Summary
Donation after circulatory death (DCD) has become an accepted practice in many countries and remains a focus of intense interest in the transplant community. The present study is aimed at ...providing a description of the current situation of DCD in European countries. Specific questionnaires were developed to compile information on DCD practices, activities and post‐transplant outcomes. Thirty‐five countries completed the survey. DCD is practiced in 18 countries: eight have both controlled DCD (cDCD) and uncontrolled DCD (uDCD) programs, 4 only cDCD and 6 only uDCD. All these countries have legally binding and/or nonbinding texts to regulate the practice of DCD. The no‐touch period ranges from 5 to 30 min. There are variations in ante and post mortem interventions used for the practice of cDCD. During 2008–2016, the highest DCD activity was described in the United Kingdom, Spain, Russia, the Netherlands, Belgium and France. Data on post‐transplant outcomes of patients who receive DCD donor kidneys show better results with grafts obtained from cDCD versus uDCD donors. In conclusion, DCD is becoming increasingly accepted and performed in Europe, importantly contributing to the number of organs available and providing acceptable post‐transplantation outcomes.
Vaccination against amyloid β-peptide (Aβ) has been shown to be successful in reducing Aβ burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although Aβ immunization did ...not show T cell infiltrates in the brain of these mice, an Aβ vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of Aβ-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong Aβ-specific T cell response is critically dependent on the immunizing T cell epitope and that epitopes differ depending on MHC genetic background. Moreover, we show that a single immunization with the dominant T cell epitope Aβ10-24 induced transient meningoencephalitis only in amyloid precursor protein (APP)-transgenic (Tg) mice expressing limited amounts of IFN-γ under an myelin basic protein (MBP) promoter. Furthermore, immune infiltrates were targeted primarily to sites of Aβ plaques in the brain and were associated with clearance of Aβ. Immune infiltrates were not targeted to the spinal cord, consistent with what was observed in AD patients vaccinated with Aβ. Using primary cultures of microglia, we show that IFN-γ enhanced clearance of Aβ, microglia, and T cell motility, and microglia-T cell immunological synapse formation. Our study demonstrates that limited expression of IFN-γ in the brain, as observed during normal brain aging, is essential to promote T cell-mediated immune infiltrates after Aβ immunization and provides a model to investigate both the beneficial and detrimental effects of Aβ-specific T cells.
Despite lack of adequate, validated, independently performed clinical studies, several molecular tests are commercially available on the market and are being used on indeterminate thyroid nodules to ...guide patient-care decisions.
We summarize the current evidence on the role and limitations of molecular tests used in combination with thyroid cytopathology to refine the presurgical diagnosis of thyroid nodules.
The clinical performance of molecular tests depends on the pretest risk of malignancy within the specific cytological group being assessed. This risk is variable and should be assessed at each institution to optimize the selection of the molecular test and the interpretation of its results. Next-generation sequencing has increased the sensitivity of oncogene panels while maintaining high specificity. Tests assessing the gene expression pattern have shown promising results, with high sensitivity but low specificity. The impacts of molecular markers on clinical practice remains in flux and their effect on health care costs remains poorly understood.
Further large, independent, confirmatory, clinical validation studies and real-world, cost-effectiveness studies are necessary before the widespread adoption of these tests can be endorsed as standard of care.
Preclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms the tumor microenvironment. We ...recently reported data from the dose escalation part of a phase I study of VT1021 in solid tumors. Here, we report findings from the dose expansion phase of the same study.
We analyzed the safety and tolerability, clinical response, and biomarker profile of VT1021 in the expansion portion of the phase I study (NCT03364400). Safety/tolerability is determined by adverse events related to the treatment. Clinical response is determined by RECIST v1.1 and iRECIST. Biomarkers are measured by multiplexed ion beam imaging and enzyme-linked immunoassay (ELISA).
First, we report the safety and tolerability data as the primary outcome of this study. Adverse events (AE) suspected to be related to the study treatment (RTEAEs) are mostly grade 1-2. There are no grade 4 or 5 adverse events. VT1021 is safe and well tolerated in patients with solid tumors in this study. We report clinical responses as a secondary efficacy outcome. VT1021 demonstrates promising single-agent clinical activity in recurrent GBM (rGBM) in this study. Among 22 patients with rGBM, the overall disease control rate (DCR) is 45% (95% confidence interval, 0.24-0.67). Finally, we report the exploratory outcomes of this study. We show the clinical confirmation of TSP-1 induction and TME remodeling by VT1021. Our biomarker analysis identifies several plasmatic cytokines as potential biomarkers for future clinical studies.
VT1021 is safe and well-tolerated in patients with solid tumors in a phase I expansion study. VT1021 has advanced to a phase II/III clinical study in glioblastoma (NCT03970447).
Alzheimer's disease is a dementia that involves progressive deposition of amyloid β-protein (Aβ) in brain regions important for memory and cognition, followed by secondary inflammation that ...contributes to the neuropathologic process. Immunization with Aβ can reduce cerebral Aβ burden and consequent neuropathologic changes in the brains of mice transgenic for the β-amyloid precursor protein (APP). We found that transgenic expression of human APP in B6SJL mice, under the prion promoter, results in immune hyporesponsiveness to human Aβ, in terms of both antibody and cellular immune responses. The decreased antibody responses were related not to B cell tolerance but rather to the inability of Aβ-specific T cells to provide help for antibody production. The immune hyporesponsiveness could be overcome if T cell help was provided by coupling an Aβ B cell epitope to BSA. Our results suggest that expression of APP in transgenic mice is associated with an Aβ-specific impaired adaptive immune response that may contribute to the neuropathology. Moreover, humans with life-long elevation of brain and peripheral Aβ (e.g., patients with presenilin mutations or Down syndrome) could have reduced immune responses to Aβ vaccination.
New technologies for molecular analysis are increasing our ability to diagnose cancer.
Several molecular analysis technologies are reviewed and their use in the clinical laboratory is discussed.
...Select key technologies, including polymerase chain reaction and next-generation sequencing, are helping transform our ability to analyze cancer specimens. As these technological advances become more and more incorporated into routine diagnostic testing, our classification systems are likely to be impacted and our approach to treatment transformed. The routine use of such technology also brings challenges for analysis and reimbursement.
These advances in technology will change the way we diagnose, monitor, and treat patients with cancer.
Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is a newly identified oncofetal mRNA-binding protein that is involved in embryogenesis and carcinogenesis of some malignant neoplasms. To ...investigate the diagnostic and clinicopathologic significance of this protein in endometrial carcinomas, we evaluated immunohistochemical expression of IMP3 in the two most common forms of endometrial malignancies, endometrioid adenocarcinoma and serous carcinoma. We selected 167 endometrial adenocarcinoma cases including 122 cases of endometrioid adenocarcinoma and 45 cases of serous carcinoma. Twenty samples of benign endometrium obtained from 20 patients with nonmalignant uterine lesions were used as controls. Positive immunohistochemical stain for IMP3 was identified in all serous carcinoma cases, among which, 39 (86%) and 3 (7%) cases showed IMP3 immunoreactivity in >50%, and 21-50, or 6-20% of tumor cells, respectively. Immunohistochemical reaction intensity for IMP3 was identified to be strong in 38 (84%) and intermediate in 7 (16%) cases of serous carcinoma. Fifty-four (44%) cases of endometrioid adenocarcinoma were negative for IMP3. Thirty (25%), 20 (16%), 10 (8%), and 8 (7%) cases of endometrioid adenocarcinoma demonstrated positive immunoreactivity for IMP3 in 1-5, 6-20, 21-50, and >50% of the tumor cells. Strong IMP3-staining intensity was noted in 34 (28%), intermediate in 26 (21%), and weak in 8 (7%) cases of endometrioid adenocarcinoma. All 20 control cases were negative for IMP3. To compare p53 with IMP3 expressions, we found that 35 (78%) of the serous carcinoma cases showed strong p53 immunohistochemical activity in >50% of the tumor cell nuclei. In contrast, 11 of 112 (10%) endometrioid adenocarcinoma cases demonstrated strong p53 positivity in >50% of the tumor cell nuclei. In conclusion, our findings demonstrate significant expression of IMP3 in serous carcinoma as compared to endometrioid adenocarcinoma (P<0.0001). Expression of IMP3 and p53 may be helpful biomarkers in the distinction of endometrial serous carcinoma from endometrioid adenocarcinoma. In addition, expression of IMP3 in endometrioid adenocarcinoma correlates with higher nuclear and architecture grades of the tumor (P=0.0000 and P=0.0002, respectively).
Abstract
Inflammatory bowel disease (IBD) is characterized symptomatically by chronic inflammation in the colonic tract. Despite the increased understanding of the physiological symptoms of Crohn’s ...Disease, and IBD in general, there have been no significant breakthroughs in understanding its etiology or improving treatment. As such, there is an urgent need for efficacious therapies that are aimed specifically at preventing or curing IBD. Bolstering the need for better therapies is the fact that patients with IBD have increased risk of developing intestinal cancers. One of the pathological traits of IBD that heightens the risk of cancer is the increased level of angiogenesis that accompanies the inflammation. As the biological processes of angiogenesis and inflammation are intricately linked, we believe increasing the levels of thrombospondin-1 (TSP-1), an anti-angiogenic and anti-inflammatory protein, can reprogram immune and inflammatory cells to inhibit angiogenesis and induce the resolution of inflammation.
Vigeo has developed VT1021 which stimulates the expression of TSP-1 in inflammatory myeloid derived suppressor cells (MDSCs) systemically. VT1021 achieved proof of concept in a Phase 1/2 clinical trial with multiple cohorts and is currently in Phase 2/3 trials for oncology indications. IBD patients have increased MDSCs in both lesions and peripheral blood. MDSCs are genomically stable and not mutated in IBD patients and thus represent ideal therapeutic targets. Two dextran sulfate sodium (DSS)-induced colitis models were used to evaluate the pre-clinical efficacy of VT1021. In the preventative model, mice were treated with 4% DSS from Day 0 to Day 6 and either saline or VT1021 from Day 0 to Day 8, then sacrificed on Day 8 to collect colon tissue and plasma samples. In the rescue model, mice were treated with 4% DSS from Day 0 to Day 4, then treated with either saline, VT1021 (25, 50, 100 mg/kg) or anti-TNFa from Day 5 to Day 10. Mice were sacrificed on Day 11; colon tissue and plasma samples were collected. In both models, VT1021 treatment significantly prevented the mouse weight loss and bloody stool compared to the saline treatment. VT1021 treatment also decreased the colon inflammation by the measurement of both plasma myeloperoxidase (MPO) level and colon tissue histopathology score. Immunohistochemistry staining of colon tissue samples confirmed that VT1021 treatment stimulated TSP-1 expression in the MDSCs.
Altogether, these findings show that VT1021 treatment has equivalent efficacy to anti-TNFa treatment, while significantly reducing damage to colon tissue. We believe VT1021 will show significantly greater efficacy in patients with longer term use, while avoiding the systemic deleterious side effects common to current approved therapies.
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