), DM (831 genes), and D-MPNST (614 genes), some of which hold promise for development as immunohistochemical markers (SOX8 and PLCH1) or aids (MLPH, CALB2, SOX11, and TBX4). H3K27me3 immunoreactivity was diffusely lost in most D-MPNSTs (7/8, 88%) but showed variable and patchy loss in SF-MPNSTs (2/8, 25%). PRAME was entirely negative in the majority (0+ in 20/31, 65%), including 11/15 melanomas, and showed no significant difference between groups (P = .105, Kruskal-Wallis test). Expression of immune cell transcripts was upregulated in melanomas relative to MPNSTs. Next-generation sequencing revealed multiple differential features between SF- MPNST, D-MPNST, SCM, and DM, including tumor mutation burden, mutational signatures, and differentially expressed genes. These findings help advance our understanding of disease pathogenesis and improve diagnostic modalities., (Copyright © 2024. Published by Elsevier Inc.)

Pilomatrical skin tumors harbor mutations in CTNNB1, which encodes for β-catenin, a downstream effector of the Wnt signaling pathway responsible for the differentiation, proliferation, and adhesion of epithelial stem cells. Therefore, downstream molecules, such as CDX2, LEF-1, and SATB2, in the Wnt signaling pathway could be useful diagnostic markers. Here, we sought to investigate the potential of immunohistochemistry (IHC) to differentiate between pilomatricoma and pilomatrical carcinoma, as well as from other cutaneous adnexal tumors. We studied 88 cases of cutaneous tumors (14 pilomatrical carcinomas, 18 pilomatricomas, 13 basal cell carcinomas, 12 squamous cell carcinomas, 12 sebaceous carcinomas, 10 Merkel cell carcinomas, 7 trichoblastomas, and 2 hidradenocarcinomas) using a broad panel of IHC markers: β-catenin, SATB2, CDX2, LEF1, Ber-EP4, and PRAME. Pilomatricoma and pilomatrical carcinoma displayed >75% nuclear staining for β-catenin. CDX2 also strongly stained pilomatrical tumors; however, the staining distribution was limited in pilomatricoma and more widespread in pilomatrical carcinoma. But, overall, it was less than β-catenin. SATB2 and Ber-EP4 expressions were noted only in a subset of both pilomatrical carcinoma and pilomatricoma, whereas LEF-1 showed strong, diffuse nuclear positivity in both pilomatricoma and pilomatrical carcinoma. Among the IHC markers evaluated, none could distinguish between pilomatricoma and pilomatrical carcinoma. However, the combined use of β-catenin with CDX2 markers may assist in not only confirming the pilomatrical nature of the proliferation but also in differentiating benign from malignant cases when there is a significant presence of CDX2 staining. Despite these findings, the diagnosis should continue to primarily depend on a thorough histopathologic examination., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The first approved vaccines for human use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are nanotechnology-based. Although they are modular, rapidly produced, and can reduce disease severity, the currently available vaccines are restricted in preventing infection, stressing the global demand for novel preventive vaccine technologies. Bearing this in mind, we set out to develop a flexible nanovaccine platform for nasal administration to induce mucosal immunity, which is fundamental for optimal protection against respiratory virus infection. The next-generation multiepitope nanovaccines co-deliver immunogenic peptides, selected by an immunoinformatic workflow, along with adjuvants and regulators of the PD-L1 expression. As a case study, we focused on SARS-CoV-2 peptides as relevant antigens to validate the approach. This platform can evoke both local and systemic cellular- and humoral-specific responses against SARS-CoV-2. This led to the secretion of immunoglobulin A (IgA), capable of neutralizing SARS-CoV-2, including variants of concern, following a heterologous immunization strategy. Considering the limitations of the required cold chain distribution for current nanotechnology-based vaccines, it is shown that the lyophilized nanovaccine is stable for long-term at room temperature and retains its in vivo efficacy upon reconstitution. This makes it particularly relevant for developing countries and offers a modular system adaptable to future viral threats., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The first example of sonodynamic therapy (SDT) with a cyanine dye-antibody conjugate is reported. The aim of this study was to evaluate the sonodynamic efficacy of a trastuzumab-guided diiodinated heptamethine cyanine-based sensitizer, 2ICy7-Ab, versus its non-iodinated counterpart, Cy7-Ab , in a human epidermal growth factor receptor 2-positive (HER2+) xenograft model. In addition, the combined sonodynamic and photodynamic (PDT) effects were investigated. A single intravenous injection of 2ICy7-Ab followed by sonication or combined sonication and photoirradiation in mice resulted in complete tumor growth suppression compared with the nontreated control and showed no detectable toxicity to off-target tissues. In contrast, Cy7-Ab provided only a moderate therapeutic effect (~1.4-1.6-fold suppression). SDT with 2ICy7-Ab resulted in a 3.5-fold reduction in tumor volume within 45 days and exhibited 13-fold greater tumor suppression than PDT alone. In addition, 2ICy7-Ab showed more durable sonostability than photostability. The sonotoxicity of the iodinated versus noniodinated counterparts is attributed to the increased generation of hydroxyl radicals, superoxide, and singlet oxygen. We observed no significant contribution of PDT to the efficacy of the combined SDT and PDT, indicating that SDT with 2ICy7-Ab is superior to PDT alone. These new findings set the stage for the application of cyanine-antibody conjugates for fluorescently monitored targeted sonodynamic treatment of cancer.

Objectives: Cutaneous diseases that disproportionately affect patients with darker pigmentation and their histologic features are historically understudied and undertreated. This review article aims to highlight the key clinical features, histopathology, and diagnostic pearls of several cutaneous diseases that commonly present in patients with darker pigmentation., Methods: A literature search was conducted, and a list of cutaneous diseases that frequently affect patients with darker pigmentation was compiled. A group of experts expounded upon those that were most common or misdiagnosed according to scientific evidence and clinical practice., Results: The diseases were divided into hypopigmented disorders, hyperpigmented disorders, scarring disorders, and alopecic disorders. Within each category, the etiology, clinical features, histopathology, and key histologic differential diagnoses are described and discussed., Conclusions: As many clinicians are taught that there are no effective treatment options or that these diseases are considered "cosmetic" in nature, patients often do not get a thorough medical workup or skin biopsy. This article aims to decrease the knowledge gap and serve as a resource for anyone involved in the care of patients with these cutaneous conditions., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Erdheim-Chester disease is a rare form of non-Langerhans cell histiocytosis that preferentially involves long bones but can affect a variety of other organs. Initial presentation with extraskeletal involvement is not unusual and is most commonly observed in the central nervous system, heart, retroperitoneum, lungs, and skin. Initial presentation of the disease as a subcutaneous soft tissue mass is exceedingly rare and may pose difficulties for diagnosis. We describe a case of Erdheim-Chester disease that initially presented as a cutaneous and subcutaneous soft tissue mass in the right posterior shoulder of a 52-year-old man., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Crystal-storing histiocytosis (CSH) is a rare condition in which crystals accumulate in the cytoplasm of histiocytes and is usually associated with a lymphoplasmacytic neoplasm. Cutaneous CSH is extraordinarily rare and limited to case reports in the literature. We report two cases of this disease with cutaneous involvement. Case 1 was a 65-year-old male with a 4-month history of a pruritic eruption that started as a solitary pink to skin-colored indurated plaque on the anterior neck before progressing to involve the whole neck, chest wall, and face. Case 2 was a 54-year-old woman with a history of unspecified "lymphoma" who presented with a soft nodule on the forearm. Biopsies from both cases had similar findings and showed a proliferation of epithelioid cells with pink cytoplasm and intracellular crystalline structures infiltrating the dermis and subcutaneous fat. In the first case, the cells were positive for CD43, CD45, CD68, and IgG kappa, and in the second case, the crystals were positive for IgG lambda. Based on these findings, the patients were diagnosed with cutaneous CSH. We highlight this rare diagnosis and the importance of investigating an underlying lymphoplasmacytic neoplasm., (© 2024 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

The extraordinary diversity of T cells and B cells is critical for body maintenance. This diversity has an important role in protecting against tumor formation. In humans, the T-cell receptor (TCR) repertoire is generated through a striking stochastic process called V(D)J recombination, in which different gene segments are assembled and modified, leading to extensive variety. In ovarian cancer (OC), an unfortunate 80% of cases are detected late, leading to poor survival outcomes. However, when detected early, approximately 94% of patients live longer than 5 years after diagnosis. Thus, early detection is critical for patient survival. To determine whether the TCR repertoire obtained from peripheral blood is associated with tumor status, we collected blood samples from 85 women with or without OC and obtained TCR information. We then used machine learning to learn the characteristics of samples and to finally predict, over a set of unseen samples, whether the person is with or without OC. We successfully stratified the two groups, thereby associating the peripheral blood TCR repertoire with the formation of OC tumors. A careful study of the origin of the set of T cells most informative for the signature indicated the involvement of a specific invariant natural killer T (iNKT) clone and a specific mucosal-associated invariant T (MAIT) clone. Our findings here support the proposition that tumor-relevant signal is maintained by the immune system and is coded in the T-cell repertoire available in peripheral blood. It is also possible that the immune system detects tumors early enough for repertoire technologies to inform us near the beginning of tumor formation. Although such detection is made by the immune system, we might be able to identify it, using repertoire data from peripheral blood, to offer a pragmatic way to search for early signs of cancer with minimal patient burden, possibly with enhanced sensitivity., (© The Author(s) 2024. Published by Oxford University Press.)

Endometrial dating (ED) is the process by which the menstrual cycle day is estimated and is an important tool for the evaluation of uterine status. To date, ED methods remain inaccurate and controversial. We demonstrate how the rise of computerized virtual histology changes the state of affairs and introduce a new ED method. We present the results of a clinical trial where magnified images of ex-vivo endometrial tissue samples were captured at different cycle days, together with measurements of serum hormone levels on the same day. Patient testimonies about their cycle day were also collected. Computerized image analysis, followed by statistical representation of the tissue features, allowed mathematical representation of the cycle day. The samples underwent ED histological assessment, which is currently the ED gold standard. We compared dating results from patient reports, serum hormone levels, and histology to establish their concordance level. We then compared histology-based ED with the new method ED in the secretory phase (i.e. post ovulation). The correlation coefficient between the two resulted in an R = 0.89 with a P-value of P < 10 -4 . The new method, Virtual Pathology Endometrial Dating (VPED), has the benefit of being a real time, in-vivo method that can be repeatedly applied without tissue damage, using a dedicated hysteroscope. One practical use of this method may be the determination of accurate real-time embryo transfer timing in IVF treatments., (© 2023. The Author(s).)

Background: Changes in immunophenotype in mycosis fungoides (MF) are rarely reported, making this phenomenon a diagnostic challenge with unclear significance for the disease's biological behavior. This study examines a large series of MF patients who exhibited a phenotype switch (PS) and analyzes their clinical and histopathologic characteristics., Design: Institutional files were searched for MF cases exhibiting PS between 2010 and 2020. Clinical, follow-up, and histopathological data were collected., Results: Forty-two biopsies from 32 patients (13 women and 19 men, median age 67.5) showed PS. Eight patients (25 %) experienced multiple PS during their disease course. The median time for PS was 22 months from the initial diagnosis. In 5 cases tested, identical TCR clone peaks were detected in the immunophenotypically distinct lesions. Median follow-up was 14.5 months. Among deceased patients, median time from MF diagnosis to PS was 20.6 months, while among the patients who were still alive, median time was 44.1 months., Conclusion: MF biopsies can show PS during the course of the disease and may indicate a change in clinical behavior. 28.1 % of patients displayed more than one PS, further indicating high plasticity of MF cells. No obvious association was found between PS and therapy initiation or response. Features that appeared to portend a worse clinical course were earlier PS in the course of the disease and PS from CD4-/CD8-to CD8 + , and CD8 + to CD4-/CD8-. Awareness of this phenomenon is crucial to avoid misdiagnosing phenotypically distinct lymphomas as second primaries and to alert clinicians about potential changes in the disease's clinical course., Competing Interests: Declaration of competing interest No relevant conflicts., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Subcutaneous leiomyosarcoma (LMS) is a rare, poorly understood variant. The current literature on the subject is sparse, consisting of isolated case reports and small clinicopathologic studies compromised by the inclusion of both its more common and indolent counterpart, cutaneous LMS (atypical intradermal smooth muscle neoplasm), as well as highly aggressive deep-seated tumors. Thus, precise clinicopathologic characterization is limited. Cases of subcutaneous LMS reviewed at the University of Michigan and Cleveland Clinic from 1994 to 2022 were included in this retrospective study. A total of 39 cases were identified. The mean age was 61 years, and the cohort was predominantly male (23/39; 59%). Tumors averaged 4.2 cm and most commonly arose on the extremities (32/39; 82%). The majority (38/39; 97%) were diagnosed at an early pathologic stage (pT1 or pT2). Histopathologically, most tumors were well-circumscribed and were assigned a Fédération Nationale des Centers de Lutte Contre le Cancer grade of either 1 or 2 (24/39; 62%). The majority (22/39; 56%) appeared to arise in association with a blood vessel. Of the 36 cases with accessible clinical data and follow-up (mean 34 mo, range 0 to 94 mo), 12 (33%) were noted to have metastasized, with the lung representing the most common anatomic location. One case recurred locally. Six of 36 patients (17%) died from the disease at an average of 47 months after diagnosis (range 16 to 94 mo). Metastasis or death from disease was significantly associated with the Fédération Nationale des Centers de Lutte Contre le Cancer grade ( P =0.0015), the presence of necrosis ( P =0.032), tumor size ( P =0.049), and AJCC tumor stage ( P =0.036). These data demonstrate that subcutaneous LMS are more aggressive than dermal-based tumors and have a prognosis akin to that of deep-seated LMS., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The EnPlace ® device is a novel minimally invasive tool allowing transvaginal sacrospinous ligament (SSL) fixation of apical pelvic organ prolapse (POP). The study aimed to investigate the safety and short-term efficacy of the EnPlace ® SSL fixation for significant apical POP repair., Methods: A retrospective cohort study of 123 consecutive patients (mean age 64.4 ± 11.1 years) with stage III or IV apical POP who underwent SSL fixation by the EnPlace ® device. Safety and 6-month outcome results were analyzed and compared between 91 (74%) patients with uterine prolapse versus 32 (26%) patients with vaginal vault prolapse., Results: There were no intraoperative or early postoperative complications. The mean (± standard deviation) duration of surgery was 30 ± 6.9 min and mean blood loss was 30.5 ± 18.5 mL. The average position of point C by POP-Quantification measurements before surgery and at 6 months postoperatively was 4.5 ± 2.8 cm and -3.1 ± 3.3 cm, respectively. Of 91 patients with preoperative uterine prolapse, eight (8.8%) patients developed a recurrent uterine prolapse within 6 months postoperatively. Of 32 patients with preoperative vault prolapse, two patients (6.3%) had recurrent vault prolapse., Conclusion: Short-term outcome results of EnPlace ® SSL fixation suggest that it is a safe and effective minimally invasive transvaginal procedure for significant apical POP repair., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

MC1R, a G-protein coupled receptor, triggers ultraviolet light-induced melanin synthesis and DNA repair in melanocytes and is implicated in the pathogenesis of melanoma. Although widely expressed in different tissue types, its function in non-cutaneous tissue is relatively unknown. Herein, we demonstrate that disruptive MC1R variants associated with melanomagenesis are less frequently found in patients with several cancers. Further exploration revealed that breast cancer tissue shows a significantly higher MC1R expression than normal breast tissue, and knocking down MC1R significantly reduced cell proliferation in vitro and in vivo. Mechanistically, MC1R signaling through the MC1R-cAMP-CREB/ATF-1 and MC1R-ERK-NFκB axes accelerated the G1-S transition in breast cancer cells. Our results revealed a new association between MC1R and breast cancer, which could be potentially targeted therapeutically. Moreover, our results suggest that MC1R-enhancing/activating therapies should be used cautiously, as they might be pro-tumorigenic in certain contexts., (© 2023. Nature Publishing Group UK.)

Nipple adenoma (NA) is a rare, benign proliferation of the nipple ducts. It may be clinically mistaken for Paget disease or squamous cell carcinoma; thus, microscopic evaluation is paramount. A large case series of NA has not been undertaken since the 1980s. Therefore, we undertook this study to evaluate the clinicopathologic characteristics of NA, emphasizing differential diagnoses and follow-up data. We retrieved 50 cases from our in-house archives or consultation files between 2003 and 2022. Available slides were reviewed, and clinical data and follow-up information were obtained. Cases must have exhibited a dense ductal proliferation in the breast tissue with proximity to the nipple epidermis. All patients were women; median age was 56 years. In all, 68% of patients were symptomatic; 53% demonstrated a skin growth. Overall, 67% were excised completely, either primarily (33%) or via re-excision after biopsy (33%). Four histologic patterns were noted: adenosis (dense proliferation of small-to-medium ducts); large duct (medium-to-large caliber ducts); papillary-like (frond-like architecture with branching, slit-like lumens); and pseudoinfiltrative (ducts squished and distorted by dense stromal fibrosis). Follow-up in 44 patients (88%) with a median time of 66 months showed no evidence of recurrence. NA demonstrates a wide spectrum of histopathologic variation. Subtyping of this entity is unlikely to be clinically relevant. Differentiation from invasive carcinoma or other histologic mimics (syringocystadenoma papilliferum, syringomatous adenoma) may be difficult. Simple excision is curative, and recurrence is rare. A definitive link to invasive carcinoma has not been established., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Chronic stress promotes obesity and metabolic comorbidities. The ability of individuals to cope with stress may serve as an important parameter in the development of obesity-related metabolic outcomes. The aim of this study was to clarify whether differences in stress response affect metabolic health under obesity., Methods: The study was performed in a selectively bred mouse model of social dominance (Dom) and submissiveness (Sub), which exhibit stress resilience or vulnerability, respectively. Mice were given a high-fat diet (HFD) or standard diet, followed by physiological, histological, and molecular analyses., Results: The HFD caused hyperleptinemia, glucose intolerance, insulin resistance, steatosis of the liver and pancreas, and brown adipose tissue whitening in Sub mice, whereas Dom mice were protected from these consequences of the HFD. The HFD increased circulating levels of interleukin (IL)-1β and induced the expression of proinflammatory genes in the liver and in epididymal white adipose tissue of Sub mice, with no changes in Dom mice. The Cox2 inhibitor celecoxib (15 mg/kg/d) reduced serum IL-1β, improved glucose tolerance and insulin sensitivity, and prevented hepatic and brown adipose tissue whitening in HFD-fed Sub mice., Conclusions: The extent of stress resiliency is associated with inflammation and contributes to population heterogeneity in the development of healthy or unhealthy obesity., (© 2023 The Obesity Society.)

Background: Ultraviolet (UV) A1 phototherapy is considered a beneficial treatment for various inflammatory, sclerotic, malignant, and other skin conditions. However, the available data regarding its efficacy for different indications, the potential side effects, and the recommended treatment protocols are sparse., Objectives: To assess the efficacy of UVA1 phototherapy and identify correlation between different indications and treatment protocols to response rates., Methods: We performed a retrospective study of a cohort of 335 patients treated with UVA1 phototherapy at the Department of Dermatology at Hadassah Medical Center, Jerusalem, Israel, between 2008 and 2018., Results: The study population included 163 patients with inflammatory diseases (mainly atopic dermatitis and other types of eczema), 67 patients with sclerotic diseases (morphea and graft versus host disease), nine patients with neoplastic diseases (cutaneous T cell lymphoma), and 188 patients with other cutaneous disorders. Response rates ranged between 85% and 89% across indications, without differences in response rates among the indication groups (p = .941). In a multivariant logistic regression model, increased number of treatments and higher maximal dosages were associated with response to treatment (p < .001). Using ROC analysis, a cut-off of 8 UVA1 phototherapy treatments was chosen as predictive for beneficial response (86.4% sensitivity, 78% specificity). A cut-off of 40 J/cm 2 was chosen as an optimal maximal dosage for differentiating between responders and non-responders (51.1% sensitivity, 83.1% specificity)., Conclusions: UVA1 phototherapy is an effective treatment for a variety of skin conditions. In most patients, at least eight treatments of a medium-high dosage are required for clinical response., (© 2022 The Authors. Photodermatology, Photoimmunology & Photomedicine published by John Wiley & Sons Ltd.)

Although both the 2014 and 2020 World Health Organization (WHO) criteria require unequivocal glandular and squamous differentiation for a diagnosis of cervical adenosquamous carcinoma (ASC), in practice, ASC diagnoses are often made in tumors that lack unequivocal squamous and/or glandular differentiation. Considering the ambiguous etiologic, morphologic, and clinical features and outcomes associated with ASCs, we sought to redefine these tumors. We reviewed slides from 59 initially diagnosed ASCs (including glassy cell carcinoma and related lesions) to confirm an ASC diagnosis only in the presence of unequivocal malignant glandular and squamous differentiation. Select cases underwent immunohistochemical profiling as well as human papillomavirus (HPV) testing by in situ hybridization. Of the 59 cases originally classified as ASCs, 34 retained their ASC diagnosis, 9 were reclassified as pure invasive stratified mucin-producing carcinomas, 10 as invasive stratified mucin-producing carcinomas with other components (such as HPV-associated mucinous, usual-type, or ASCs), and 4 as HPV-associated usual or mucinous adenocarcinomas with benign-appearing squamous metaplasia. Two glassy adenocarcinomas were reclassified as poorly differentiated HPV-associated carcinomas based on morphology and immunophenotype. There were no significant immunophenotypic differences between ASCs and pure invasive stratified mucin-producing carcinomas with regard to HPV and other markers including p16 expression. Although limited by a small sample size, survival outcomes seemed to be similar between all groups. ASCs should be diagnosed only in the presence of unequivocal malignant glandular and squamous differentiation. The 2 putative glassy cell carcinomas studied did not meet our criteria for ASC and categorizing them as such should be reconsidered., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Women are underrepresented across the field of orthopedic surgery and may face barriers to academic advancement. Research presentation at national meetings and publication record are important drivers of advancement in academic orthopedic surgery. However, little is known regarding potential gender differences in publication after orthopedic conference research presentation. This investigation analyzed research presentations at the Annual Meeting of the American Academy of Orthopaedic Surgeons in 2016 and 2017. Author gender was determined through a search of institutional and professional networking websites for gender-specific pronouns. Resulting publications were identified using a systematic search of PubMed and Google Scholar databases. A total of 1696 of 1803 (94.1%) abstracts from 2016 to 2017 had identifiable gender for both the first and last authors, with 1213 (71.5%) abstracts ultimately being published. There were no differences in average sample size or level of evidence between genders. Abstracts authored by women were significantly less likely to lead to publication compared with those by men (67.1% vs 72.1%, P =.023), with articles authored by women having a longer median time to publication (median, 20 months [interquartile range, 19] vs 17 months [interquartile range, 15]; P =.003). This discrepancy was most apparent in adult reconstruction, with women having a 15.5% lower rate of publication (55.1% [27/49] vs 70.6% [307/435]; P =.026) and lower publication journal impact factor (2.7±1.4 vs 3.4±3.4, P =.040) than men. Potential reasons for these discrepancies, including disproportionate domestic obligations, inadequate mentorship, and bias against female researchers, should be addressed. [ Orthopedics . 2023;46(2):e118-e124.].

Background: The distribution of the blood vessel network at any point in time in any body tissue, may provide valuable information with regards to the tissue condition and its angiogenesis functionality. The blood vessel three-dimensional network of the endometrium goes through a process of change over a relatively short period of 4 weeks on average. It is well accepted that this angiogenesis is closely related to the success or failure of the implantation of the embryo Objective and rationale: Our study aims to present a method to follow the three-dimensional evolution of the superficial blood vessel distribution in the endometrium throughout the uterine cycle., Method: This method utilizes differences in the observed broadband colors of the blood vessels in order to assess their depth coordinate below the endometrial tissue surface. We implemented the method using microscopic images of fresh, ex-vivo, endometrial samples of different cycle days to obtain the statistical evolution track of the superficial blood vessel population in both human and animal (swine) samples., Outcomes: In human samples we observed a systematic and consistent trend in the BV diameter distribution at different tissue depths. We demonstrate that the magnitude of this trend evolves throughout the course of the female cycle., Wider Implications: This method has the potential to further our understanding of the mechanisms of angiogenesis in tissues other than the endometrium. We propose that this method may also contribute to more precise endometrial dating and may assist in more accurate determination of embryo transfer timing within IVF treatments.

Background: Spitzoid melanocytic neoplasms are diagnostically challenging; criteria for malignancy continue to evolve. The ability to predict chromosomal abnormalities with immunohistochemistry (IHC) could help select cases requiring chromosomal evaluation., Methods: Fluorescence in situ hybridization (FISH)-tested spitzoid neoplasms at our institution (2013-2021) were reviewed. p16, BRAF V600E, and preferentially expressed antigen in melanoma (PRAME) IHC results were correlated with FISH., Results: A total of 174 cases (1.9F:1M, median age 28 years; range, 5 months-74 years) were included; final diagnoses: Spitz nevus (11%), atypical Spitz tumor (47%), spitzoid dysplastic nevus (9%), and spitzoid melanoma (32%). Sixty (34%) were FISH positive, most commonly with absolute 6p25 gain (RREB1 > 2). Dermal mitotic count was the only clinicopathologic predictor of FISH. Among IHC-stained cases, p16 was lost in 55 of 134 cases (41%); loss correlated with FISH positive (p < 0.001, Fisher exact test). BRAF V600E (14/88, 16%) and PRAME (15/56, 27%) expression did not correlate with FISH alone (p = 0.242 and p = 0.359, respectively, Fisher exact test). When examined together, however, p16-retained/BRAF V600E-negative lesions had low FISH-positive rates (5/37, 14%; 4/37, 11% not counting isolated MYB loss); all other marker combinations had high rates (56%-75% of cases; p < 0.001)., Conclusions: p16/BRAF V600E IHC predicts FISH results. "Low-risk" lesions (p16 + /BRAF V600E - ) uncommonly have meaningful FISH abnormalities (11%). PRAME may have limited utility in this setting., (© 2022 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background: Low-grade fibromyxoid sarcoma (LGFMS) typically involves deep soft tissue (beneath the fascia) of the proximal extremities and trunk. Long-term follow-up has shown a high rate of local recurrence, metastasis, and death. To the best of our knowledge, there is only one previous large series focusing on superficial LGFMS suggesting superficial tumors are disproportionately more common in children and may have a better prognosis. Our study's primary goals are to confirm these findings and increase general awareness that LGFMS may arise in superficial soft tissue., Methods: We retrieved our cases of superficial LGFMS diagnosed between 2008 and 2020. Available slides were reviewed, and clinical data and follow-up information were obtained., Results: The patients included nine males and 14 females with a median age of 29 years; eight (35%) were children (<18 years) and five (22%) were young adults (18-30 years). The majority involved the lower extremities (65%). The tumors were primarily centered in the subcutis (91%) and dermis (9%). Microscopically, they had typical features of LGFMS with alternating fibrous and myxoid zones composed of bland, slightly hyperchromatic spindled cells. All were positive for MUC4 by immunohistochemistry and/or FUS rearrangement by FISH. Follow-up on 14 cases ranged from 11 to 148 months (median 61 months) with no evidence of recurrences or distant metastases., Conclusions: Compared to conventional deep-seated counterparts, superficial LGFMS is more likely to occur in the extremities of children and young adults and may have a better clinical outcome. Further studies with longer follow-up will likely help support these findings., (© 2022 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Colorectal cancer (CRC) can been sub-divided, based on the generation of tertiary lymphoid structures (TLS), into CRC with a Crohn's like lymphoid reaction (CLR) representing de novo formation of TLSs or CRC lacking TLSs that show Diffuse Inflammatory infiltration (DII). The association between TLS, early treatment initiation and longer survival highlights the need for deeper patient stratification that could lead to more targeted therapies. We hypothesized that such stratification might be achieved by using digital image analyses. Here we retrospectively analyzed 35 CRC patient samples classified as CLR or DII by digital analysis, focusing on the parameters Fractal dimension, Lacunarity and the textural features Angular second momentum, Correlation, Inverse difference momentum and Entropy. Significant differences in the grades of these parameters between the two patient groups provided preliminary data that additional biophysical information can divide CRC into at least 3 subgroups which encompass CLR and DII. Additional studies are needed to test if this sub-classification aids in the selection of targeted therapy for patients with CRC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Abstract: An unusual benign skin lesion is reported in a 19-year-old man with no significant medical history. The lesion had been present since he was an infant and had been slowly enlarging over the past 15 years. The lesion caused pain and discomfort, and the patient underwent an excisional biopsy. Histologic examination showed a subcutaneous lesion with ill-defined borders and peripheral areas of infiltration between adnexal structures. The lesion was composed of small round to ovoid cells embedded in a collagenous stroma with prominent cystic pseudovascular appearing channels causing a pseudopapillary or lymphangitic appearance that mimicked a vascular neoplasm. Immunohistochemistry performed showed positive staining for EMA, progesterone receptor, D2-40, and vimentin within the lesional cells. The tumor cells were negative for cytokeratin AE1/AE3, CD34, CD31, HHV-8, STAT6, SMA, Desmin, S-100, Melan A, and HMB45. A next-generation sequencing study using a hybrid capture-based panel examining 50 commonly mutated genes in human neoplasia was performed and showed no molecular alterations suggesting a nonneoplastic nature. Based on the clinical presentation, histologic features, and results of ancillary studies, the case was diagnosed as a hamartoma of the scalp with meningothelial-like elements. Reported cases of this lesion have behaved in a benign manner; however, as the histologic differential includes low-grade malignant vascular neoplasms such as angiosarcoma, it is important to recognize the salient features of this lesion., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: This study examines relationships between door to balloon (D2B) time and subsequent admissions due to heart failure (HF), acute coronary syndrome (ACS), and mortality for up to 1 year., Background: Current guidelines set 90-min for D2B time for primary percutaneous coronary intervention (PPCI) as a goal, which has been shown to reduce mortality and adverse events., Methods: Using the MDclone ADAMS system integrated with our electronic medical records, we conducted retrospective analysis of all patients admitted due to ST-elevation myocardial infarction from home, without any history of HF or coronary disease, and who underwent PPCI during 2013-2019. Data on D2B time, baseline clinical and demographic characteristics, and outcomes of HF, ACS and mortality were collected. Adjusted HR for each of the outcomes was calculated by multivariate Cox model., Results: A total of 826 patients were included in the final analysis. D2B had no significant effect on incidence of heart failure admissions for up to 1-year follow-up. D2B had a significant effect on mortality at 180 days, showing a 30% increase for each 30-min increase (HR 1.308; CI, 1.046-1.635) as for ACS at 90 days (HR 1.307; 1.025-1.638). The 30-min D2B cutoff showed a significant increase in ACS recurrence throughout the follow-up period at 90 days (HR 2.871, 1.239-6.648), 180 days (HR 2.607, 1.255-5.413), and 1 year (HR 1.886, 1.073-3.317)., Conclusions: Patients with shorter D2B times had significantly reduced mortality and recurrence of ACS, with no effect on heart failure admission incidence., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Acral melanocytic neoplasms often pose diagnostic difficulty. Preferentially expressed antigen in melanoma (PRAME) expression and loss of p16 expression have diagnostic utility in melanocytic tumors. We examined PRAME and p16 expression in 30 acral melanocytic neoplasms (n = 11 nevi; n = 2 dysplastic nevi; n = 7 Spitz nevi; n = 10 acral melanomas). PRAME was scored as % positive nuclei: negative = 0%; 1% to 25% = 1+; 25% to 50% = 2+; 50% to 75% = 3+, or positive: 75% to 100% = 4+. p16 expression was defined as retained (homogeneous or checkerboard) or lost (complete or partial/regionally). PRAME expression was negative in all benign, dysplastic, and Spitz nevi. Conversely, all acral melanomas were diffusely (4+) positive for PRAME expression. p16 expression was retained in all benign acral nevi (8/11 homogeneous, 3/11 checkerboard), completely lost in one dysplastic nevus, and retained in all acral Spitz nevi (3/7 homogeneous, 4/7 checkerboard). p16 was retained in five of 10 acral melanomas (3/10 homogeneous; 2/10 checkerboard), and negative in five of 10 acral melanomas (absent in 3/10, partially lost in 2/10). Our data suggest that 4+ PRAME expression is highly sensitive and specific in the setting of acral melanomas and is a more predictive diagnostic tool compared with p16 immunohistochemistry., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Photodynamic therapy (PDT) utilizing an organic dye (photosensitizer) capable of killing cancer cells in the body upon light irradiation is one of the promising non-invasive treatment modalities for many cancers. A known drawback of PDT is a side-effect caused by existing photosensitizers to organs due to insufficient specificity and accidental light exposure of a patient during the delivery of the photosensitizer in the bloodstream. To overcome this issue, we developed a novel antibody guided, activatable photosensitizing system, Ab-mI 2 XCy-Ac, where the trastuzumab (Ab) is linked to the non-active (not phototoxic and not fluorescent) dye, mI 2 XCy-Ac, that contains the hydroxyl group protected by acetyl (Ac). This targeting, non-photo-active conjugate was shown to be safely (without detectable side-effects) delivered to the targeted tumor, where it is activated by the esterase-mediated acetyl group cleavage and effectively treats the tumor upon NIR light irradiation. It was demonstrated in the Her2 positive BT-474 tumor mouse model that the treatment efficacy of the activatable photosensitizing system is about the same as for the permanently active photosensitizer, Ab-mI 2 XCy, while the side-effects are noticeably reduced. In addition, this activatable system enables fluorescence monitoring of the photosensitizer activation events., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Abstract: An unusual benign skin tumor is reported occurring in a 68-year-old woman with no significant medical history. The lesion presented as a small skin nodule in the neck. Histologic examination showed a well-circumscribed superficial dermal nodule composed of a solid proliferation of large, round cells with abundant eosinophilic cytoplasm and small centrally placed nuclei displaying a vaguely chondroid appearance. Immunohistochemical studies showed strong positivity of the tumor cells for S100 protein and vimentin and negative staining for SOX10, melanoma cocktail, HMB45, Melan-A, cytokeratin AE1/AE3, inhibin, desmin, smooth muscle actin, CD68, CD164, and neuron specific enolase. Next-generation sequencing using a panel of 50 actionable genes commonly encountered in human neoplasia did not reveal the presence of any mutations. Owing to the remarkable similarity of the lesion to immature cartilage, we consider this to be a benign tumor, most likely resulting from an embryologic defect. We propose the term immature chondroid choristoma to designate this lesion., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Context.—: Accurate diagnosis of melanocytic lesions is fundamental for appropriate clinical management., Objective.—: To evaluate the degree of discordance, if any, between histopathologic diagnoses of melanocytic lesions at referring institutions and at a tertiary referral cancer center and the potential impact of such discordance on clinical management., Design.—: We retrospectively identified all patients referred to our comprehensive cancer center for evaluation of a melanocytic lesion from January 2010 to January 2011. For each patient, the histopathologic diagnosis from the referring institution was compared with the histopathologic diagnosis from a dermatopathologist at our center. Discordances were classified as major if they resulted in a change in clinical management and minor if they did not., Results.—: A total of 1521 cases were included. The concordance rates were 72.2% (52 of 72) for dysplastic nevus, 75.0% (15 of 20) for all other types of nevi, 91.1% (143 of 157) for melanoma in situ, 96.1% (758 of 789) for invasive melanoma, and 99.6% (478 of 480) for metastatic melanoma. Major discordances were found in 20.2% of cases (307 of 1521), and minor discordances were found in 48.8% of cases (742 of 1521). Compared with the guideline-based treatment recommendation based on the referring-institution diagnosis, the guideline-based treatment recommendation based on the cancer center diagnosis was more extensive in 5.9% (89 of 1521) of patients and less extensive in 5.0% (76 of 1521) of patients., Conclusions.—: Our findings underscore the importance of secondary histopathologic review of melanocytic lesions by expert dermatopathologists because significant changes in the diagnosis, tumor classification, and/or staging may be identified, thus, resulting in critical changes in recommendations for clinical management.

Nontuberculous mycobacteria are pathogens with diverse manifestations in immunocompromised hosts. The lesser-known Mycobacterium haemophilum usually causes cutaneous infection. Diagnosis is challenging but is aided by molecular testing and multidisciplinary communication. We present an immunocompromised patient with disseminated cutaneous mycobacterial infection with digital tenosynovitis.

Abstract: Cutaneous metastasis may be the initial sign of internal malignancy but more often represents a late manifestation of widely disseminated disease. Breast carcinoma is the most common malignancy to metastasize to the skin. Although several studies have detailed the histopathologic patterns of cutaneous metastasis from internal malignancies, very little has been published regarding metastases of breast carcinoma to the skin. Furthermore, the histopathologic and clinical features observed in the cases of breast carcinoma with local skin involvement as opposed to cases exhibiting distant cutaneous metastases have not been adequately investigated. We have reviewed 232 cases of breast carcinoma with cutaneous metastases from 2 large institutions. All cases of carcinoma of the breast with involvement of the skin of the anterior chest wall were compared with those with distant cutaneous metastases. Two hundred thirty-two cases in 199 patients were included, of which 126 had skin involvement exclusively involving the ipsilateral anterior chest, and 106 had biopsy-proven distant cutaneous metastases. Twelve patients had both local and distal spread. Distant cutaneous metastases showed a predilection for the contralateral anterior chest wall area, followed by the head and neck, back, and abdomen. Histologically, most of the tumors presented in this series showed features of infiltrating ductal carcinoma. In both ipsilateral and distant metastases, the tumors demonstrated little change in histologic features from the primary lesion; however, the distant metastases showed a tendency to display more poorly differentiated features. The mean patient survival when cutaneous involvement was localized to the skin of the anterior chest wall was 23 months as compared with 20.6 months when distant sites were affected. A comparison of the clinicopathologic features of the patients presented in this series suggests that alternate biological mechanisms may apply for local and distant skin metastases from breast carcinoma., Competing Interests: V.G. Prieto has disclosed that he was a consultant for Myriad Genetic Laboratories/myPath Melanoma. Lippincott CME Institute has identified and resolved all conflicts of interest concerning this educational activity. All other authors, faculty, and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations relevant to this educational activity., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate mechanisms of primordial follicle (PMF) loss in vivo in human ovaries shortly after alkylating agent (AA) chemotherapy., Design: Cohort study., Setting: Tertiary university medical center., Patient(s): Ninety-six women aged 15-39 years who underwent ovarian tissue cryopreservation for fertility preservation., Intervention(s): Fresh ovarian tissue samples were harvested from women treated with AA (n = 24) or non-AA (n = 24) chemotherapy <6 months after treatment and age-matched untreated women (n = 48)., Main Outcome Measure(s): Differential follicle counts, time from chemotherapy exposure, immunostaining for apoptosis (cleaved caspase-3) and FOXO3A on tissue harvested within ultrashort time intervals (4-12 days), collagen (Sirius red) and neovascularization (CD34)., Result(s): AA-treated ovaries had significant loss of PMFs, and significant increase in absolute numbers of growing follicles compared with untreated control ovaries. The number of growing follicles was inversely correlated with time from chemotherapy. Representative staining for FOXO3A observed decreased nuclear localization in PMF oocytes in AA-treated ovaries removed within the ultrashort time interval compared with untreated ovaries. Neither significant loss of PMFs, increase in growing follicles, nor decrease in nuclear FOXO3A were observed in non-AA-treated ovaries. No increased expression of cleaved caspase-3 was seen in PMFs within the ultrashort time interval after AA or non-AA chemotherapy. Significant stromal fibrosis and neovascularization were observed in AA-treated ovaries only after follicle loss had already occurred (4-6 months)., Conclusion(s): Follicle activation occurs in vivo in ovaries of patients treated with AA, indicating a pathologic mechanism which may contribute to chemotherapy-induced follicle loss., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Cutaneous carcinosarcomas are rare biphenotypic tumors that simultaneously show epithelial and mesenchymal differentiation. The most common carcinomatous components in skin carcinosarcomas are basal cell carcinoma and squamous cell carcinoma; adnexal carcinomas are rarely encountered. We report a case of an adnexal carcinoma with ductal and squamous differentiation and spindle cell component, which is interpreted as carcinosarcoma. Loss of immunohistochemical expression of E-cadherin and β-catenin detected in the sarcomatous component suggested epithelial mesenchymal transition (EMT). RNA sequencing analysis identified several gene mutations and alterations such as translocations and upregulations/downregulations, either shared by the two components of the tumor or differentially present in the carcinoma or the sarcoma parts. Thus, mutations in genes, such as TP53, were found in both components of the tumor while mutations in PDGFRA and RB1 (a pathogenic missense mutation) were exclusively present in the sarcomatous areas, further supporting EMT. EMT is a dynamic process by which tumors acquire mesenchymal phenotype while simultaneously losing epithelial properties. Although the pathways involved in EMT have been extensively studied, this phenomenon still needs to be investigated in cutaneous tumors of adnexal origin for a better understanding of their pathogenesis. These molecular changes may represent promising targets for personalized therapies., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Langerhans cell sarcoma (LCS) is rare and aggressive; patients have an overall survival rate of less than 50%. We present a 62-year-old man with a history of superficial spreading melanoma of the upper back with sentinel lymph node metastasis, Langerhans cell histiocytosis, and LCS. The patient presented with erythematous papules and scaly areas on his face, neck, arms, chest, abdomen, and legs. A skin biopsy revealed a proliferation of large neoplastic cells involving the dermis and with epidermotropism. These cells had atypical bean-shaped nuclei, with ample cytoplasm and abundant mitotic figures including atypical forms. Immunohistochemical studies showed the tumor to be diffusely positive for CD1a, S100 protein, and langerin (CD207) and negative for melanocytic markers. Some tumor cells were positive for cyclin D1. A diagnosis of LCS involving the skin was established. The present study is a very unusual case of LCS showing epidermotropism. The patient's history of metastatic melanoma posed additional challenges for diagnosis, underlying the need of immunophenotyping in these cases. Consensus for optimal standard therapy has not been established in LCS, and thus, early recognition is important since these neoplasms tend to recur and metastasize. LCS in skin is discussed and published cases are comprehensively reviewed., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Gastric-type carcinoma (GAS) is the most common human papilloma virus-independent endocervical adenocarcinoma (ECA), characterized by an aggressive behavior. Trefoil factor 2 (TFF2) is a mucin-associated peptide expressed in normal gastric but not endocervical glands. This study was carried out to investigate whether TFF2 could be a surrogate marker to separate GAS from other types of ECA. ECAs from 9 international institutions were reviewed for consensus histotype. Of them, expression of TFF2 was immunohistochemically examined compared with that of HIK1083, using whole sections of 50 ECAs (10 GASs and 40 non-GASs) and 179 ECAs (24 GASs and 155 non-GASs) with tissue microarrays (TMAs). TMAs were assessed to simulate assessment of immunohistochemical stains in small biopsies. Both markers were similarly scored, and any cytoplasmic/membranous staining of >5% of tumor cells was considered positive. Of 50 ECAs with whole sections, TFF2 was significantly more frequently expressed in GASs (8/10) compared with non-GASs (5/40) (P<0.01). In 179 ECAs with TMAs, TFF2 was also significantly more frequently expressed in GASs (7/24) compared with non-GASs (4/155) (P<0.01). There was no significant difference in specificity among the 2 markers. Double positivity for TFF2 and HIK1083 in ECAs was highly specific in separating GASs from non-GAS (P<0.01). A significantly smaller percentage of GASs were TFF2 positive in TMAs than in whole sections (P<0.01). Our results suggest that TFF2 is a promising marker, along with HIK1083, to confirm a diagnosis of GAS. This marker may be negative in small biopsies, indicating the necessity of using other exclusionary markers in combination with rigorous morphologic review and extensive sampling in resection specimens.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade soft tissue neoplasm preferentially arising in the extremities of young to middle-aged adults characterized histologically by a variegated appearance and absence of a distinctive immunophenotype. Herein we have evaluated a series of 73 cases of MIFS to define potential features and markers that may facilitate diagnosis. An immunohistochemical study with a large panel of antibodies showed strong positivity of the tumor cells for bcl-1 (94.5%), FXIIIa (89%), CD10 (80%), and D2-40 (56%). FISH and array comparative genomic hybridization (aCGH) were performed in a large subset of cases to investigate the utility for detecting the TGFBR3 and OGA t(1;10) rearrangement and BRAF abnormalities. Using a combination of FISH and/or aCGH, t(1;10) was detected in only 3 of 54 cases (5.5%). The aCGH study also demonstrated amplification of VGLL3 on chromosome 3 that was detected in 8 of 20 cases (40%). BRAF alterations were observed by FISH in 4 of 70 cases (5.7%) and correlated with gain of chromosome 3p12 (VGLL3). A novel fusion transcript involving exon 6 of ZNF335 and exon 10 of BRAF was identified in one case. Demonstration of amplification of VGLL3 on chromosome 3 in combination with expression of bcl-1 and FXIIIa may help support the diagnosis, however, due to their low specificity these markers are not sufficient for a definitive diagnosis in the absence of the appropriate clinical-pathological context. Until a more robust genetic or immunohistochemical signature is identified, the diagnosis of MIFS rests on its characteristic clinicopathological features.

The presence or absence of metastasis in sentinel lymph nodes often drives melanoma staging, prognosis, and treatment. However, distinguishing between metastatic melanoma cells and clusters of benign melanocytic nevus cells is not always straightforward. When morphologic hematoxylin and eosin interpretation alone is not sufficient, additional hematoxylin and eosin sections and immunohistochemical (IHC) studies may be beneficial. This review and small cases series of 3 diagnostically challenging melanocytic sentinel lymph node cases highlights the IHC approach to evaluate intraparenchymal nodal melanocytic nevi, coexistent metastatic melanoma with adjacent melanocytic nevi cells, and nodal blue nevi. In challenging cases, cytological morphology of the melanocytes, location within the lymph node, and IHC studies may assist in diagnosis. If these tools yield conflicting results, expert opinion is recommended.

Microcystic, elongated, and fragmented (MELF) pattern of myometrial invasion is correlated with lymphovascular invasion (LVI) and lymph node metastases in uterine endometrioid carcinoma but has not been described in endocervical adenocarcinoma (ECA). A total of 457 ECAs were collected, and clinical/morphologic parameters correlated with follow-up data. Potential associations between MELF pattern and age, human papillomavirus status, tumor size/grade, LVI, lymph node metastases, Silva pattern were analyzed. Statistical analyses of overall survival (OS), disease-free survival, progression-free survival (PFS) were conducted using Kaplan-Meier analysis, and compared using the Log-rank test. Of 292 ECAs analyzed, 94 (32.19%) showed MELF invasion pattern (MELF-positive). Significant statistical correlation was found between MELF-positive and tumor size (P=0.0017), LVI (P=0.007), Silva pattern (P=0.0005); age, human papillomavirus status, tumor grade, lymph node metastases did not correlate. Fifty-five of 292 patients recurred (18.83%): 18/94 (19.14%) MELF-positive, 37/198 (18.68%) MELF-negative. PFS in MELF-positive: 77.2% and 64.5% at 5 and 10 yr, respectively; PFS in MELF-negative: 82% and 68.5% at 5 and 10 yr, respectively. On multivariate analysis for PFS and other prognostic parameters, only LVI was statistically significant (P=0.001). OS in MELF-positive was 86% and 74.1% at 5 and 10 yr, respectively; OS in MELF-negative, was 89.7% and 86% at 5 and 10 yr, respectively. Median survival was worse in MELF-positive (199.8 mo) versus MELF-negative (226.1 mo); this was not statistically significant. On multivariate analysis for OS and other prognostic parameters, only tumor stage was statistically significant (P=0.002). In ECAs, MELF is not independently associated with survival. Pathologic characteristics of MELF-positive (size, LVI, Silva pattern) versus MELF-negative tumors differ significantly.