Somatostatin receptor 2 (SSTR2) has been shown to be expressed in a subset of neuroendocrine tumors and carcinomas and plays a role in imaging studies and guiding therapy. Patients with tumors ...expressing SSTR2 may be successfully treated with somatostatin inhibitors or radiolabeled somatostatin analogues. We studied SSTR2 expression in TET and correlated it with 68Ga-DOTATATE PET/CT or 68Ga-DOTATATE PET/MR results and treatment outcome. An institutional database of TET was searched for thymoma, thymic carcinoma, and thymic neuroendocrine tumor (TNET) with available resection specimens. Cases were subtyped (2021 WHO classification) and staged (8
AJCC/UICC staging). A section was stained with anti-SSTR2 antibody (clone UMB1). Percent tumor cells with membranous staining was recorded if present in ≥1% of tumor cells. Medical records were searched for 68Ga-DOTATATE PET scans and treatment. Statistical analysis was performed. Eighty patients (1969-2021) with a median age of 61.3 years (range, 19.1-87.3) (37 males, 46.3%) had thymic carcinoma (N=33), TNET (N=7), or thymoma (N=40). SSTR2 expression was identified in 29 (of 80, 36.3%) TET including 2/2 (100%) small cell carcinomas, 2/5 (40.0%) atypical carcinoid tumors, 16/23 (69.6%) squamous cell carcinomas, 2/2 (100%) lymphoepithelial carcinomas, 1/1 (100%) adenosquamous carcinoma, and 6/40 (15.0%) thymomas. SSTR2 expression in ≥50% of tumor cells (vs 1-49%) was associated with younger age (p=0.023) and shorter recurrence/metastasis-free survival (p=0.007). 68Ga-DOTATATE PET scans (N=9) revealed a Krenning score of 3 in patients with atypical carcinoid tumor, small cell carcinoma, and squamous cell carcinoma (N=1 each) with SSTR2 expression in 95, 100, and 5% of tumor cells, respectively. Scans with Krenning scores of ≤2 (N=5) were seen in tumors with no SSTR2 expression in 80% of cases and a single atypical carcinoid tumor with SSTR2 expression in 10% of tumor cells. One scan resulted as "increased uptake" was in a patient with no SSTR2 expression. In conclusion, 68Ga-DOTATATE PET scans correlated with SSTR2 expression in TET in most patients and appeared to be useful to identify patients with TET who may be amenable to treatment with somatostatin analogues. Larger studies including more patients with 68Ga-DOTATATE PET scans are necessary to independently and prospectively validate our findings.
Introduction
Reductions in HIV acquisition have slowed, and the global community is significantly off track from global goals. Oral pre‐exposure prophylaxis (PrEP) alone cannot address the diverse ...needs of the millions of people at risk of HIV acquisition. Long‐acting injectable cabotegravir (CAB‐LA) received United States Food and Drug Administration approval for HIV prevention in December 2021. When studied, CAB‐LA demonstrated high effectiveness, provides months of protection versus daily use, is preferred by some users and has the potential to achieve commodity cost reduction. These factors position CAB‐LA to catalyse transformation in HIV prevention. Significant work must be undertaken to ensure at‐scale uptake in low‐ and middle‐income countries. Leveraging decades of product introduction experience, Clinton Health Access Initiative (CHAI) has developed an innovative roadmap to support equitable CAB‐LA introduction, comprising tightly executed market‐shaping, product development, regulatory, and programmatic and implementation action.
Discussion
Proven models exist (e.g. long‐acting reversible contraceptives, paediatric tuberculosis treatment and antiretrovirals (ARVs), such as paediatric dolutegravir and tenofovir disoproxil fumarate, lamivudine, and dolutegravir) for partnership‐driven, accelerated, impactful product introduction. Based on learnings from these models and needs in the prevention space, CHAI developed a roadmap to maximize the near‐term impact of CAB‐LA and accelerate the development of, access to and impact of quality‐assured, low‐cost generic CAB‐LA. This roadmap is intended to inform introduction planning and investment decision‐making across a range of stakeholders, including donors, governments, manufacturers and other partners working in the HIV prevention space. Elements include (1) ensuring coordination and alignment across partners, and avoiding redundancy experienced during oral PrEP introduction; (2) preparing national programmes and providing support to maximize impact, including the development of national policies, guidelines and introduction plans; system strengthening; quantification and procurement; and addressing evidence needs, among other areas; (3) supporting community engagement, ensuring that demand generation and delivery approaches are person‐centred and community‐led; (4) incentivizing generic product development through, for example, milestone‐based commercialization incentives and product development cost‐sharing; and (5) expediting regulatory reviews.
Conclusions
Accelerating access to affordable, generic CAB‐LA can transform progress towards HIV epidemic control. This vision of impact at scale in prevention is achievable, if informed by results‐backed approaches to introduction.
Graft-versus-host disease (GVHD) remains a major complication for patients who have undergone hematopoietic stem cell transplantation. The Lerner system is the most widely used histologic grading ...score for gastrointestinal GVHD but its clinic utility is debated. The aim of our study was to develop a novel histologic grading system for gastrointestinal GVHD that incorporates independent evaluation of both apoptotic counts and crypt destruction. Colonic biopsies taken to assess for GVHD were retrospectively assessed for: Crypt damage (No crypt dropout or ulceration–0; crypt dropout without ulceration–1; ulceration–2) and crypt apoptotic counts (No apoptosis–0; 1–6 apoptotic bodies per 10 contiguous crypts–1; >6apoptotic bodies per 10 contiguous crypts–2). The two scores were added together to get an overall grade (0–4). Alternative apoptotic cutoff points were examined. An apoptotic cutoff of >9 apoptotic bodies per 10 contiguous crypts marginally improved the area under the curve (AUC), but the AUCs from the resulting novel grade calculations were not significantly different (p = 0.10). Lerner grading was also applied. The study group consisted of an initial analysis cohort (n = 191) and a second validation cohort from a separate institution (n = 97). In the initial analysis cohort, our histologic grading system provided prognostic stratification for GVHD-related death within 6 months (p = 0.0004, AUC = 0.705). The Lerner system performed similarly in terms of providing prognostic stratification for GVHD-related death (p = 0.0001, AUC = 0.707). In the external validation cohort, our histologic grading system was not associated with GVHD-related death (p = 0.14, AUC = 0.621), but the Lerner system was associated with GVHD-related death (p = 0.048, AUC = 0.663). While our grading system may have some advantages compared to the Lerner system, due to lack of reproducibility we do not currently recommend widespread adoption of this system. Nonetheless, we present a standardized tool for assessing both apoptosis and crypt damage. Future studies assessing alternative histologic grading systems with external validation and further examination the lower apoptotic threshold for GVHD diagnosis are warranted.
Perihilar cholangiocarcinoma (pCCA) has a dismal prognosis. Protocols incorporating chemotherapy, radiotherapy, and liver transplantation (LT) have emerged as curative options for unresectable tumors ...with 70% 5-year survival rates. We aimed to assess the value of extent of residual tumor (ERT) and other pathologic factors following chemoradiation in predicting outcome; 152 liver explants with pCCA treated with neoadjuvant chemoradiation and LT between 1993 and 2013 were reviewed for ERT, pathologic stage, histologic grade, and perineural and lymphovascular invasion. ERT was quantified as the percentage of viable carcinoma in the tumor bed. Tumors were classified into 4 ERT categories(1) complete/near-complete response (≤1% ERT); (2) marked response (>1 to <10% ERT); (3) moderate response (10 to <30% ERT); and (4) minimal response (≥30% ERT). Overall 5-year survival rate was 69%. 5-year disease-free estimate was 74%. 57%, 16%, 18%, and 9% of explants were placed in ERT categories 1, 2, 3, and 4, respectively. ERT correlated significantly with the overall 5-year survival rate and 5-year, disease-free estimate by univariate (P<0.0001) and multivariate analysis (P=0.004 and 0.009, respectively). By multivariate analysis, pathologic stage was also an independent predictor of recurrence (P=0.003). Other variables that correlated with risk of death and recurrence by univariate analysis included perineural (P<0.0001) and lymphovascular invasion (P<0.0001), absence of primary sclerosing cholangitis (P=0.006 and P<0.0001, respectively), and pretreatment CA19-9 level (P=0.001 and 0.02, respectively). Histologic grade did not predict outcome. In summary, ERT independently predicts outcome in pCCA patients following neoadjuvant chemoradiation and LT and can stratify patient prognosis.
Reticulin stain is used routinely in the histological evaluation of hepatocellular carcinoma (HCC). The goal of this study was to assess whether the histological reticulin proportionate area (RPA) in ...HCCs predicts tumour-related outcomes.
We developed and validated a supervised artificial intelligence (AI) model that utilises a cloud-based, deep-learning AI platform (Aiforia Technologies, Helsinki, Finland) to specifically recognise and quantify the reticulin framework in normal livers and HCCs using routine reticulin staining. We applied this reticulin AI model to a cohort of consecutive HCC cases from patients undergoing curative resection between 2005 and 2015. A total of 101 HCC resections were included (median age = 68 years, 64 males, median follow-up time = 49.9 months). AI model RPA reduction of > 50% (compared to normal liver tissue) was predictive of metastasis hazard ratio (HR) = 3.76, P = 0.004, disease-free survival (DFS, HR = 2.48, P < 0.001) and overall survival (OS), HR = 2.80, P = 0.001. In a Cox regression model, which included clinical and pathological variables, RPA decrease was an independent predictor of DFS and OS and the only independent predictor of metastasis. Similar results were found in the moderately differentiated HCC subgroup (WHO grade 2), in which reticulin quantitative analysis was an independent predictor of metastasis, DFS and OS.
Our data indicate that decreased RPA is a strong predictor of various HCC-related outcomes, including within the moderately differentiated subgroup. Reticulin, therefore, may represent a novel and important prognostic HCC marker, to be further explored and validated.
Background
African Americans (AAs) and other racial/ethnic minority groups continue to be underrepresented in medical research and clinical trials. Failure to create more racially diverse research ...cohorts can exacerbate existing health disparities among these groups.
Objective
To investigate best practices and strategies for enhancing participation of AAs in medical research among attendees of a preconference Institute at a faith-based public health conference.
Design
Qualitative study using semi-structured interviews.
Participants
A total of 21 out of 29 attendees (90% AA) of the Institute (72% response rate).
Approach
A culturally tailored preconference Institute was held at the 2017 Healthy Churches 2020 National Conference. The Institute was led by AA researchers focused on underrepresentation of AAs in medical research. Semi-structured interviews were conducted 1-year post-Institute (
n
=21) and were audio-recorded, transcribed verbatim, and reviewed using thematic analysis.
Key Results
The majority of attendees reported that they were more likely to participate in medical research after attending the Institute (75%). Salient learning points reported by attendees demonstrated attainment of the Institute objectives. Key themes emerged describing barriers preventing AAs from participating in medical research including fear/lack of trust, lack of information on research projects, and not being approached to participate. Key themes regarding facilitators for participation in medical research by AAs were clear communication of study objectives and research benefits along with trust in researchers.
Conclusions
Attendees’ perceptions of participation in medical research were largely positive following their attendance at a conference-based Institute aimed to address the underrepresentation of AAs in medical research. Our culturally tailored approach to disseminating knowledge of the research process could extend to other national conferences prioritizing AAs and other racial/ethnic minority populations to improve research participation.
Summary Background Antibodies have been implicated in the pathogenicity of multiple sclerosis by findings of immunoglobulins in patients' CSF and often IgG and complement in lesions, and by a 2012 ...report that nearly half of patients' serum samples contain IgG specific for a glial potassium-channel, KIR4.1. We aimed to establish the frequency of KIR4.1-binding IgG in serum and CSF of patients with multiple sclerosis, and whether KIR4.1 immunoreactivity is retained or lost in demyelinating lesions. Methods Using ELISA with a KIR4.1 peptide, we tested archival serum from 229 population-based and 57 clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, and CSF from 25 patients with multiple sclerosis and 22 disease controls. We tested all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1, using cell-based immunofluorescence and immunoprecipitation (solubilised recombinant human KIR4.1). We assessed KIR4.1 immunoreactivity in archival brain samples from 15 patients with histopathologically confirmed multiple sclerosis (22 plaques eight early active, eight inactive, and six remyelinated, 13 periplaque regions and eight normal-appearing white-matter and grey-matter regions) and from three controls with non-neurological diseases. Findings Three of 286 serum samples from patients with multiple sclerosis and two of 208 serum samples from controls showed KIR4.1 reactivity on ELISA; none of the CSF samples from patients or controls showed KIR4.1 reactivity. IgG in none of the 50 serum samples from clinic-based patients immunoprecipitated KIR4.1, but a commercial KIR4.1-specific control IgG did. By immunofluorescence, one of 50 serum samples from patients with multiple sclerosis yielded faint plasmalemmal staining on both KIR4.1-expressing and non-expressing cells; 16 bound faintly to intracellular components. In all cases, IgG binding was quenched by absorption with liver powder or lysates from non-transfected cells. Binding by the KIR4.1-specific control IgG was quenched only by lysates containing KIR4.1. IgG in none of the 25 CSF samples from patients with multiple sclerosis bound to KIR4.1-transfected cells. Glial KIR4.1 immunoreactivity was increased relative to expression in healthy control brain in all active demyelinating lesions, remyelinated lesions, and periplaque white matter regions. Interpretation We did not detect KIR4.1-specific IgG in serum or CSF from patients with multiple sclerosis or KIR4.1 loss from glia in multiple sclerosis lesions. Serological testing for KIR4.1-specific IgG is unlikely to aid diagnosis of multiple sclerosis. The target antigen of multiple sclerosis remains elusive. Funding The National Institutes of Health, the National Multiple Sclerosis Society, and the Mayo Clinic Robert and Arlene Kogod Center on Aging.
Meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) are considered to be distinct entities in the WHO Classification of CNS Tumours (2007). They harbor NAB2-STAT6 fusions similar to ...their soft tissue counterparts, supporting the view that they are part of a tumor continuum. We examined 30 meningeal-based tumors originally diagnosed as either SFT or HPC. These showed a spectrum of morphologic features and were diagnosed as SFTs, malignant SFTs, HPCs, or tumors with “intermediate” features. All of the tumors showed nuclear expression of STAT6. SFTs consistently expressed diffuse CD34, while HPCs and intermediate tumors had heterogeneous staining. NAB2-STAT6 fusions were identified in 20 cases, including 7 with exon 4-exon 3, 9 with exon 6-exon 17, and 4 with exon 6-exon 18 fusions. NAB2 exon 4-STAT6 exon 3 fusion correlated with classic SFT morphology and older age and showed a trend toward less mitotic activity; there was also a trend toward more aggressive behavior in tumors lacking NAB2 exon 4-STAT6 exon 3. Thus, despite their clinical and morphologic differences, meningeal-based SFTs, HPCs, and tumors with intermediate features, similar to their soft tissue counterparts, form a histopathologic spectrum unified by STAT6 immunoexpression and NAB2-STAT6 fusion.
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