Pathological characterization and clinical outcome of penile intraepithelial neoplasia variants: a North American series.

Penile intraepithelial neoplasia (PeIN) is classified as human papillomavirus (HPV)- and non-HPV-related. This classification is associated with distinct morphologic subtypes. The natural history and prognosis of PeIN subtypes are not well known. This study aims to evaluate clinicopathological features, HPV status, and outcome of PeIN subtypes. Eighty-two lesions from 64 patients with isolated PeIN were retrospectively reviewed. Mean age was 59 years. Lesions were multicentric in 34% of patients and affected glans (33%), shaft (26%), and foreskin (20%). Histologically, 22% of patients had coexisting lesions, classified as hybrid and mixed. HPV-related PeIN (97%) included basaloid (59%), warty (8%), warty-basaloid (8%), hybrid (19%) and mixed (3%) types. P16 and HPV positivity occurred in 99% and 82% of lesions, respectively. HPV 16 was more common in basaloid PeIN. Multiple genotypes were detected in 35%, more commonly in hybrid PeIN (P = 0.051). Positive margins occurred in 63% of excisions. PeIN recurred in 48% of excisions and 30% of overall repeated procedures, and progression to invasive carcinoma occurred in 2%. At follow-up, 86% of patients had no evidence of disease and 12% were alive with disease. Lichen sclerosus occurred in non-HPV and HPV-related PeIN (100% and 47%).In conclusion, HPV-related and, more specifically basaloid PeIN were the predominant types and preferentially associated with HPV 16. While PeIN had a high recurrence rate, there was a slow and infrequent progression to invasive or metastatic carcinoma with multimodal treatments. Additional studies are needed to understand biology and natural history of PeIN.

Backpack health reduces data-sharing barriers between the medical community and individuals with rare diseases.

Technology has changed the way we approach medical care: health data is constantly being generated, medical discoveries are progressing more rapidly, and individuals are more connected across the world than ever before. Backpack Health is a global personal health record platform that harnesses the power of technology to connect users to their primary health data sources, the medical community, and researchers. By syncing with existing patient portals, health data can be stored on the Backpack Health platform and easily accessed and controlled by users in one connected interface. Individuals manage and collate their current and past conditions, genetic test results, symptoms, medications, procedures, labs, and other health data. Users are empowered to disseminate their information to clinicians, researchers, foundations, and pharmaceutical and biotechnology companies they connect with through the Backpack Health application. Here, we describe how two rare disease advocacy groups, The Marfan Foundation and Project Alive, utilize Backpack Health to connect with their target populations. Through secure transfer of pseudonymized data, groups can query their members to improve understanding of clinical features and to facilitate meaningful research. Responses to the groups' surveys show strong member engagement with high completion rates and increases in new Backpack Health users when surveys are deployed. Data from these surveys have been published and used to better inform clinical outcomes for treatment trials. By connecting users directly to the foundations, clinicians, researchers, and industry partners working on their condition, Backpack Health is instrumental in fast-tracking medical discoveries and treatment for rare diseases.

Therapy development for the mucopolysaccharidoses: Updated consensus recommendations for neuropsychological endpoints.

Neurological dysfunction represents a significant clinical component of many of the mucopolysaccharidoses (also known as MPS disorders). The accurate and consistent assessment of neuropsychological function is essential to gain a greater understanding of the precise natural history of these conditions and to design effective clinical trials to evaluate the impact of therapies on the brain. In 2017, an International MPS Consensus Panel published recommendations for best practice in the design and conduct of clinical studies investigating the effects of therapies on cognitive function and adaptive behavior in patients with neuronopathic mucopolysaccharidoses. Based on an International MPS Consensus Conference held in February 2020, this article provides updated consensus recommendations and expands the objectives to include approaches for assessing behavioral and social-emotional state, caregiver burden and quality of life in patients with all mucopolysaccharidoses.

Differences in immunohistochemistry utilization by general and breast subspecialty pathologists at a large academic institution.

OBJECTIVES: Immunohistochemistry (IHC) can be a useful adjunct in diagnostic breast pathology, but best practices have not been clearly established. We sought to compare the patterns of p63 utilization between general pathologists (GP) and subspecialized breast pathologists (BP), analyze diagnostic discrepancy rates, and identify types of lesions requiring immunohistochemistry. METHODS: The pathology database was searched over 6-year period to identify breast needle core biopsy cases utilizing p63 and subsequent excision results. RESULTS: P63 was ordered more frequently by BP (2.3% of cores) compared to GP (1.1% of cores, p = 0.0005). The most frequent utilization of p63 by GP for benign lesions (44.0%) followed by invasive carcinomas (36.0%) while BP most frequently ordered p63 on invasive carcinomas (49.5%) and DCIS (26.6%). CONCLUSIONS: While IHC use may be thought to be most helpful to those with less experience or knowledge in breast pathology, these results suggest that utilization is increased with subspecialty training.

Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure.

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here.

(R)evolution: toward a new paradigm of policy and patient advocacy for expanded access to experimental treatments.

In life-threatening conditions such as cancer and rare diseases, where there is no cure and no U.S. Food and Drug Administration (FDA)-approved therapy, patients sometimes seek access to an unapproved, experimental therapy through expanded access programs as their last, best hope for treatment to save their lives. Since the 1980s, the policies and the practice of expanded access have evolved, but a common challenge remains that there is no obligation, and often little incentive, for manufacturers to offer expanded access programs, especially for individual patients. In recent years, online campaigns seeking access to an experimental therapy have become more common, paralleling growth in and representing an intersection of social media, digital health, and patient advocacy.Mackey and Schoenfeld have examined the evolution of expanded access policy, practice, and trends, as well as case studies of online campaigns to access experimental therapies, to arrive at several recommendations for the future of expanded access. This commentary puts their paper in context, examines their recommendations, and suggests further reforms.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0568-8.

Neurocognitive clinical outcome assessments for inborn errors of metabolism and other rare conditions.

Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs.

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.

The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.

Cytology and LGBT+ health: establishing inclusive cancer screening programs.

There are substantial disparities in cancer screening for sexual minorities and gender non-conforming patients. In additional to patients having trauma due to negative experiences with the healthcare system, disparities may be heightened due to heteronormative and cisnormative design of screening programs and electronic medical record systems. Furthermore, there are morphologic challenges specific to certain specimen types from the LGBT + population, such as anal cytology samples, cervical cytology from transgender men taking testosterone, and neovaginal cytology samples. Men who have sex with men are at increased risk for anal cancer compared with the general population. While early detection of anal dysplasia decreases the risk of invasive carcinoma, screening programs are not widespread. Cervical cancer screening may be psychologically and physically challenging for transgender men and non-binary patients. The use of exogenous testosterone therapy causes atrophic changes in cervical cytology samples which mimic high-grade dysplasia. The rate of unsatisfactory samples are also increased in this population. Although HPV driven cancers have been reported in patients with neovaginas, there are currently no guidelines about appropriate screening for transgender women and intersex patients who have neovaginas. Cytopathologists can optimize the health of LGBT + patients in many ways including advocating for inclusive screening guidelines, validating self-collection for HPV and cytology samples, updating requisition forms to better capture the spectrum of gender expression, and recognizing the morphologic changes in cytology samples due to exogenous hormone use.

Diagnostic renal mass biopsy is associated with individual categories of PADUA and RENAL nephrometry scores: Analysis of diagnostic and concordance rates with surgical resection.

BACKGROUND: Renal mass biopsy (RMB) is a safe and accurate method for diagnosis and clinical management of renal masses. However, the non-diagnostic rate is a limiting factor. We tested the hypothesis that imaging characteristics and anatomic complexity of the mass may impact RMB diagnostic outcome using the preoperative aspects and dimensions used for an anatomical (PADUA) classification and radius-exophytic/endophytic-nearness-anterior/posterior-location (RENAL) score. MATERIAL AND METHODS: Single institution, retrospective study of 490 renal masses from 443 patients collected from 2001 to 2018. Outcome measurements include (1) diagnostic and concordance rates amongst RMB types and RMB with surgical resection specimens; (2) association between diagnostic RMB and anatomical complexity of renal masses. The analysis was conducted in unselected masses and small renal masses (SRMs). RESULTS: RMB was performed by fine needle aspiration (FNA), core needle biopsy (CNB), or both (FNA+CNB). Non-diagnostic rate was significantly higher for FNA compared to CNB and FNA+CNB in both unselected and SRMs. Subset analysis in the FNA+CNB group showed similar diagnostic rates for FNA and CNB. In unselected masses, specificity for FNA, CNB, and FNA+CNB was 100%. Sensitivity was higher for CNB (90.1%, P = 0.002) and FNA+CNB (96.3%, P = 0.004) compared to FNA (66.7%). For unselected masses, endophytic growth predicted a non-diagnostic CNB. R.E.N.A.L location entirely between the polar lines (central) and entirely above the upper polar line predicted a diagnostic CNB. Sonography-guidance predicted a diagnostic FNA. For SRMs, non-diagnostic CNB was associated with endophytic growth, while diagnostic CNB was associated with renal sinus invasion and operator experience. More cystic masses were sampled by FNA, but diagnostic results were similar for FNA and CNB. CONCLUSIONS: Endophytic growth consistently predicted a non-diagnostic CNB in unselected and SRMs, whereas sonography-guidance predicted a diagnostic FNA. Cystic masses could be adequately sampled by FNA.

Toileting Abilities Survey as a surrogate outcome measure for cognitive function: Findings from neuronopathic mucopolysaccharidosis II patients treated with idursulfase and intrathecal idursulfase.

An outcome measure of toileting skills, the Toileting Abilities Survey or TAS, with sensitivity to detect change in a neurodegenerative disorder such as MPS II, was developed. The TAS was used in a research study of patients (n = 86) with the neuronopathic form of MPS II to measure treatment benefit of intrathecal idursulfase. Treatment with idursulfase and intrathecal idursulfase is associated with significantly higher individual and overall toileting skills versus treatment with idursulfase alone.

Cooperative interaction of Zhangfei and ATF4 in transactivation of the cyclic AMP response element.

Zhangfei (ZF) is a basic region-leucine zipper protein that has been implicated in herpesvirus infection cycle and related cellular processes. Here we show both in vivo and in vitro data demonstrating that ZF is a novel cellular binding partner of activating transcription factor 4 (ATF4) (or CREB2). We found that ZF competed with ATF4 to form ATF4-ZF heterodimeric complexes through the bZIP regions. ZF enhanced ATF4 binding to the cAMP response element (CRE), and augmented activation of a CRE reporter by ATF4, in response to MEK1 activation. These results suggest an important role of ZF in the MEK1-ATF4 signaling pathway.

Identification and characterization of the DNA-binding properties of a Zhangfei homologue in Japanese pufferfish, Takifugu rubripes.

Zhangfei is a basic region-leucine zipper (bZIP) transcription factor identified through its interaction with a herpesvirus-related host cell factor HCF1 (C1). Unlike most bZIP proteins, the mammalian Zhangfei protein does not bind DNA as homodimers. It is believed due to the absence of an asparagine residue in the basic region, which forms the DNA-recognition motif, NxxAAxxCR, in all bZIP proteins. Here, we report the identification and characterization of a novel Zhangfei homologue in Takifugu rubripes, which has an intact DNA-recognition motif by sequence analysis. We found that the pufferfish Zhangfei (pZF) appeared to have all the functional domains known in human Zhangfei, including the conserved HCF1-binding motif; however, pZF did not appear to bind DNA either. These findings suggest that the distinct property of the Zhangfei basic region is conserved during the evolution of vertebrates and that Zhangfei requires interaction with other proteins to regulate transcription from target promoters.

Luman is capable of binding and activating transcription from the unfolded protein response element.

Luman (or LZIP, CREB3) is a transcription factor with an endoplasmic reticulum (ER)-transmembrane domain. Due to its structural similarities with ATF6, it is thought that Luman might also be involved in cellular stress responses. Here we report that Luman can bind and activate transcription from the consensus unfolded protein response element (UPRE). Mutations that disrupted the binding of Luman to the UPREs impaired its ability to activate transcription from these sites. Overexpression of Luman stimulated transcription of EDEM, a downstream effector of the mammalian unfolded protein response involved in ER-associated degradation (ERAD). Unlike ATF6, however, Luman was not activated by proteolytic cleavage in response to endoplasmic reticulum stressors such as tunicamycin and thapsigargin. These results suggest that the activation of ERAD by Luman is likely through a pathway different from the common ER stress response, and that additional factor(s) are required for the activation of this Luman-mediated pathway.