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BACKGROUND: With the easily available option for surgeons to soak their suture in antibiotic irrigation solution intraoperatively in mind, this study was designed to evaluate the ability of suture soaked in bacitracin irrigation solution to inhibit the growth of Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus. MATERIALS AND METHODS: Using standard experimental procedure, sterile suture was soaked in Bacitracin, and dried for 10 minutes or 6 hours, incubated for 24 h on inoculated plates, and examined for zone of inhibition around the suture. This was compared to control unsoaked suture and antimicrobial suture (AMS) currently on the market to determine if the minor intraoperative procedural change of placing suture in antibiotic irrigation solution instead of on the sterile table could confer comparable antimicrobial activity. RESULTS: The study found the Bacitracin soaked suture (BSS) consistently inhibited the growth of the test organisms. For both organisms, the BSS exhibited a significantly larger zone of inhibition compared to the unsoaked control suture (p < 0.0001). However, both the AMS currently on the market, and a bacitracin aliquot, exhibited significantly larger zones of inhibition compared to both drying times of the BSS (p < 0.0001). CONCLUSIONS: Placing sutures in a bacitracin irrigation solution intraoperatively instead of directly on the sterile table can achieve some of the in vitro antimicrobial effect seen from AMS currently on the market. This may result in reduced rates of surgical site infections and associated costs without major procedural change and at reduced overhead.

The presence of therapy-resistant cancer stem cells (CSCs) in recurrent high-grade glioma (HGG) patients contributes to poor clinical outcomes. The ChemoID functional anti-cancer assay targets cancer stem cells along with the bulk of the tumor cells. This trial aims to determine if ChemoID assay-guided treatment improves survival rates for recurrent HGG patients compared to the empirically physician-selected treatment. Patients with grade-III/IV recurrent glioma who failed standard of care (SOC) therapy were randomized (1:1) between two intervention groups. They received one of fourteen mono or combination chemotherapies based on the ChemoID assay or physician choice. The study met the primary outcome in the first interim analysis of 50 patients as per protocol. The ChemoID group had an improved survival rate (vs physician-choice). Median OS (mOS) was 12.5 months in the ChemoID group (95% CI, 10.2-14.7) vs 9 months in the physician-choice (95% CI, 4.2-13.8; log-rank P = .010). Mortality risk was lower in the ChemoID group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression-free survival was 10.1 months in the ChemoID group vs 3.5 months in the physician choice (95% CI, 4.8-15.4 vs 1.9-5.1; log-rank < 0.001). Risk of progression was lower in the ChemoID group (HR = 0.25; 95% CI, 0.14-0.44; P < 0.001). The intention to treat (ITT) analysis of 78 patients showed substantially improved OS. The ChemoID group had a statistically significant longer median survival of 4.5 months. mOS was 12.0 months in the ChemoID group (95% CI, 10.8-13.2) vs 7.5 in the physician-choice group (95% CI, 3.5-11.5; log-rank P = .009). The ChemoID group had a decreased mortality risk (HR = 0.52; 95% CI, 0.24-0.81; P = .008). Compared with the physician-choice, the ChemoID group had a significantly longer OS in the ITT population. Our findings support that screening standard cytotoxic chemotherapies with a patient-specific anti-cancer assay improves survival outcomes in recurrent HGG patients.

BACKGROUND Clinical outcomes in patients with recurrent high-grade glioma (HGG) remain poor. Cancer stem cells (CSCs) have been implicated in metastasis, treatment resistance and recurrence of HHGs. We have shown in several clinical studies that anti-CSC-directed therapy provides benefits in many cancer types; however, this is the first report of a randomized clinical trial evaluating it for recurrent HGGs. OBJECTIVE Determine whether CSC-targeted cytotoxic agents selected by ChemoID assay-guided therapy improves survival in patients with recurrent HGG. DESIGN, SETTING, AND PARTICIPANTS In this parallel-group, randomized, phase-3 clinical trial, patients at 13 clinical sites in the USA with grade-III/IV recurrent glioma (2016 WHO guidelines) were randomized 1:1 to either ChemoID assay-guided therapy or physician-choice therapy, and then treated and followed until unacceptable toxic effects, hospice, or death. MAIN OUTCOMES AND MEASURES The primary endpoint was overall survival (OS). RESULTS Combined median follow-up was 9 months. Median OS (mOS) was 12.5 months (95% CI, 10.2-14.7) in the ChemoID assay-guided group vs 9 months (95% CI, 4.2-13.8) in the physician-choice group (log-rank P = .010). Risk of death was significantly lower in the ChemoID assay group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression free survival (PFS) was 10.1 vs 3.5 months (95% CI, 4.8-15.4 vs 1.9-5.1) (HR, 0.25; 95% CI, 0.14-0.44; P < .001). CONCLUSIONS AND RELEVANCE Primary endpoint was met in this randomized clinical trial. The mOS was 3.5 months longer in the ChemoID assay-guided group vs the physician-choice group.

Background: Clinical outcomes in patients with recurrent high-grade glioma (HGG) remain poor. Cancer stem cells (CSCs) have been implicated in metastasis, treatment resistance and recurrence of HHGs. We have shown in several clinical studies that anti-CSC-directed therapy provides benefits in many cancer types; however, this is the first report of a randomized clinical trial evaluating it for recurrent HGGs. Objective: Determine whether CSC-targeted cytotoxic agents selected by ChemoID assay-guided therapy improves survival in patients with recurrent HGG. Design, Settings, and Participants: In this parallel-group, randomized, phase-3 clinical trial, patients at 13 clinical sites in the USA with grade-III/IV recurrent glioma (2016 WHO guidelines) were randomized 1:1 to either ChemoID assay-guided therapy or physician-choice therapy, and then treated and followed until unacceptable toxic effects, hospice, or death. Main Outcomes and Measures: The primary endpoint was overall survival (OS). Results: Combined median follow-up was 9 months. Median OS (mOS) was 12.5 months (95% CI, 10.2-14.7) in the ChemoID assay-guided group vs 9 months (95% CI, 4.2-13.8) in the physician-choice group (log-rank P = .010). Risk of death was significantly lower in the ChemoID assay group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression free survival (PFS) was 10.1 vs 3.5 months (95% CI, 4.8-15.4 vs 1.9-5.1) (HR, 0.25; 95% CI, 0.14-0.44; P < .001). Conclusions and Relevance: Primary endpoint was met in this randomized clinical trial. The mOS was 3.5 months longer in the ChemoID assay-guided group vs the physician-choice group demonstrating the clinical advantage of treating HGG patients using CSC personalized therapy. Citation Format: Tulika Ranjan, Soma Sengupta, Alexander Yu, Candace M. Howard, Ricky Chen, Rekha Chaudhary, Nicholas Marko, Dawit Aregawi, Michael Glantz, Jon Glass, Richard M. Green, Christine Lu-Emerson, Aaron Mammoser, Hugh Moulding, Steven Jubelirer, Jason Schroeder, Mark Anderson, Frances Chow, Seth Lirette, Krista Denning, Anthony Alberico, Jagan Valluri, Pier Paolo Claudio. Multi-institutional randomized phase-3 trial comparing cancer stem cell-targeted vs physician-choice treatments in patients with recurrent high-grade gliomas (NCT03632135) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT224.

2028 Background: Clinical outcomes in patients with recurrent high-grade glioma (HGG) remain poor. Cancer stem cells (CSCs) have been implicated in metastasis, treatment resistance and recurrence of HHGs. We have shown in several clinical studies that anti-CSC-directed therapy selected by ChemoID assay provides benefits in many cancer types; however, this is the first report of a randomized clinical trial evaluating whether CSC-targeted cytotoxic agents selected by ChemoID assay-guided therapy improves survival in patients with recurrent HGG. Methods: In this parallel-group, randomized, phase-3 clinical trial, patients at 13 clinical sites in the USA with grade-III/IV recurrent glioma (2016 WHO guidelines) were randomized 1:1 to either ChemoID assay-guided therapy or physician-choice therapy, and then treated and followed until unacceptable toxic effects, hospice, or death. The primary endpoint was overall survival (OS). Results: Combined median follow-up was 9 months. Median OS (mOS) was 12.5 months (95% CI, 10.2-14.7) in the ChemoID assay-guided group vs 9 months (95% CI, 4.2-13.8) in the physician-choice group (log-rank P =.010). Risk of death was significantly lower in the ChemoID assay group (HR = 0.44; 95% CI, 0.24-0.81; P =.008). Median progression free survival (PFS) was 10.1 vs 3.5 months (95% CI, 4.8-15.4 vs 1.9-5.1) (HR, 0.25; 95% CI, 0.14-0.44; P

Sedation is a ubiquitous practice in ICUs and NCCUs. It has the benefit of reducing cerebral energy demands, but also precludes an accurate neurologic assessment. Because of this, sedation is intermittently stopped for the purposes of a neurologic assessment, which is termed a neurologic wake-up test (NWT). NWTs are considered to be the gold-standard in continued assessment of brain-injured patients under sedation. NWTs also produce an acute stress response that is accompanied by elevations in blood pressure, respiratory rate, heart rate, and ICP. Utilization of cerebral microdialysis and brain tissue oxygen monitoring indicates that this is not mirrored by alterations in overall cerebral metabolism, and seldom affects oxygenation. The hard contraindications for the NWT are preexisting intracranial hypertension, barbiturate treatment, status epilepticus, and hyperthermia. However, hemodynamic instability, sedative use for primary ICP control, and sedative use for severe agitation or respiratory distress are considered significant safety concerns. Despite ubiquitous recommendation, it is not clear if additional clinically relevant information is gleaned through its use, especially with the contemporaneous utilization of multimodality monitoring. Various monitoring modalities provide unique and pertinent information about neurologic function, however, their role in improving patient outcomes and guiding treatment plans has not been fully elucidated. There is a paucity of information pertaining to the optimal frequency of NWTs, and if it differs based on type of injury. Only one concrete recommendation was found in the literature, exemplifying the uncertainty surrounding its utility. The most common sedative used and recommended is propofol because of its rapid onset, short duration, and reduction of cerebral energy requirements. Dexmedetomidine may be employed to facilitate serial NWTs, and should always be used in the non-intubated patient or if propofol infusion syndrome (PRIS) develops. Midazolam is not recommended due to tissue accumulation and residual sedation confounding a reliable NWT. Thus, NWTs are well tolerated in most patients and remain recommended as the gold-standard for continued neuromonitoring. Predicated upon one expert panel, they should be performed at least one time per day. Propofol or dexmedetomidine are the main sedative choices, both enabling a rapid awakening and consistent NWT.

With the easily available option for surgeons to soak their suture in anti-biotic irrigating solution intraoperatively in mind, this study was designed to evaluate the ability of suture soaked in bacitracin irrigating solution to inhibit the growth of Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus. Using standard experimental procedure, sterile suture was soaked in Bacitracin suture, and dried for 10 minutes or 6 hours, incubated for 24 h on inoculated plates, and examined for zone of inhibition around the suture. This was compared to control unsoaked suture and antimicrobial suture (AMS) currently on the market to determine if the minor intra operative procedural change of placing suture in antibiotic irrigation solution instead of on the sterile table could confer some antimicrobial activity. The study found the Bacitracin soaked suture (BSS) consistently inhibited the growth of the test organisms. For both organisms, the BSS exhibited a significantly larger zone of inhibition compared to the unsoaked control suture. However, the AMS currently on the market exhibited a larger zone of inhibition compared to the BSS. Placing sutures in a bacitracin irrigation solution intraoperatively instead of directly on the sterile table can achieve some of the in vitro antimicrobial effect seen from AMS currently on the market. This may result in reduced rates of SSIs and associated costs without major procedural change and at reduced overhead.

Sedation is a ubiquitous practice in ICUs and NCCUs. It has the benefit of reducing cerebral energy demands, but also precludes an accurate neurologic assessment. Because of this, sedation is intermittently stopped for the purposes of a neurologic assessment, which is termed a neurologic wake-up test (NWT). NWTs are considered to be the gold-standard in continued assessment of brain-injured patients under sedation. NWTs also produce an acute stress response that is accompanied by elevations in blood pressure, respiratory rate, heart rate, and ICP. Utilization of cerebral microdialysis and brain tissue oxygen monitoring in small cohorts of brain-injured patients suggests that this is not mirrored by alterations in cerebral metabolism, and seldom affects oxygenation. The hard contraindications for the NWT are preexisting intracranial hypertension, barbiturate treatment, status epilepticus, and hyperthermia. However, hemodynamic instability, sedative use for primary ICP control, and sedative use for severe agitation or respiratory distress are considered significant safety concerns. Despite ubiquitous recommendation, it is not clear if additional clinically relevant information is gleaned through its use, especially with the contemporaneous utilization of multimodality monitoring. Various monitoring modalities provide unique and pertinent information about neurologic function, however, their role in improving patient outcomes and guiding treatment plans has not been fully elucidated. There is a paucity of information pertaining to the optimal frequency of NWTs, and if it differs based on type of injury. Only one concrete recommendation was found in the literature, exemplifying the uncertainty surrounding its utility. The most common sedative used and recommended is propofol because of its rapid onset, short duration, and reduction of cerebral energy requirements. Dexmedetomidine may be employed to facilitate serial NWTs, and should always be used in the non-intubated patient or if propofol infusion syndrome (PRIS) develops. Midazolam is not recommended due to tissue accumulation and residual sedation confounding a reliable NWT. Thus, NWTs are well-tolerated in selected patients and remain recommended as the gold-standard for continued neuromonitoring. Predicated upon one expert panel, they should be performed at least one time per day. Propofol or dexmedetomidine are the main sedative choices, both enabling a rapid awakening and consistent NWT.

BACKGROUND: Over the past 20 years even with the aggressive standard of care (SoC) Stupp treatment protocol the prognosis of glioblastoma (GBM) has only minimally improved from 12 to 14 months. This is due in large part to the presence of chemo- and radiation-resistant GBM cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. We are using ChemoID, a CLIA certified and CAP accredited drug response assay to identify the most effective chemotherapy treatment against CSCs and bulk of tumor cells from of a panel of chemotherapies, offering great promise for individualized cancer management. A prospective study was conducted evaluating the use of the ChemoID drug response assay in glioblastoma patients. METHODS: Fresh tissue samples were collected for drug sensitivity testing from 61 glioblastoma patients enrolled in IRB approved protocol. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds Ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSCs, bulk tumor and combined assay responses to treatment; sensitivities/specificities, areas under the curve (AUC) were examined. RESULTS: The data suggests that ChemoID guided treatment significantly enhanced tumor response. For every 5% increase in cell kill of CSCs by assay-guided chemotherapy, 12-month patient response (non-recurrence of cancer) increased 2.5-fold, OR=2.3 (p=0.01). Bulk of tumor assay was found not statistically significant. Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSCs test versus only 3 months with a negative CSCs test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. CONCLUSIONS: The ChemoID CSCs drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. Glioblastoma cancer recurrence may occur quickly if the CSC test has a low cell kill rate, even if the bulk tumor test cell kill rate is high.

2057Background: Over the past 20 years even with the aggressive standard of care (SoC) Stupp treatment protocol the prognosis of glioblastoma (GBM) has only minimally improved from 12 to 14 months....

e13544 Background: We have developed a drug response assay (ChemoID) that identifies effective chemotherapy against cancer stem cells (CSCs) vs. bulk of tumor cells from of a panel of potential treatments. A prospective study was conducted evaluating the use of the CSC drug response assay in glioblastoma patients treated with standard-of-care. Methods: 41 glioblastoma patients were enrolled in an IRB-approved protocol. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Results: For every 5% increase in in-vitro CSC cell kill by TMZ, 12-month patient response (non-recurrence of cancer) increased 2-fold, OR=2.2 (p=0.016). Similar associations with the bulk tumor test were seen, OR=2.75 (p=0.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 (p=0.036) but a much attenuated remaining bulk tumor association, OR=1.46 (p=0.472). Areas under the curve (AUC) and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [Sens=100/Spec=97], 0.972 [100/89] and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification non-event NRI and overall NRI = 0.111, p=0.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS. Results across 14 potential other treatments indicated that 34/41 (83%) and 27/41 (66%) potentially more optimal alternative therapies may have been chosen using CSC results and Bulk results, respectively. Conclusions: The ChemoID assay has the potential to increase the accuracy of bulk tumor assays.

Administration of ineffective anticancer therapy is associated with unnecessary toxicity and development of resistant clones. Cancer stem-like cells (CSLCs) resist chemotherapy, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for individualized anticancer treatments. We have developed an ex vivo chemotherapy sensitivity assay (ChemoID), which measures the sensitivity of CSLCs as well as the bulk of tumor cells to a variety of chemotherapy agents. Two patients, a 21-year old male (patient 1) and a 5-month female (patient 2), affected by anaplastic WHO grade-III ependymoma were screened using the ChemoID assay. Patient 1 was found sensitive to the combination of irinotecan and bevacizumab, which resulted in a prolonged disease progression free period of 18 months. Following recurrence, the combination of various chemotherapy drugs was tested again with the ChemoID assay. We found that benzyl isothiocyanate (BITC) greatly increased the chemosensitivity of the ependymoma cells to the combination of irinotecan and bevacizumab. After patient 1 was treated for two months with irinotecan, bevacizumab and supplements of cruciferous vegetable extracts containing BITC, we observed over 50% tumoral regression in comparison with pre-ChemoID scan as evidenced by MRI. Patient 2 was found resistant to all treatments tested and following 6 cycles of vincristine, carboplatin, cyclophosphamide, etoposide, and cisplatin in various combinations, the tumor of this patient rapidly progressed and proton beam therapy was recommended. As expected animal studies conducted with patient derived xenografts treated with ChemoID screened drugs recapitulated the clinical observation. This assay demonstrates that patients with the same histological stage and grade of cancer may vary considerably in their clinical response, suggesting that ChemoID testing which measures the sensitivity of CSLCs as well as the bulk of tumor cells to a variety of chemotherapy agents could lead to more effective and personalized anticancer treatments in the future.

e13028 Background: Glioblastoma multiforme (GBMs) are brain tumors with low survival rates due to the presence of chemoresistant Glioma Cancer Stem-Like Cells (GCSLCs). Development of a test that i...

e13012 Background: Cancer stem-like cells (CSLCs) in primary brain tumors can resist certain chemotherapies, thereby causing relapse of the disease. Thus, development of a test that identifies the ...

e13040 Background: Cancer stem-like cells (CSLCs) can resist certain chemotherapies, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for individualized anticancer treatments. Methods: We have developed ChemoID, an in vitro chemotherapy assay, designed to predict the sensitivity and resistance of a given patient’s CSLCs and bulk of tumor cells to a variety of chemotherapy agents. Results: A 5-month female (Patient A), and a 21-year old male (Patient B), both affected by anaplastic WHO grade 3 ependymoma were screened using the ChemoID assay. A range of concentrations flanking the clinical doses for vincristine, carboplatin, cyclophosphamide, etoposide, cisplatin, methotrexate, cytosine arabinoside, oxaliplatin, irinotecan, avastin, procarbazine, lomustine, and busulfan were tested. The CSLCs and bulk of tumor ependymoma cells of Patient A were found moderately sensitive (30% cell kill) to only cisplatin and procarbazine, both as single agents and in combination. Following 6 cycles of vincristine, carboplatin, cyclophosphamide, etoposide, and cisplatin in various combinations, Patient A rapidly progressed and proton beam therapy was recommended. The CSLCs and bulk of tumor ependymoma cells of Patient B were found highly sensitive (80% cell kill) to the combination of irinotecan and avastin, which resulted in 18 months free of disease progression. After recurrence, chemotherapies were tested in combination with benzyl-isothiocyanate (BITC), a bioactive natural food component contained in extracts from cruciferous vegetables. BITC greatly increased the chemosensitivity in Patient B to the combination of irinotecan and avastin, resulting in average 90% CSLCs and bulk of tumor ependymoma cell eradication. MRI scan of Patient B showed over 50% tumor regression after two months of treatment with a combination of irinotecan, avastin, and supplements containing BITC. Conclusions: Our findings suggest that no patients are alike in their chemotherapy response. ChemoID assay that measures cell death of CSLCs and bulk of tumor cells from patient biopsies to standard chemotherapy agents in vitro is a feasible approach to personalized anticancer treatments.