From Image to Diagnosis: Characterizing Sources of Error in Histopathologic Interpretation.

An accurate histopathologic diagnosis on surgical biopsy material is necessary for the clinical management of patients and has important implications for research, clinical trial design/enrollment, and public health education. This study used a mixed methods approach to isolate sources of diagnostic error while residents and attending pathologists interpreted digitized breast biopsy slides. Ninety participants, including pathology residents and attending physicians at major United States medical centers reviewed a set of 14 digitized whole-slide images of breast biopsies. Each case had a consensus-defined diagnosis and critical region of interest (cROI) representing the most significant pathology on the slide. Participants were asked to view unmarked digitized slides, draw their participant region of interest (pROI), describe its features, and render a diagnosis. Participants' review behavior was tracked using case viewer software and an eye-tracking device. Diagnostic accuracy was calculated in comparison to the consensus diagnosis. We measured the frequency of errors emerging during 4 interpretive phases: (1) detecting the cROI, (2) recognizing its relevance, (3) using the correct terminology to describe findings in the pROI, and (4) making a diagnostic decision. According to eye-tracking data, trainees and attending pathologists were very likely (∼94% of the time) to find the cROI when inspecting a slide. However, trainees were less likely to consider the cROI relevant to their diagnosis. Pathology trainees (41% of cases) were more likely to use incorrect terminology to describe pROI features than attending pathologists (21% of cases). Failure to accurately describe features was the only factor strongly associated with an incorrect diagnosis. Identifying where errors emerge in the interpretive and/or descriptive process and working on building organ-specific feature recognition and verbal fluency in describing those features are critical steps for achieving competency in diagnostic decision making.

Searching for a Potential Algorithm for Clostridium difficile Testing at a Tertiary Care Hospital: Does Toxin Enzyme Immunoassay Testing Help?

Clostridium difficile is a major contributor to morbidity and mortality in the United States. Methods for identifying the organism in stool include molecular platforms, enzyme immunoassays (EIAs) for toxin, and culture. Controversy persists over whether molecular tests are too sensitive at identifying C. difficile, and there are questions about how additional laboratory information could inform clinical management and reduce over treatment. The aim of this study was to assess whether clinical factors are related to the toxin status of patients and whether information about toxin status could potentially inform clinical management of patients. A total of 201 PCR-positive C. difficile stool samples from adult patients at our institution underwent EIA toxin testing. Clinical and laboratory data were collected, and the percentage of PCR-positive/EIA-positive (PCR+/EIA+) patients and PCR+ and EIA-negative (PCR+/EIA-) patients was calculated. Of the 201 samples, 47% were EIA positive and 53% were EIA negative. Although PCR+/EIA+ patients were more likely to have had a prior C. difficile infection (P = 0.015), there was no statistical difference between the additional data collected that correlated with a positive EIA result. We were unable to show that patients with an EIA+ result had worse clinical parameters than those with EIA- results and concluded that establishing a testing algorithm that included both PCR and EIA testing would not change the clinical management of patients at our hospital.

Electroconvulsive Therapy Considerations for Transgendered Patients.

As the transgender patient population continues to grow, health care providers will need to become aware of elements unique to the transgender community in order to provide the highest quality of care. Neuromuscular blockade with succinylcholine is routinely administered to patients undergoing electroconvulsive therapy (ECT). Decreased amounts or activity of pseudocholinesterase in serum can lead to prolonged duration of muscle paralysis. Causes of reduced action by pseudocholinesterase include genetically abnormal enzymes, reduced hepatic production, pregnancy, and various drug interactions. Estrogen supplementation taken by transitioning patients may affect the duration of neuromuscular blockade.This is a case of a 32-year-old male-to-female transgender patient with prolonged apnea following ECT treatment for severe, refractory depression. Further investigation revealed the patient was on estrogen therapy as a part of her transition and laboratory testing demonstrated reduced serum pseudocholinesterase activity. Further laboratory testing demonstrated reduced serum pseudocholinesterase activity. Succinylcholine dosing was titrated to an appropriate level to avoid prolonged apnea in subsequent ECT treatments. Physicians and other health care providers are faced with a unique population in the transgender community and must be aware of distinctive circumstances when providing care to this group. Of specific interest, many transitioning and transitioned patients can be on chronic estrogen supplementation. Neuromuscular blockade in those patients require attention from the anesthesiology care team as estrogen compounds may decrease pseudocholinesterase levels and lead to prolonged muscle paralysis from succinylcholine.

Disseminated cutaneous Curvularia infection in an immunocompromised host; diagnostic challenges and experience with voriconazole.

An increasing spectrum and number of opportunistic fungal pathogens have been reported to cause disease in humans over the past decade. Disseminated phaeohyphomycoses caused by rare dematiaceous molds in immunocompromised patients have a high mortality rate and are increasingly reported in the literature. Early diagnosis of disseminated phaehyphomycosis is critical especially in neutropenic patients but can be hindered by the low sensitivity of fungal blood cultures and low clinical suspicion. Cutaneous manifestations are often the earliest sign of disease and conducting a thorough skin exam in febrile neutropenic patients can lead to more rapid diagnosis and initiation of treatment. PCR amplification and sequencing of mold RNA extracted from paraffin-embedded tissue can be useful for diagnosing rare fungal infections when negative fungal cultures preclude morphologic diagnosis. Effective treatment for disseminated phaehyphomycosis is lacking and there is a need to report experiences with the use of newer antifungals.

California Cannabis Research Briefing, April 2023: Meeting Summary.

On April 28, 2023, the University of California Office of the President, in partnership with the California Department of Cannabis Control (DCC), hosted the California Cannabis Research Briefing. The California Cannabis Research Briefing brought together researchers and state agencies/policymakers to discuss pertinent policy issues on cannabis within the state. Researchers across six different topic areas (environment, cannabis markets, social equity matters, public health, medicinal cannabis use, and public safety) provided brief explanations of their research and its policy implications. A moderated discussion with stakeholders followed these presentations. The goals of this event were to highlight research that can inform policy issues relevant to the state, and to discuss how research can be incorporated into the cannabis policy landscape.

Neurodegeneration Markers in the Cerebrospinal Fluid of 100 Patients with Schizophrenia Spectrum Disorder.

BACKGROUND: Schizophrenia spectrum disorders (SSD) can be associated with neurodegenerative processes causing disruption of neuronal, synaptic, or axonal integrity. Some previous studies have reported alterations of neurodegenerative markers (such as amyloid beta [Aß], tau, or neurofilaments) in patients with SSD. However, the current state of research remains inconclusive. Therefore, the rationale of this study was to investigate established neurodegenerative markers in the cerebrospinal fluid (CSF) of a large group of patients with SSD. STUDY DESIGN: Measurements of Aß1-40, Aß1-42, phospho- and total-tau in addition to neurofilament light (NFL), medium (NFM), and heavy (NFH) chains were performed in the CSF of 100 patients with SSD (60 F, 40 M; age 33.7 ± 12.0) and 39 controls with idiopathic intracranial hypertension (33 F, 6 M; age 34.6 ± 12.0) using enzyme-linked immunoassays. STUDY RESULTS: The NFM levels were significantly increased in SSD patients (P = .009), whereas phospho-tau levels were lower in comparison to the control group (P = .018). No other significant differences in total-tau, beta-amyloid-quotient (Aß1-42/Aß1-40), NFL, and NFH were identified. CONCLUSIONS: The findings argue against a general tauopathy or amyloid pathology in patients with SSD. However, high levels of NFM, which has been linked to regulatory functions in dopaminergic neurotransmission, were associated with SSD. Therefore, NFM could be a promising candidate for further research on SSD.

Pathologic Evaluation of Lymph Nodes in Breast Cancer: Contemporary Approaches and Clinical Implications.

The presence of detected metastases in locoregional lymph nodes of women with breast cancer is an important prognostic variable for cancer staging, prognosis, and treatment planning. Systematic and standardized lymph node evaluation with gross and microscopic protocols designed to detect all macrometastases larger than 2.0 mm is the appropriate objective based on clinical outcomes evidence. Pathologists will detect smaller micrometastases and isolated tumor cell clusters (ITCs) by random chance but will also leave similar sized metastases undetected in paraffin blocks. Although these smaller metastases have prognostic significance, they are not predictive of recurrence for chemotherapy naïve patients. Thus, protocols to reliably detect metastases smaller than 2.0 mm are not required or recommended by guidelines. Women with T1-T2 breast cancer with a clinically negative axilla but with 1 or 2 pathologically positive sentinel nodes now have alternative options including observation and axillary irradiation and do not require completion axillary dissection.

A Decision 85 Years in the Making.

On October 6, 2022, President Biden announced that he is taking steps to pardon those convicted of simple marijuana possession at the federal level and reconsider the classification of cannabis as a Schedule I substance. At the same time, Congress is working to pass legislation to streamline research in the cannabis space. These efforts signal that federal marijuana laws that have been in place for the past 85 years have created a multitude of problems, including barriers to research, and the federal government is finally considering decisions to create change.

University of California Cannabis Research Workshop, May 2021: Meeting Summary.

This meeting report describes the University of California's (UC) Cannabis Research Workshop on May 26-27, 2021, which was organized by the UC Office of the President (UCOP) in partnership with the University of California, Davis (UCD). The event was designed to explore ways to strengthen research collaborations within and between campuses, discuss federal and state regulations and scientific priorities, and provide updates on current or recent cannabis and cannabinoid research studies. Topical areas were highlighted in four breakout sessions, including: 1) agronomy and environmental impacts; 2) biomedicine and public health; 3) economics, law, public policy, and social science; and 4) administrative considerations for supporting university research on cannabis and cannabinoids.

Antibody indices of infectious pathogens from serum and cerebrospinal fluid in patients with schizophrenia spectrum disorders.

INTRODUCTION: Infectious and immunological theories of schizophrenia have been discussed for over a century. Contradictory results for infectious agents in association with schizophrenia spectrum disorders (SSDs) were reported. The rationale of this study was to investigate intrathecal antibody synthesis of the most frequently discussed neurotropic pathogens using a pathogen-specific antibody index (AI) in patients with SSD in comparison to controls. METHODS: In 100 patients with SSD and 39 mentally healthy controls with idiopathic intracranial hypertension (IIH), antibodies against the herpesviruses EBV, CMV, and HSV 1/2 as well as the protozoan Toxoplasma gondii, were measured in paired cerebrospinal fluid (CSF) and serum samples with ELISA-kits. From these antibody concentrations the pathogen-specific AIs were determined with the assumption of intrathecal antibody synthesis at values > 1.5. RESULTS: No significant difference was detected in the number of SSD patients with elevated pathogen-specific AI compared to the control group. In a subgroup analysis, a significantly higher EBV AI was observed in the group of patients with chronic SSD compared to patients with first-time SSD diagnosis (p = 0.003). In addition, two identified outlier EBV patients showed evidence for polyspecific immune reactions (with more than one increased AI). CONCLUSIONS: Evidence for the role of intrathecal EBV antibody synthesis was found in patients with chronic SSD compared to those first diagnosed. Apart from a possible infectious factor in SSD pathophysiology, the evidence for polyspecific immune response in outlier patients may also suggest the involvement of further immunological processes in a small subgroup of SSD patients.

Δ8-THC: Legal Status, Widespread Availability, and Safety Concerns.

Delta-8-tetrahydrocannabinol (Δ8-THC) is chemically and functionally similar to delta-9-tetrahydrocannabinol (Δ9-THC) (the primary psychoactive cannabinoid in the cannabis plant) and is currently widely available "over-the-counter" across the United States due to unregulated sales. However, these products have a questionable legal status based on current U.S. laws, as Δ8-THC is considered a Schedule I drug by the federal Drug Enforcement Administration (DEA). Despite this designation, Δ8-THC products (e.g., gummies, edibles, oils, and vapes) are largely unregulated and are sold in gas stations, online, and other marketplaces (most often outside of authorized dispensaries) and are marketed as legal hemp products. This problem arises from a purposeful misinterpretation of the 2018 Farm Bill, which some interpret as legalization of non-Δ9-THC cannabinoids (notably, Δ8-THC). The widespread availability of Δ8-THC products has not been without health consequences. The lack of regulation means that there are no required warning labels or packaging protections in place and no mandated laboratory analysis to assure label accuracy or product purity. As Δ8-THC produces physiological and toxicological effects that are similar to Δ9-THC, high-dose exposure of Δ8-THC (e.g., consuming a full bag of Δ8-THC gummies) has resulted in recent reports of medical emergencies, including calls to poison control centers and presentations to emergency departments, with some pediatric patients arriving unconscious and unresponsive. Several states and regulatory agencies have called for legislation to regulate Δ8-THC, but little progress has occurred nationally thus far.

University of California Cannabis Research Workshop May 2019 Meeting Summary.

On May 30, 2019, the University of California Office of the President, in partnership with University of California, Irvine, hosted a daylong University of California Cannabis Research Workshop designed to explore ways to advance research collaborations on a range of relevant topics, develop a common understanding of the current regulatory framework for conducting cannabis-related research, and formulate next steps for facilitating synergistic cannabis research. This report provides a summary of that meeting.

Small-cell transformation of ALK-rearranged non-small-cell adenocarcinoma of the lung.

Anaplastic lymphoma kinase (ALK) gene rearrangements are present in ∼5% of non-small-cell lung cancers (NSCLCs). These rearrangements occur because of a chromosomal inversion within the short arm of Chromosome 2, which results in the formation of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion oncogene. Whereas NSCLC transformation to SCLC is a rare phenomenon described in epidermal growth factor receptor (EGFR) mutant cancers primarily after treatment with targeted therapy, it is exceedingly rare in ALK-rearranged adenocarcinomas. It is currently unclear what the therapeutic significance of the rearrangement is in this transformed tumor as there is a paucity of medical literature describing follow-up care and outcomes of patients in this rare scenario. We describe a unique case in which a patient with ALK-rearranged adenocarcinoma underwent small-cell transformation at a metastatic site with retained ALK rearrangement and was provided clinical follow-up after treatment with second-generation tyrosine kinase inhibiter (TKI) therapy.

Comprehensive Validation of Cytology Specimens for Next-Generation Sequencing and Clinical Practice Experience.

Biopsy specimens are subjected to an expanding portfolio of assays that regularly include mutation profiling via next-generation sequencing (NGS). Specimens derived via fine-needle aspiration, a common biopsy technique, are subjected to a variety of cytopreparatory methods compared with surgical biopsies that are almost uniformly processed as formalin-fixed, paraffin-embedded tissue. Therefore, the fine-needle aspiration-derived specimens most commonly accepted for molecular analysis are cell blocks (CBs), because they are processed most similarly to surgical biopsy tissue. However, CB preparations are fraught with challenges that risk unsuccessful sequencing and repeat biopsies, with the potential to further increase health care costs and delay clinical care. The diversity of cytopreparations and the resource-intensive clinical validation of NGS pose significant challenges to more consistent use of non-CB (NCB) cytology specimens. As part of clinical validation of a targeted NGS assay, DNA subjected to nine cytopreparatory methods was evaluated for sequencing performance and was shown to be uniformly acceptable for clinical NGS. Of the 379 clinical cases analyzed after validation, the majority (56%) were derived from NCB cytology specimens. This specimen class had the lowest DNA insufficiency rate (1.5%) and showed equivalent sequencing performance to surgical and CB formalin-fixed, paraffin-embedded tissue. NCB cytology specimens are valuable sources of tumor nucleic acid and are the preferred specimen type for clinical NGS at our institution.

Use of an Additional 19-G EBUS-TBNA Needle Increases the Diagnostic Yield of EBUS-TBNA.

BACKGROUND: Although endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has an excellent diagnostic yield, there remain cases where the diagnosis is not obtained. We hypothesized that additional sampling with a 19-G EBUS-TBNA needle may increase diagnostic yield in a subset of cases where additional tissue sampling was required. METHODS: Indications for use of the 19-G needle following 22-G sampling with rapid on-site cytologic examination were: (1) diagnostic uncertainty of the on-site cytopathologist (eg, nondiagnostic, probable lymphoma, etc.), (2) non-small cell lung cancer with probable need for molecular genetic and/or PD-L1 testing, or (3) need for a larger tissue sample for consideration of inclusion in a research protocol. RESULTS: A 19-G EBUS-TBNA needle was utilized following standard sampling with a 22-G needle in 48 patients (50 sites) during the same procedure. Although the diagnostic yield between the needles was equivalent, the concordance rate was only 83%. The 19-G determined a diagnosis in 4 additional patients (8%) and provided additional histopathologic information in 6 other cases (12%). Conversely, in 3 cases (6%) diagnostic information was provided only by the 22-G needle. Compared with 22-G EBUS-TBNA alone, sampling with both the 22- and 19-G EBUS needles resulted in an increase in diagnostic yield from 92% to 99% (P=0.045) and a number needed to sample of 13 patients to provide one additional diagnosis. There were no significant complications. CONCLUSION: In select cases where additional tissue may be needed, sampling with a 19-G EBUS needle following standard aspiration with a 22-G needle results in an increase in diagnostic yield.