Optimizing the Diagnosis and Biomarker Testing for Patients with Intrahepatic Cholangiocarcinoma: A Multidisciplinary Approach

Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review.

Geographical Distribution and Pattern of Pesticides in Danish Drinking Water 2002–2018: Reducing Data Complexity

Pesticides are a large and heterogenous group of chemicals with a complex geographic distribution in the environment. The purpose of this study was to explore the geographic distribution of pesticides in Danish drinking water and identify potential patterns in the grouping of pesticides. Our data included 899,169 analyses of 167 pesticides and metabolites, of which 55 were identified above the detection limit. Pesticide patterns were defined by (1) pesticide groups based on chemical structure and pesticide–metabolite relations and (2) an exploratory factor analysis identifying underlying patterns of related pesticides within waterworks. The geographic distribution was evaluated by mapping the pesticide categories for groups and factor components, namely those detected, quantified, above quality standards, and not analysed. We identified five and seven factor components for the periods 2002–2011 and 2012–2018, respectively. In total, 16 pesticide groups were identified, of which six were representative in space and time with regards to the number of waterworks and analyses, namely benzothiazinone, benzonitriles, organophosphates, phenoxy herbicides, triazines, and triazinones. Pesticide mapping identified areas where multiple pesticides were detected, indicating areas with a higher pesticide burden. The results contribute to a better understanding of the pesticide pattern in Danish drinking water and may contribute to exposure assessments for future epidemiological studies.

Gene-Based Therapeutics for Inherited Retinal Diseases

Inherited retinal diseases (IRDs) are a heterogenous group of orphan eye diseases that typically result from monogenic mutations and are considered attractive targets for gene-based therapeutics. Following the approval of an IRD gene replacement therapy for Leber’s congenital amaurosis due to RPE65 mutations, there has been an intensive international research effort to identify the optimal gene therapy approaches for a range of IRDs and many are now undergoing clinical trials. In this review we explore therapeutic challenges posed by IRDs and review current and future approaches that may be applicable to different subsets of IRD mutations. Emphasis is placed on five distinct approaches to gene-based therapy that have potential to treat the full spectrum of IRDs: 1) gene replacement using adeno-associated virus (AAV) and nonviral delivery vectors, 2) genome editing via the CRISPR/Cas9 system, 3) RNA editing by endogenous and exogenous ADAR, 4) mRNA targeting with antisense oligonucleotides for gene knockdown and splicing modification, and 5) optogenetic approaches that aim to replace the function of native retinal photoreceptors by engineering other retinal cell types to become capable of phototransduction.

The observee’s paradox

Ego-documents are at the heart of historical sociolinguistics. Contrary to what a label such as ego-document may suggest, Early and Late Modern ego-documents constitute a heterogenous group of genres comprising, among others, private letters, diaries and travel journals. Empirical studies have shown that there are important linguistic differences between private letters on the one hand, and diaries/journals on the other. The latter often seem surprisingly standard-like or formal. Theoretical models of register variation and conceptual orality can partially explain the differences, without however offering a full explanation of the surprising formality of diaries/journals. We argue that it is crucial to take into account recent work by social historians concerning diaries/journals in the eighteenth and nineteenth centuries. Diary-writing was an inherently reflexive practice allowing authors to reflect on their lives, and to create a textually fixed point of reference. Authors of diaries had a variable and multilayered audience in mind of known and unknown readers. We introduce the observee’s paradox: while creating private texts for themselves in which they were their own observers and observees, authors of diaries also reckoned with unknown readers in a possibly distant future, which prompted them to shift into a more formal or standard-like register.

Discussion of Issues Related to Score Use and Interpretation of First Spoken and Signed Language Assessments

A standardized assessment of spoken languages will collect data from native, monolingual speakers, thus establishing the range of receptive and/or expressive abilities of children across different ages. Similarly, normative data for standardized assessments of signed language are established by collecting data from native signing deaf children. Where the difference arises is the way in which the normative data relate to the target populations and the individuals within those populations who are being assessed. While standardized assessments of spoken language are normed on and predominantly intended for use with native speakers of that language, standardized assessments of signed language are intrinsically designed for use with a heterogenous group of children, of whom only a minority have the opportunity of learning signed language as their native language. In this chapter, key items related to score use and interpretation in first language (L1) assessment that were presented in Chapters 2.1 and 2.2 will be jointly discussed by the authors.

Clinicopathological Characteristics of Ocular Surface Squamous Neoplasia: A 10-Year Review form a Referral Tertiary Centre in Nigeria

Background: Ocular surface squamous neoplasia is a heterogenous group of proliferative squamous lesions on the ocular surface with varying biologic behaviours. This study aims to report the clinical profile and pathologic characteristics of cases of OSSN seen at a tertiary referral centre in North West NigeriaMethods: A retrospective review of all cases of OSSN diagnosed over a 10-year period was doneResults: OSSN accounted for 68 out of 91 ocular surface lesions affecting twice as many males as females and a peak incidence in the 30-39 years age group. They frequently presented as higher grade and higher stage lesions with invasive squamous cell carcinoma being the most frequently diagnosed OSSN. They also frequently show association with HIV infection and a relatively long duration of symptoms before presentationConclusion: OSSN occur in a relatively young age group in our environment. Certain clinical and epidemiological features appear to [predict the occurrence of higher grade lesions and this may help in the clinical prediction of likely pathologic grade and/or biologic behaviour of these lesions.

FSHB Genotype Identified as a Relevant Diagnostic Parameter Revealed by Cluster Analysis of Men With Idiopathic Infertility

Introduction and ObjectivesAbout 30-75% of infertile men are diagnosed with idiopathic infertility, thereby lacking major causative factors to explain their impaired fertility status. In this study, we used a large cohort of idiopathic infertile men to determine whether subgroups could be identified by an unbiased clustering approach and whether underlying etiologic factors could be delineated.Patients and MethodsFrom our in-house database Androbase®, we retrospectively selected patients (from 2008 to 2018) with idiopathic male infertility (azoo- to normozoospermia) who fit the following selection criteria: FSH ≥ 1 IU/l, testosterone ≥ 8 nmol/l, ejaculate volume ≥ 1.5 ml. Patients with genetic abnormalities or partners with female factors were excluded.For the identified study population (n=2742), we used common andrologic features (somatic, semen and hormonal parameters, including the FSHB c.-211G>T (rs10835638) single nucleotide polymorphism) for subsequent analyses. Cluster analyses were performed for the entire study population and for two sub-cohorts, which were separated by total sperm count (TSC) thresholds: Cohort A (TSC ≥ 1 mill/ejac; n=2422) and Cohort B (TSC < 1 mill/ejac; n=320). For clustering, the partitioning around medoids method was employed, and the quality was evaluated by average silhouette width.ResultsThe applied cluster approach for the whole study population yielded two separate clusters, which showed significantly different distributions in bi-testicular volume, FSH and FSHB genotype. Cluster 1 contained all men homozygous for G (wildtype) in FSHB c.-211G>T (100%), while Cluster 2 contained most patients carrying a T allele (>96.6%). In the analyses of sub-cohorts A/B, two clusters each were formed too. Again, the strongest segregation markers between the respective clusters were bi-testicular volume, FSH and FSHB c.-211G>T.ConclusionWith this first unbiased approach for revealing putative subgroups within a heterogenous group of idiopathic infertile men, we did indeed identify distinct patient clusters. Surprisingly, across all diverse phenotypes of infertility, the strongest segregation markers were FSHB c.-211G>T, FSH, and bi-testicular volume. Further, Cohorts A and B were significantly separated by FSHB genotype (wildtype vs. T-allele carriers), which supports the notion of a contributing genetic factor. Consequently, FSHB genotyping should be implemented as diagnostic routine in patients with idiopathic infertility.

Cardiac Amyloidosis: A Review of Current Imaging Techniques

Systemic amyloidosis is a rare, heterogenous group of diseases characterized by extracellular infiltration and deposition of amyloid fibrils. Cardiac amyloidosis (CA) occurs when these fibrils deposit within the myocardium. Untreated, this inevitably leads to progressive heart failure and fatality. Historically, treatment has remained supportive, however, there are now targeted disease-modifying therapeutics available to patients with CA. Advances in echocardiography, cardiac magnetic resonance (CMR) and repurposed bone scintigraphy have led to a surge in diagnoses of CA and diagnosis at an earlier stage of the disease natural history. CMR has inherent advantages in tissue characterization which has allowed us to better understand the pathological disease process behind CA. Combined with specialist assessment and repurposed bone scintigraphy, diagnosis of CA can be made without the need for invasive histology in a significant proportion of patients. With existing targeted therapeutics, and novel agents being developed, understanding these imaging modalities is crucial to achieving early diagnosis for patients with CA. This will allow for early treatment intervention, accurate monitoring of disease course over time, and thereby improve the length and quality of life of patients with a disease that historically had an extremely poor prognosis. In this review, we discuss key radiological features of CA, focusing on the two most common types; immunoglobulin light chain (AL) and transthyretin (ATTR) CA. We highlight recent advances in imaging techniques particularly in respect of their clinical application and utility in diagnosis of CA as well as for tracking disease change over time.

Tumor Microenvironment of Lymphomas and Plasma Cell Neoplasms: Broad Overview and Impact on Evaluation for Immune Based Therapies

Lymphomas and plasma cell neoplasms are a heterogenous group of malignancies derived from lymphocytes. They are a significant cause of patient morbidity and mortality. Advances in morphologic, immunophenotypic and molecular techniques have led to better understanding of the pathogenesis and diagnosis of these neoplasms. Advances in treatment, particularly immune-based therapies, increasingly allow for targeted therapies of these diseases. Mechanistic studies using animal models and clinical trials have revealed the importance of the tumor microenvironment on disease pathogenesis, progression, and response to therapy in these malignancies. Simultaneous progress in diagnostic techniques has made it feasible to generate high-resolution, high-throughput data from the tumor microenvironment with spatial context. As the armamentarium of targeted therapies and diagnostic techniques grows, there is potential to harness these advances to better stratify patients for targeted therapies, including immune-based therapies, in hematologic malignancies.

An Overview of Intracranial Ependymomas in Adults

Ependymomas are rare primary central nervous system tumors. They can form anywhere along the neuraxis, but in adults, these tumors predominantly occur in the spine and less frequently intracranially. Ependymal tumors represent a heterogenous group of gliomas, and the WHO 2016 classification is based essentially on a grading system, with ependymomas classified as grade I, II (classic), or III (anaplastic). In adults, surgery is the primary initial treatment, while radiotherapy is employed as an adjuvant treatment in some cases of grade II and in all cases of anaplastic ependymoma; chemotherapy is reserved for recurrent cases. In recent years, important and interesting advances in the molecular characterization of ependymomas have been made, allowing for the identification of nine molecular subgroups of ependymal tumors and moving toward subgroup-specific patients with improved risk stratification for treatment-decisions and future prospective trials. New targeted agents or immunotherapies for ependymoma patients are being explored for recurrent disease. This review summarizes recent molecular advances in the diagnosis and treatment of intracranial ependymomas including surgery, radiation therapy and systemic therapies.