Cobalt compensator-based IMRT device: A treatment planning study of head and neck cases.

PURPOSE: Our goal is to develop a novel cobalt-compensator-based IMRT device for low- and middle-income countries that is reliable and cost-effective while delivering treatment plans of equal quality to those from linac-MLC devices. The present study examines the quality of treatment plans using this device. METHODS: A commercial treatment planning system (TPS; RayStation v.8B) was commissioned for this device using Monte Carlo simulations from the Geant4 toolkit. Patient-specific compensators were created as regions-of-interest. Thirty clinical head & neck cases were planned and compared to clinical plans with a 6MV linac using IMRT. The mock head and neck plan from TG-119 was used for further validation. RESULTS: PTV objectives were achieved in all 30 plans with PTV V95% >95 %. OAR sparing was similar to clinical plans. There were 14 cases where OAR dose limits exceeded the recommended QUANTEC limits in the clinical plan in order to achieve target coverage. OAR sparing was better in the cobalt compensator plan in 8 cases and worse in 3 cases, in the latter cases exceeding the clinical plan doses by an average of 8.22 % (0.0 %-13.5 %). Average field-by-field gamma pass-rate were 93.7 % (2 %/2mm). Estimated treatment times using the Co-60 compensator device were 1 min 27 s vs 1 min 2 s for the clinical system. CONCLUSION: This system is the first of its kind to allow for IMRT with a Co-60 device. Data here suggests that the delivery meets plan quality criteria while maintaining short treatment times which may offer a sustainable and cost-low option for IMRT on the global scale.

Systemic Treatment Patterns and Outcomes in Patients With EGFR Mutated Non-small Cell Lung Cancer and Leptomeningeal Disease.

INTRODUCTION: Leptomeningeal (LM) disease occurs in 9% to 10% of EGFR mutated non-small cell lung cancer (NSCLC) cases. The natural history and optimal systemic treatment strategies for this disease are not well-characterized, particularly in the era of osimertinib. MATERIALS AND METHODS: We identified 54 patients with EGFR mutated NSCLC and LM disease diagnosed between January 3, 2000 to March 31, 2020 and treated at an academic oncology practice in Seattle, Washington. We abstracted demographic, tumor, treatment, and outcome data from the electronic medical record. Univariate Cox models were run to evaluate the association between post-LM disease systemic therapy and overall survival. Differences in LM disease natural history and healthcare utilization between groups were assessed using Student's t test or a chi-squared test. RESULTS: Patients that received osimertinib prior to LM disease had a longer median time to LM disease diagnosis and trended toward better performance status than those that did not. Patients that received any post-LM disease systemic therapy had a lower risk of death relative to those that did not (HR 0.17, P < .001), with a suggestion that osimertinib-containing regimens result in longer median overall survival. Emergency department, hospital and hospice utilization were not associated with receipt of post-LM disease systemic therapy. CONCLUSION: Prior exposure to osimertinib appears to favorably influence the natural history of LM disease. Any systemic therapy after LM disease diagnosis is associated with longer survival and does not increase healthcare utilization. Additional research is needed to assess whether an osimertinib-containing regimen confers a survival benefit after LM disease diagnosis among patients who received prior osimertinib.

Socio-economic factors do not affect overall survival in soft tissue sarcoma when patients treated at a single high-volume center.

BACKGROUND: Treatments for soft tissue sarcoma (STS) include extensive surgical resection, radiation and chemotherapy, and can necessitate specialized care and excellent social support. Studies have demonstrated that socioeconomic factors, such as income, marital status, urban/rural residence, and educational attainment as well as treatment at high-volume institution may be associated with overall survival (OS) in STS. METHODS: In order to explore the effect of socio-economic factors on OS in patients treated at a high-volume center, we performed a retrospective analysis of STS patients treated at a single institution. RESULTS: Overall, 435 patients were included. Thirty-seven percent had grade 3 tumors and 44% had disease larger than 5 cm. Patients were most commonly privately insured (38%), married (67%) and retired or unemployed (43%). Median distance from the treatment center was 42 miles and median area deprivation index (ADI) was 5 (10 representing most deprived communities). The majority of patients (52%) were treated with neoadjuvant therapy followed by resection. As expected, higher tumor grade (HR 3.1), tumor size > 5 cm (HR 1.3), and involved lymph nodes (HR 3.2) were significantly associated with OS on multivariate analysis. Demographic and socioeconomic factors, including sex, age at diagnosis, marital status, employment status, urban vs. rural location, income, education, distance to the treatment center, and ADI were not associated with OS. CONCLUSIONS: In contrast to prior studies, we did not identify a significant association between socioeconomic factors and OS of patients with STS when patients were treated at a single high-volume center. Treatment at a high volume institution may mitigate the importance of socio-economic factors in the OS of STS.

Stereotactic radiosurgery in the treatment of adults with metastatic brain tumors.

Brain metastasis is the most common type of intracranial tumor affecting a significant proportion of advanced cancer patients. In recent years, stereotactic radiosurgery (SRS) has become commonly utilized. It has contributed significantly to decreased toxicity, prolonged quality of life and general improvement in outcomes of patients with brain metastases. Frequent imaging and advanced treatment techniques have allowed for the treatment of more patients with large and numerous metastases extending their overall survival. The addition of targeted therapy and immunotherapy to SRS has introduced novel treatment paradigms and has further improved our ability to effectively treat brain lesions. In this review, we examined in detail the available evidence for the use of SRS alone or in combination with surgery and systemic therapies. Given our developing understanding of the importance of primary tumor histology, the use of different treatment strategies for different metastasis is evolving. Combining SRS with immunotherapy and targeted therapy in breast cancer, lung cancer and melanoma as well as the use of preoperative SRS have shown significant promise in recent years and are investigated in multiple ongoing prospective trials. Further research is needed to guide the optimal sequence of therapies and to identify specific patient subgroups that may benefit the most from aggressive, combined treatment approaches.

uPAR induces expression of transforming growth factor ß and interleukin-4 in cancer cells to promote tumor-permissive conditioning of macrophages.

Cancer cells condition macrophages and other inflammatory cells in the tumor microenvironment so that these cells are more permissive for cancer growth and metastasis. Conditioning of inflammatory cells reflects, at least in part, soluble mediators (such as transforming growth factor ß and IL-4) that are released by cancer cells and alter the phenotype of cells of the innate immune system. Signaling pathways in cancer cells that potentiate this activity are incompletely understood. The urokinase receptor (uPAR) is a cell-signaling receptor known to promote cancer cell survival, proliferation, metastasis, and cancer stem cell-like properties. The present findings show that uPAR expression in diverse cancer cells, including breast cancer, pancreatic cancer, and glioblastoma cells, promotes the ability of these cells to condition co-cultured bone marrow-derived macrophages so that the macrophages express significantly increased levels of arginase 1, a biomarker of the alternatively activated M2 macrophage phenotype. Expression of transforming growth factor ß was substantially increased in uPAR-expressing cancer cells via a mechanism that requires uPA-initiated cell signaling. uPAR also controlled expression of IL-4 in cancer cells via a mechanism that involves activation of ERK1/2. The ability of uPAR to induce expression of factors that condition macrophages in the tumor microenvironment may constitute an important mechanism by which uPAR promotes cancer progression.

A transformation in the mechanism by which the urokinase receptor signals provides a selection advantage for estrogen receptor-expressing breast cancer cells in the absence of estrogen.

Binding of urokinase-type plasminogen activator (uPA) to its receptor, uPAR, in estrogen receptor-α (ERα) expressing breast cancer cells, transiently activates ERK downstream of FAK, Src family kinases, and H-Ras. Herein, we show that when uPAR is over-expressed, in two separate ERα-positive breast cancer cell lines, ERK activation occurs autonomously of uPA and is sustained. Autonomous ERK activation by uPAR requires H-Ras and Rac1. A mutated form of uPAR, which does not bind vitronectin (uPAR-W32A), failed to induce autonomous ERK activation. Expression of human uPAR or mouse uPAR but not uPAR-W32A in MCF-7 cells provided a selection advantage when these cells were deprived of estrogen in cell culture for two weeks. Similarly, MCF-7 cells that express mouse uPAR formed xenografts in SCID mice that survived and increased in volume in the absence of estrogen supplementation, probably reflecting the pro-survival activity of phospho-ERK. Autonomous uPAR signaling to ERK was sensitive to the EGFR tyrosine kinase inhibitors, Erlotinib and Gefitinib. The transition in uPAR signaling from uPA-dependent and transient to autonomous and sustained is reminiscent of the transformation in ErbB2/HER2 signaling observed when this gene is amplified in breast cancer. uPAR over-expression may provide a pathway for escape of breast cancer cells from ERα-targeting therapeutics.

Cell signaling by urokinase-type plasminogen activator receptor induces stem cell-like properties in breast cancer cells.

Signaling by urokinase-type plasminogen activator receptor (uPAR) can cause epithelial-mesenchymal transition (EMT) in cultured breast cancer cells. In this report, we show that uPAR signaling can also induce cancer stem cell (CSC)-like properties. Ectopic overexpression of uPAR in human MDA-MB-468 breast cancer cells promoted the emergence of a CD24(-)/CD44(+) phenotype, characteristic of CSCs, while increasing the cell surface abundance of integrin subunits ß1/CD29 and α6/CD49f that represent putative mammary gland stem cell biomarkers. uPAR overexpression increased mammosphere formation in vitro and tumor formation in an immunocompromized severe combined immunodeficient (SCID) mouse model of orthotopic breast cancer. Hypoxic conditions that are known to induce EMT in MDA-MB-468 cells also increased cell surface ß1/CD29, mimicking the effects of uPAR overexpression. Antagonizing uPAR effector signaling pathways reversed the increase in cell surface integrin expression. Whereas uPAR overexpression did not induce EMT in MCF-7 breast cancer cells, CSC-like properties were nevertheless still induced along with an increase in tumor initiation and growth in the orthotopic setting in SCID mice. Notably, in MCF-7 cell mammospheres, which display a well-defined acinus-like structure with polarized expression of E-cadherin and ß1-integrin, cell collapse into the central cavity was decreased by uPAR overexpression, suggesting that uPAR signaling may stabilize epithelial morphology. In summary, our findings show that uPAR signaling can induce CSC-like properties in breast cancer cells, either concomitantly with or separately from EMT.

Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell signaling.

Hypoxia induces expression of the urokinase receptor (uPAR) and activates uPAR-dependent cell signaling in cancer cells. This process promotes epithelial-mesenchymal transition (EMT). uPAR overexpression in cancer cells also promotes EMT. In this study, we tested whether uPAR may be targeted to reverse cancer cell EMT. When MDA-MB 468 breast cancer cells were cultured in 1% O(2), uPAR expression increased, as anticipated. Cell-cell junctions were disrupted, vimentin expression increased, and E-cadherin was lost from cell surfaces, indicating EMT. Transferring these cells back to 21% O(2) decreased uPAR expression and reversed the signs of EMT. In uPAR-overexpressing MDA-MB 468 cells, EMT was reversed by silencing expression of endogenously produced urokinase-type plasminogen activator (uPA), which is necessary for uPAR-dependent cell signaling, or by targeting uPAR-activated cell signaling factors, including phosphatidylinositol 3-kinase, Src family kinases, and extracellular signal-regulated kinase. MDA-MB 231 breast cancer cells express high levels of uPA and uPAR and demonstrate mesenchymal cell morphology under normoxic culture conditions (21% O(2)). Silencing uPA expression in MDA-MB-231 cells decreased expression of vimentin and Snail, and induced changes in morphology characteristic of epithelial cells. These results demonstrate that uPAR-initiated cell signaling may be targeted to reverse EMT in cancer.