Cancer metastasis is a key event in tumor progression associated not only with mortality but also significant morbidity. Metastatic disease can promote end-organ dysfunction and even failure through mass effect compression of various vital organs including the spinal cord. In such cases, prompt medical attention is needed to restore neurological function, relieve pain, and prevent permanent damage. The three therapeutic approaches to managing metastatic spinal cord compression include corticosteroids, surgery, and radiation therapy. Although each may improve patients' symptoms, their combination has yielded the best outcome. In cancer patients with clinical suspicion of spinal cord compression, dexamethasone should be initiated followed by surgical decompression, when possible, and radiation. The latter becomes the preferred treatment in patients with inoperable disease.
Background: Lung cancer is the leading cause of cancer mortality. Studies have demonstrated that high macrophage density correlated with high microvessicle density and poor patient prognosis. Tumor associated macrophage are believed to predominantly possess an alternatively activated phenotype (M2). Hallmarks of this population include pro-angiogenesis, wound repair and extracellular matrix degradation. We investigated the role macrophage play in lung cancer migration. Methods: Human lung cancer lines A549, H1299, H1792, H1975 & H1650 were used. Murine bone marrow differentiated macrophages were stimulated with IFN-γ or IL-4 to achieve classically activated (M1) and M2 populations. Conditioned media (24 h) was collected and used in migration assays. Migration was assessed using BD 24 well FluoroBlok cell culture inserts. Results: qRT-PCR showed that stimulated M1 had a 344 fold increase (p<0.01) of iNos and stimulated M2 had a 39 fold increase (p<0.01) in Arg-1. Migration increased 20% (p<0.01) in A549 cells when cultured in M2 conditioned media. However, when macrophage and lung cancer cells were co-culture, migration of H1299 and H1650 increased by 82% (p<0.01) and 184% (p<0.01) respectively. Conclusions: Our studies suggest that macrophage produce cytokines that influence the migratory abilities of lung cancer cell lines.
INTRODUCTION: Postoperative stereotactic radiosurgery (postop SRS) is potentially complicated by difficulty defining the target volume and the risk of leptomeningeal seeding at the time of surgery. It is hypothesized that preop SRS may render cells less viable to disseminate in the leptomeningeal space. This retrospective study compares the leptomeningeal dissemination (LMD) rate for preop versus postop radiosurgery METHODS: We identified 140 patients with brain metastases who underwent resection and radiosurgery at the University of Alabama at Birmingham including 91 postop patients (2005–2015) and 49 preop patients (2011–2018). The preop group included 19 patients enrolled in a phase I trial of preoperative radiosurgery (12–15 Gy) for tumors 2–6 cm in greatest diameter. In that study 15 Gy was found to be safe in the preop setting but further escalation was not attempted. An additional 30 patients received preop SRS off-study (median dose 15 Gy). The median postop dose was 16 Gy. LMD recurrence was defined as focal pachymeningeal or diffuse leptomeningeal enhancement of the brain, spinal cord, or cauda equina, dural enhancement beyond 5 mm from the index metastasis, subependymal enhancement, or enhancement of cranial nerves. This definition is not limited to carcinomatosis. All events were categorized and confirmed by at least two physicians. RESULTS: 40/140 (29%) patients developed new focal or diffuse LMD. Preop SRS was associated with a higher freedom from leptomeningeal recurrence (84% vs 60% at one year, p=0.021 Breslow, p=0.128 log-rank). Since later LMD may not be related to surgery, a second analysis censoring follow-up at one year was performed and confirmed this trend (p=0.008 Breslow, p=0.014 log-rank). CONCLUSIONS: Preoperative SRS is associated with a reduction in the risk of LMD compared to postop SRS. Focal pachymeningeal dissemination may not always be recognized as related to surgery. A randomized trial of preop vs postop SRS is warranted.
Recurrence of therapy resistant Glioblastoma multiforme (GBM) is responsible for patient mortality. Not all patients qualify for surgical resection or for chemotherapy, but radiation is almost a universally tolerated therapy. We are modeling acquired radiation resistance using 8 radiation-sensitive GBM patient-derived xenolines (PDX) made resistant by six irradiation series (6x2Gy each) in vivo. In 4 resistance-induced PDX, MGMT (O6-methylguanine–DNA methyltransferase) protein expression increased over original isogenic PDX. Paradoxically, temozolomide screening of orthotopic radiation-resistant PDX with increased MGMT expression revealed increased, not decreased chemo-sensitivity. This suggests an unanticipated mechanism associating acquired radiation resistance and alkylating chemotherapy sensitivity. RNA-seq data of long non-coding RNAs (lncRNAs) has revealed associations with patient overall survival and age at diagnosis. Out of 24,076 lncRNAs, 5 are significantly differentially expressed with regard to patient overall survival and age at diagnosis. The functions of lnc-ZNF117-1, lnc-DCUN1D4-1, and LINC01397 are unknown, but they are enriched in brain over other tissues. Tissue specific expression and function are unknown for lnc-TBL1XR1-5, but it is highly expressed in HepG2 (hepatocellular carcinoma) as well as in non-functioning pituitary adenomas (NFPAs). The lnc-CDH17-1 transcript is also highly expressed in NFPAs. All 5 of these lncRNAs have complex secondary and tertiary structures, but their physiologic or pathologic functions are unknown. LncRNAs most likely contribute to acquired resistance through epigenetic regulation of transcription and chromatin state. Deep sequencing of total RNA isolated from intracranial radiation–sensitive/–resistant PDX to relate transcriptional programs and therapy resistance is underway. These data will be paired with kinomic profiling of matched tumors to elucidate basal signaling modality changes between radiation–sensitive/–resistant tumors. Analysis of differentially expressed lncRNA will be used to predict lncRNA structure/function, elucidating druggable mechanisms mediated by lncRNAs.
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