A Multidisciplinary Central Nervous System Clinic Model for Radiation Oncology and Neurosurgery (RADIANS): three-year experience with brain and skull base lesions in a community hospital setting.

BACKGROUND: Subspecialty, multidisciplinary care within community hospital settings are limited and remains a challenge. Improving outcomes for central nervous system (CNS) disease rely on integrated subspecialty care between radiation oncology (RadOnc) and neurosurgery (NS). Three-year experience with simultaneous patient evaluation with RadOnc and NS physicians in a community hospital-based CNS clinic model (RADIANS) for brain and skull base lesions (BSBL) are reported. METHODS: Clinical and demographic data were prospectively collected for patients evaluated in RADIANS. Surveys administered and three-year data reviewed. Descriptive statistics reported as mean and percentages for patient characteristics, diagnosis, treatment and outcomes. RESULTS: Sixty-seven patients with confirmed BSBL were evaluated between August 2016 and August 2019. Mean age and distance traveled was 61.0 years and 66.5 miles, respectively. Female (N.=39, 58.2%) and male (N.=28, 41.8%) patients had mean Patient Satisfaction Score of 4.77 (0-5 Scale, where 5 is very satisfied; 26 respondents). Forty-three patients had malignant disease (28 brain mets; six with both brain/spine; nine with primary brain), and 24 had benign disease. Post-evaluation treatment: radiation therapy (RT) only (N.=16), neurosurgery (NS) only (N.=12), both RT and NS (N.=15), and no RT/NS intervention (N.=24). Fractionated stereotactic radiosurgery was most common RT delivered; craniotomy with tumor resection was most common NS performed. Treatment outcomes: local control in 33 of 38 (86.8%); radiation necrosis in one of 31 (3.2%). CONCLUSIONS: The multidisciplinary community hospital-based CNS clinic continues its high patient approval at extended follow-up. Results demonstrate the clinic serves as a regional referral center where patients with BSBL with varying degrees of co-morbidities, systemic disease status, and oncologic staging can be treated with evidence-based treatment modalities yielding high rates of local control and low rates of grade 3 and 4 radiation-induced toxicity, while having access to on-going clinical trials.

Geriatric patient outcomes in a multidisciplinary central nervous system community hospital clinic for radiation oncology and neurosurgery (RADIANS).

INTRODUCTION: Management of older adult patients with central nervous system (CNS) cancers requires a patient-centric, multidisciplinary approach. Assessment of neurosurgical and radiation treatment outcomes can assist in establishing guidelines for this patient population. We previously reported on the RADIANS clinic, a novel community hospital-based multidisciplinary clinic (MDC) for CNS cancer care, providing simultaneous radiation oncology and neurosurgery evaluation in a same-day, single-setting clinic. We now provide a focused analysis of our older adult patient population and recommendations for triage and standardization of care. METHODS: Consecutive older adult patients (age ≥ 65) evaluated at the RADIANS clinic for CNS disease were identified and retrospectively reviewed. Observed 30-day neurosurgical outcomes were compared to predicted outcomes determined by the American College of Physicians NSQIP Surgical Risk Calculator. One-sample binomial exact tests were used to evaluate binary outcome measures. A two-sample t-test was used to evaluate the length of hospital stay. Brier Scores were calculated to assess the deviation between predicted probabilities and observed outcomes for binary outcome measures. Overall survival at 90 days was reported. RESULTS: Fifty-six older adult patients with malignant (42/56) and benign (14/56) CNS disease were evaluated. Mean distance traveled for multidisciplinary evaluation at the RADIANS clinic was 43.4 miles. There was no incidence of radiation-induced toxicity. Mean length of hospital stay for RADIANS patients was significantly shorter by about 1.5 to 3.5 days (95% CI). There was no statistically significant difference for other outcome measures, however, Brier Scores demonstrated that NSQIP was not a good predictive tool for any or serious complications, UTI, venous thromboembolism, return to OR, readmission, or death in our cohort. Local tumor control rate and progression-free survival at 90 days were 97.4% and 76.9%, respectively. CONCLUSIONS: This is the first report of CNS disease outcomes in older adult patients evaluated by radiation oncology and neurosurgery at a community hospital-based MDC. We observed minimal adverse radiation outcomes and high tumor control in our cohort. Findings show significantly shorter postoperative hospital stay for patients evaluated and managed at the RADIANS clinic.

Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) presents as an unmet clinical challenge for drug delivery due to its unique hypoxic biology. Vinblastine-N-Oxide (CPD100) is a hypoxia-activated prodrug (HAP) that selectively converts to its parent compound, vinblastine, a potent cytotoxic agent, under oxygen gradient. The study evaluates the efficacy of microfluidics formulated liposomal CPD100 (CPD100Li) in PDAC. CPD100Li were formulated with a size of 95 nm and a polydispersity index of 0.2. CPD100Li was stable for a period of 18 months when freeze-dried at a concentration of 3.55 mg/mL. CPD100 and CPD100Li confirmed selective activation at low oxygen levels in pancreatic cancer cell lines. Moreover, in 3D spheroids, CPD100Li displayed higher penetration and disruption compared to CPD100. In patient-derived 3D organoids, CPD100Li exhibited higher cell inhibition in the organoids that displayed higher expression of hypoxia-inducible factor 1 alpha (HIF1A) compared to CPD100. In the orthotopic model, the combination of CPD100Li with gemcitabine (GEM) (standard of care for PDAC) showed higher efficacy than CPD100Li alone for a period of 90 days. In summary, the evaluation of CPD100Li in multiple cellular models provides a strong foundation for its clinical application in PDAC.

Three-Year Experience of a Multidisciplinary Central Nervous System Clinic Model for Radiation Oncology and Neurosurgery (RADIANS) in a Community Hospital Setting.

BACKGROUND: As academic centers partner and establish healthcare systems with community hospitals, delivery of subspecialty, multidisciplinary care in community hospital settings remains a challenge. Improving outcomes for central nervous system (CNS) disease is related to integrated care between neurosurgery (NS) and radiation oncology (RadOnc) specialties. Our multidisciplinary community hospital-based clinic, RADIANS, previously reported high patient approval of simultaneous evaluation with NS and RadOnc physicians. Three-year experience is now reported. METHODS: Prospectively collected clinical and demographic patient data over three years was done, and surveys administered. Descriptive statistics reported as mean and percentages for patient characteristics, diagnosis, treatment and outcomes. RESULTS: Between August 2016 and August 2019, 101 patients were evaluated. Mean age and distanced traveled was 61.2 years, and 54.9 miles, respectively. Patient Satisfaction Score was 4.79 (0-5 Scale, 5-very satisfied). Most common referral source was medical oncologists. Seventy-two patients had malignant CNS disease (brain mets 28; spine mets 27; both 6; primary brain 9; primary spine 2), 29 had benign CNS disease. Post-evaluation treatment: radiation therapy (RT) only (n=29), neurosurgery (NS) only (n=16), both RT and NS (n=22), and no RT/NS intervention (n=34). Fractionated stereotactic radiosurgery was most common RT delivered; craniotomy with tumor resection was most common NS performed. Treatment outcomes: local control=61/67 (91%); radiation necrosis or radiation-induced myelitis=2/51 (3.9%). CONCLUSIONS: The RADIANS multidisciplinary community hospital-based CNS clinic model is first of its kind to be reported, continuing strong patient approval at extended follow-up. Data indicates the model serves as a regional referral center, delivering evidence-based treatment modalities for complex CNS disease in community hospital settings, yielding high rates of local control and low rates of grade 3 or 4 radiation-induced toxicity.

Liposomal formulation of hypoxia activated prodrug for the treatment of ovarian cancer.

In this work, a new sphingomyelin-cholesterol liposomal formulation (CPD100Li) for the delivery of a hypoxia activated prodrug of vinblastine, mon-N-oxide (CPD100), is developed. The optimized liposomal formulation uses an ionophore (A23187) mediated pH-gradient method. Optimized CPD100Li is characterized for size, drug loading, and stability. The in vitro toxicity of CPD100Li is assessed on different aspects of cell proliferation and apoptosis of ES2 ovarian cancer under normoxic and hypoxic conditions. The pharmacokinetics of CPD100Li in mice as well as the influence of A23187 on the retention of CPD100 are assessed. The dose limiting toxicity (DLT) and maximum tolerated dose (MTD) for CPD100Li are evaluated in nude mice. CPD100 is loaded in the liposome at 5.5 mg/mL. The sizes of CPD100Li using DLS, qNano and cryo-TEM techniques are 155.4 ±â€¯4.2 nm, 132 nm, and 112.6 ±â€¯19.8 nm, respectively. There is no difference between the in vitro characterization of CPD100Li with and without ionophore. Freshly prepared CPD100Li with ionophore are stable for 48 h at 4 °C, while the freeze-dried formulation is stable for 3 months under argon at 4 °C. The hypoxic cytotoxicity ratios (HCR) of CPD100 and CPD100Li are 0.16 and 0.11, respectively. CPD100Li under hypoxic conditions has a 9.2-fold lower IC50 value as compared to CPD100Li under normoxic conditions, confirming the hypoxia dependent activation of CPD100. CPD100Li treated ES2 cells show a time dependent enhanced cell death, along with caspase production and an increase in the number of cells in G0/G1 and higher cell arrest. The blood concentration profile of CPD100Li in mice without A23187 has a 12.6-fold lower area under the curve (AUC) and 1.6-fold lower circulation time compared to the CPD100Li with A23187. The DLT for both CPD100 and CPD100Li is 45 mg/kg and the MTD is 40 mg/kg in nude mice. Based on the preliminary data obtained, we clearly show that the presence of ionophore affects the in vivo stability of CPD100. CPD100Li presents a unique opportunity to develop a first-in-kind chemotherapy product based on achieving selective drug activation through the hypoxic physiologic microenvironment of solid tumors.