GLI1-induced mammary gland tumours are transplantable and maintain major molecular features

Increased expression of GLI1, the main Hedgehog signalling pathway effector, is related to unfavourable prognosis and progressive disease of certain breast cancer subtypes. We used conditional transgenic mice induced to overexpress GLI1 in the mammary epithelium either alone or in combination with deletion of one Trp53 allele to address the role of elevated GLI1 expression in breast tumour initiation and progression. Induced GLI1 expression facilitates mammary gland tumour formation and this was further increased upon heterozygous deletion of Trp53. The GLI1-induced primary tumours were of different murine molecular subtypes, including Normal-like^Ex, Class8^Ex, Claudin-Low^Ex and Erbb2-like^Ex. The gene expression profiles of some of the tumours correlated well with the PAM50 subtypes for human breast cancer. Whole-exome sequencing revealed somatic mutation profiles with only little overlap between the primary tumours. Orthotopically serially transplanted GLI1-induced tumours maintained the main morphological characteristics of the primary tumours for ≥10 generations. Independent of Trp53 status and molecular subtype, the serially transplanted GLI1-induced tumours were able to grow both in the absence of transgenic GLI1 expression and in the presence of the GLI1 inhibitor GANT61. These data suggest that elevated GLI1 expression has a determinant role in tumour initiation; however, additional genetic events are required for tumour progression.     

Patient-reported burden of intensified surveillance and surgery in high-risk individuals under pancreatic cancer surveillance

Familial Cancer - In high-risk individuals participating in a pancreatic cancer surveillance program, worrisome features warrant for intensified surveillance or, occasionally, surgery. Our...     

Epstein Barr virus associated smooth muscle tumors in the central nervous system: a case report and systematic review of the literature

Purpose

Epstein Barr virus (EBV)-associated smooth muscle tumors (SMT) in the central nervous system are rare tumors. EBV-associated SMT mainly occur in patient with compromised immune status. We report on a case of a HIV positive patient, who developed multiple EBV-SMTs, intracranially and in the spine. We systematically review the literature on the topic.

Case report

A 46 years old female with HIV was imaged for complaints of headaches for 2 years, when an intracranial lesion was found. The patient was followed with sequential MRI scans before an excision was performed 5 years later. Pathology revealed an EBV-associated SMT. Multiple other lesions appearing in the brain and in the spine over years were treated by stereotactic radiosurgery or by surgery. At the time of this report, the patient is alive under HARRT treatment without recurrence.

Methods

A systematic PRISMA guided literature research was conducted on the topic reviewing multiple databases for EBV-associated SMT located in brain or spine. We identified 52 patients from the literature and performed a pooled analysis.

Results

All patients in this cohort except one were immuno-suppressed from HIV, post-transplant therapy or because of CIS. Female predominance and a median age of 35 years was identified as was frequent multifocality. Therapeutic strategies varied but were mostly multidisciplinary with surgery.

Conclusion

Based on our results, EBV-associated SMT should be included in the differential diagnosis of intracranial lesions mimicking meningiomas in immuno-suppressed patients. Stereotactic radiosurgery can be offered as an alternate treatment option for suitable lesions. Long-term surveillance via MRI scanning is recommended for follow up.

     

Functional and cognitive rehabilitation interventions during intensive care admission: A protocol for a systematic integrative review

Background

Long-term cognitive impairment occurs in up to 60% of intensive care unit (ICU) survivors. Early use of functional and cognitive rehabilitation interventions, while patients are still in ICU, may reduce cognitive decline. We aim to describe the functional and cognitive interventions used during the ICU stay, the healthcare professionals providing interventions, and the potential impact on functional and cognitive rehabilitation.

Method

In this integrative systematic review, we will include empirical qualitative, quantitative, mixed- and multiple-methods studies assessing the use of functional and cognitive rehabilitation provided in ICU. We will identify studies in relevant electronic databases from 2012 to 2022, which will be screened for eligibility by at least two reviewers. Literature reported as narrative reviews and editorials will be excluded. We will assess the impact of interventions evaluating a cognitive and functional function, quality of life, and all-cause mortality at 6–12 months after ICU discharge. The Revised Cochrane risk-of-bias Tool will be used for assessing risk of bias in clinical trials. For observational studies, we will use the National Institutes of Health Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. Furthermore, we will use the critical appraisal skills programme for qualitative studies and the mixed methods appraisal tool for mixed methods studies. We will construct four matrices, including results describing which ICU patients and healthcare professionals were engaged in rehabilitation, which interventions were included in early rehabilitation in ICU, the potential impact on patient outcomes of rehabilitation interventions provided in ICU and a narrative synthesis of themes. A summary of the main results will be reported using modified GRADE methodology.

Impact

This integrative review will inform the feasibility randomised clinical trial testing the development of a complex intervention targeting functional and cognitive rehabilitation for patients in ICU.