Allostatic Load Markers as Predictors of Melanoma Outcomes

https://openworks.mdanderson.org/sumexp23/1046/thumbnail.jp

Monocyte/macrophage and T-cell infiltrates in peritoneum of patients with ovarian cancer or benign pelvic disease

BACKGROUND: We previously showed that tumor-free peritoneum of patients with epithelial ovarian cancer (EOC) exhibited enhanced expression of several inflammatory response genes compared to peritoneum of benign disease. Here, we examined peritoneal inflammatory cell patterns to determine their concordance with selected enhanced genes. METHODS: Expression patterns of selected inflammatory genes were mined from our previously published data base. Bilateral pelvic peritoneal and subjacent stromal specimens were obtained from 20 women with EOC and 7 women with benign pelvic conditions. Sections were first stained by indirect immunoperoxidase and numbers of monocytes/macrophages (MO/MA), T cells, B cells, and NK cells counted. Proportions of CD68+ cells and CD3+ cells that coexpressed MO/MA differentiation factors (CD163, CCR1, CXCR8, VCAM1, and phosphorylated cytosolic phospholipase A(2 )[pcPLA(2)]), which had demonstrated expression in EOC peritoneal samples, were determined by multicolor immunofluorescence. RESULTS: MO/MA were present on both sides of the pelvic peritoneum in EOC patients, with infiltration of the subjacent stroma and mesothelium. CD68+ MO/MA, the most commonly represented population, and CD3+ T cells were present more often in EOC than in benign pelvic tumors. NK cells, B cells, and granulocytes were rare. CXCL8 (IL-8) and the chemokine receptor CCR1 were coexpressed more frequently on MO/MA than on CD3+ cells contrasting with CD68+/CD163+ cells that coexpressed CXCL8 less often. An important activated enzyme in the eicosanoid pathway, pcPLA(2), was highly expressed on both CD68+ and CD163+ cells. The adherence molecule Vascular Cell Adhesion Molecule-1 (VCAM1) was expressed on CD31+ endothelial cells and on a proportion of CD68+ MO/MA but rarely on CD3+ cells. CONCLUSION: The pelvic peritoneum in EOC exhibits a general pattern of chronic inflammation, represented primarily by differentiated MO/MA, and distinct from that in benign conditions concordant with previous profiling results

Patterns of Cardiac Perfusion Abnormalities After Chemoradiotherapy in Patients with Lung Cancer

Objective:We evaluated the prevalence of myocardial perfusion defects using myocardial perfusion imaging (MPI) after chemoradiation or radiation therapy (CRT/RT) in lung cancer patients and described their patterns in relation to tumor location.Methods:MPI in 44 patients who received RT for lung cancer and 44 control patients were compared. The two groups were comparable in risk factors for coronary artery disease. Data regarding tumor stage and location, interval between CRT/RT and MPI, and mean radiation dose to the heart was collected. The level of radiation delivered to the affected segments of the left ventricle versus the normal segments was compared using the isodose lines on the simulation computed tomography.Results:Considering all tumor locations, 8 patients (18%) demonstrated MPI defects after CRT/RT versus 9 (20%) in the controls. However, 7 of 18 patients (39%) with centrally located tumors in the CRT/RT group versus only 1 of 15 patients (7%) in the control group demonstrated MPI defect (p= 0.04). The defects in the CRT/RT group were in the anterior and septal segments while the defects were in different segments in the controls. The median interval between end of RT and MPI was 12.3 months. The affected segments in the CRT/RT group received a mean radiation dose of 39.6 versus 11.4 Gy (p = 0.003) to the normal segments.Conclusions:CRT/RT to centrally located lung tumors tends to cause anterior/septal MPI defects. Abnormal MPI segments in the CRT/RT group have received significantly higher radiation than normal segments

Distant Metastases From Childhood Differentiated Thyroid Carcinoma:Clinical Course and Mutational Landscape

Context: Distant metastases (DM) from childhood differentiated thyroid carcinoma (DTC) are uncommon and published studies are limited. Objective: This work aimed to describe the outcomes of patients with DM from childhood DTC and to evaluate the molecular landscape of these tumors. Methods: A retrospective study was conducted at a tertiary cancer center including patients with pediatric DTC (diagnosed at age Results: We identified 148 patients; 144 (97%) had papillary thyroid carcinoma (PTC) and 104 (70%) were female. Median age at DTC diagnosis was 13.4 years (interquartile range [IQR], 9.9-15.9 years). Evaluable individuals received a median of 2 (IQR, 1-3) radioactive iodine (RAI) treatments at a median cumulative administered activity of 238.0 mCi (IQR, 147.5-351.0 mCi). The oncogenic driver was determined in 64 of 69 PTC samples: RET fusion (38/64; 59%), NTRK1/3 fusions (18/64; 28%), and the BRAF V600E mutation (8/64; 13%). At last evaluation, 93% had persistent disease. The median overall and disease-specific survival after DTC diagnosis were 50.7 and 52.8 years, respectively. Eight (5%) PTC patients died of disease after a median of 30.7 years (IQR, 20.6-37.6 years). Conclusion: Childhood DTC with DM persists in most patients despite multiple courses of RAI, but disease-specific death is uncommon, typically occurring decades after diagnosis. Fusion genes are highly prevalent in PTC, and all identified molecular alterations have appropriate targeted therapies. Future studies should focus on expanding genotype-phenotype correlations, determining how to integrate molecularly targeted therapy into treatment paradigms, and relying less on repeated courses of RAI to achieve cure in patients with DM from childhood DTC

Challenges and Learning Opportunities of Pre-Registration Physiotherapy Placements in First Contact Settings: The Perspectives of Musculoskeletal First Contact Physiotherapists

Objectives: As musculoskeletal first contact physiotherapy is rolled out into primary healthcare in Britain, this could offer up new practice-based educational opportunities for pre-registration physiotherapy students. Thus, the present study sought to explore the perceived challenges and learning opportunities of pre-registration physiotherapy placements in musculoskeletal first contact physiotherapy settings from first contact physiotherapists’ perspectives. Methods: Using a qualitative strategy, 15 musculoskeletal first contact physiotherapists from different geographical locations in Britain, participated in telephone mediated semi-structured interviews. Participants were self-selected through a Chartered Society of Physiotherapy fortnightly bulletin and online forum for first contact physiotherapists, or recruited via snowball sampling. Interview transcripts were analysed according to framework analysis - and the findings were member-checked by proxy. Results: Three core themes emerged: operational challenges, challenges for preregistration physiotherapy students and learning opportunities for pre-registration physiotherapy students. Operational challenges included: ensuring sufficient support from first contact physiotherapy practice educators; financial cost implications of placements, and; lack of capacity within the existing first contact physiotherapy workforce to provide placements. Challenges for physiotherapy students involved: time pressures and stressors of a first contact physiotherapy placement; identifying red flags, and; complexity of patient presentations. Identified learning opportunities for physiotherapy students were: experience of a specialised physiotherapy role in a primary healthcare setting; bringing awareness of first contact physiotherapy as a potential career pathway, and; experience multidisciplinary team working in primary care. Conclusions: By seeking the perspectives of first contact physiotherapists, this study provides the first step for the development of placements in an emerging practice area

Cytokines, GM-CSF and IFNγ administered by priming and post-chemotherapy cycling in recurrent ovarian cancer patients receiving carboplatin

BACKGROUND: Monocyte/macrophages (MO/MA), a polymorphic population of innate immune cells, have the potential to mediate antitumor effects, and may also contribute to protumor effects. A priming and post-chemotherapy schedule of the myeloid cell mobilizing and immune stimulatory growth factor, granulocyte monocyte stimulating factor (GM-CSF, Leukine(®)) and the MO/MA activating cytokine recombinant interferon gamma 1b (rIFN-γ1b, Actimmune(®)) has been developed. The pre- and post-chemotherapy design is based upon known in vivo kinetics and immune modulatory effects of these molecules. Carboplatin (Paraplatin(®)) was selected as the cornerstone of treatment of epithelial ovarian cancer (EOC). METHODS: We studied hematopoietic and immunologic effects of GM-CSF and rIFN-γ1b before and after carboplatin in patients with recurrent EOC. Potentially chemotherapy-sensitive patients with recurrent measurable tumors received subcutaneous GM-CSF (starting at 400 μg/day) for 7 days plus subcutaneous rIFN-γ1b (100 μg) on days 5 and 7, before and after intravenous carboplatin (area under the curve of 5). We performed standard hematologic assessment and monitored monocyte (MO), dendritic cell, major cell subset counts, and antibody-dependent cell-mediated cytotoxicity (ADCC) against a Her2neu(+ )tumor cell line, as well as selected plasma inflammatory cytokine, chemokine and growth factor levels. RESULTS: Our analysis comprised only the first 3 months of treatment in the initial 25 patients. Relative to pretreatment baseline values, white blood cell, neutrophil, MO, and eosinophil counts increased (P ≤ .001 for each); the proportion of platelets increased 9 days after the second (P ≤ .002) and third (P ≤ .04) carboplatin treatments; and the number of cells in the activated MO subsets CD14+HLA-DR+, CD14+CD64+, and CD14(+)CXCR3(+ )increased (P ≤ .04 for each); plasma levels of the proangiogenic interleukins 1α, 6, and 8 were lower (P ≤ .03 for each); M-CSF, a product of activated MO/MA, was increased on day 9 (P = .007); and GM-CSF was increased in plasma after GM-CSF administration (P ≤ .04). Quality of life measurements were reduced during the GM-CSF/IFN-γ1b cycle while recovering at pre-chemotherapy baseline for FACT-G scores only. CONCLUSION: A novel regimen of GM-CSF plus IFN-γ1b administered to 25 EOC patients receiving carboplatin increased myeloid cells, platelets and total activated MO populations during the initial 3 months; however, ADCC responses were not consistently enhanced during this period

In situ functional dissection of RNA cis-regulatory elements by multiplex CRISPR-Cas9 genome engineering.

RNA regulatory elements (RREs) are an important yet relatively under-explored facet of gene regulation. Deciphering the prevalence and functional impact of this post-transcriptional control layer requires technologies for disrupting RREs without perturbing cellular homeostasis. Here we describe genome-engineering based evaluation of RNA regulatory element activity (GenERA), a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 platform for in situ high-content functional analysis of RREs. We use GenERA to survey the entire regulatory landscape of a 3'UTR, and apply it in a multiplex fashion to analyse combinatorial interactions between sets of miRNA response elements (MREs), providing strong evidence for cooperative activity. We also employ this technology to probe the functionality of an entire MRE network under cellular homeostasis, and show that high-resolution analysis of the GenERA dataset can be used to extract functional features of MREs. This study provides a genome editing-based multiplex strategy for direct functional interrogation of RNA cis-regulatory elements in a native cellular environment