Acute toxic shock syndrome associated with intra-operative debridement and instrumentation removal for chronic osteomyelitis: A report of two cases.

Gram-positive organisms are known causative agents in toxic shock syndrome (TSS), an acute disease caused by bacterial exotoxins. During routine instrumentation removal for chronic osteomyelitis, intraoperative debridement, reaming, and irrigation can lead to cell lysis and subsequent dissemination of the bacterium exotoxin, which can result in acute cardiovascular compromise. We present two cases of chronic osteomyelitis in healed long-bone fractures that were treated with deep instrumentation removal and surgical debridement using a reamer-irrigator-aspirator (RIA) system. Both patients had positive Streptococcus agalactiae wound cultures and both developed acute intraoperative hypotension during the reaming/irrigation portion of the procedure. Case 1 experienced cardiac arrest and was resuscitated for several days in the ICU. Case 2 underwent intra-operative hypotension and was resuscitated appropriately. The RIA or standard reaming systems must be used with caution during debridement of osteomyelitis in the presence of known toxin producing bacteria. The risk of iatrogenic spread of infection or extravasation of intramedullary contents is present; a high index of suspicion with any change in vital signs and prompt response can help mitigate the effect of adverse outcomes associated with acute and severe intraoperative hypotension.

Controlling Hypertension through Education and Coaching in Kidney Disease (CHECK-D): protocol of a cluster randomised controlled trial.

INTRODUCTION: Chronic kidney disease (CKD) affects 30 million Americans. Early management focused on blood pressure (BP) control decreases cardiovascular morbidity and mortality. Less than 40% of patients with CKD achieve recommended BP targets due to many barriers. These barriers include a lack of understanding of the implications of their diagnosis and how to optimise their health.This cluster randomised control trial hypothesises that the combination of early primary care CKD education, and motivational interviewing (MI)-based health coach support, will improve patient behaviours aligned with BP control by increasing patient knowledge, self-efficacy and motivation. The results will aid in sustainable interventions for future patient-centric education and coaching support to improve quality and outcomes in patients with CKD stages 3-5. Outcomes in patients with CKD stages 3-5 receiving the intervention will be compared with similar patients within a control group. Continuous quality improvement (CQI) and systems methodologies will be used to optimise resource neutrality and leverage existing technology to support implementation and future dissemination. The innovative approach of this research focuses on the importance of a multidisciplinary team, including off-site patient coaching, that can intervene early in the CKD care continuum by supporting patients with education and coaching. METHODS AND ANALYSIS: We will test impact of BP control when clinician-delivered education is followed by 12 months of MI-based health coaching. We will compare outcomes in 350 patients with CKD stages 3-5 between intervention and control groups in primary care. CQI and systems methodologies will optimise education and coaching for future implementation and dissemination. ETHICS AND DISSEMINATION: This study was approved by the University of Michigan Institutional Review Boards (IRBMED) HUM00136011, HUM00150672 and SITE00000092 and the results of the study will be published on ClinicalTrials.gov, in peer-reviewed journals, as well as conference abstracts, posters and presentations. TRIAL REGISTRATION NUMBER: NCT04087798.

Investigating potential disparities in clinical trial eligibility and enrollment at an NCI-designated comprehensive cancer center.

BACKGROUND: Although barriers to trial accrual are well-reported, few studies have explored trial eligibility and trial offers as potential drivers of disparities in cancer clinical trial enrollment. METHODS: We identified patients with gastrointestinal (GI) or head/neck (HN) malignancies who were seen as new patients at the University of Michigan Health Rogel Cancer Center in 2016. By exhaustive review of the electronic medical record, we assessed the primary outcomes: (1) eligibility for, (2) documented offer of, and (3) enrollment in a clinical trial. All 41 of the clinical trials available to these patients were considered. Independent variables included clinical and non-clinical patient-related factors. We assessed associations between these variables and the primary outcomes using multivariable regression. RESULTS: Of 1446 patients, 43% were female, 15% were over age 75, 6% were Black. 305 (21%) patients were eligible for a clinical trial. Among eligible patients, 154 (50%) had documentation of a trial offer and 90 (30%) enrolled. Among the GI cohort, bivariate analyses demonstrated that older age was associated with decreased trial eligibility. Bivariate analyses also demonstrated that Black race was associated with increased trial offer. After adjustment, patients 75 or older were less likely to be eligible for a clinical trial in the GI cohort; however, we found no significant associations between race and any of the outcomes after adjustment. Among eligible GI patients, we found no significant associations between non-clinical factors and enrollment. Among the HN cohort, bivariate analyses demonstrated that female sex, older age, Black race, and unpartnered marital status were associated with decreased likelihood of trial offer; however, we found no significant associations between race, age, and marital status and any of the outcomes after adjustment. We found no significant associations between non-clinical factors and eligibility after adjustment; however, women were less likely to be offered and to enroll in a clinical trial in the HN cohort. CONCLUSION: Factors associated with eligibility, documented offer, and enrollment differed between disease site cohorts at our institution. Future work is needed to ensure the equitable inclusion of women and elderly patients in clinical trials.

Phase II Investigation of TVB-2640 (Denifanstat) with Bevacizumab in Patients with First Relapse High-Grade Astrocytoma.

PURPOSE: Glioblastoma represents the most common primary brain tumor. Although antiangiogenics are used in the recurrent setting, they do not prolong survival. Glioblastoma is known to upregulate fatty acid synthase (FASN) to facilitate lipid biosynthesis. TVB-2640, a FASN inhibitor, impairs this activity. PATIENTS AND METHODS: We conducted a prospective, single-center, open-label, unblinded, phase II study of TVB-2640 plus bevacizumab in patients with recurrent high-grade astrocytoma. Patients were randomly assigned to TVB-2640 (100 mg/m2 oral daily) plus bevacizumab (10 mg/kg i.v., D1 and D15) or bevacizumab monotherapy for cycle 1 only (28 days) for biomarker analysis. Thereafter, all patients received TVB-2640 plus bevacizumab until treatment-related toxicity or progressive disease (PD). The primary endpoint was progression-free survival (PFS). RESULTS: A total of 25 patients were enrolled. The most frequently reported adverse events (AE) were palmar-plantar erythrodysesthesia, hypertension, mucositis, dry eye, fatigue, and skin infection. Most were grade 1 or 2 in intensity. The overall response rate (ORR) for TVB-2640 plus bevacizumab was 56% (complete response, 17%; partial response, 39%). PFS6 for TVB-2640 plus bevacizumab was 31.4%. This represented a statistically significant improvement in PFS6 over historical bevacizumab monotherapy (BELOB 16%; P = 0.008) and met the primary study endpoint. The observed OS6 was 68%, with survival not reaching significance by log-rank test (P = 0.56). CONCLUSIONS: In this phase II study of relapsed high-grade astrocytoma, TVB-2640 was found to be a well-tolerated oral drug that could be safely combined with bevacizumab. The favorable safety profile and response signals support the initiation of a larger multicenter trial of TVB-2640 plus bevacizumab in astrocytoma.

Routine postoperative computed tomography (CT) scans following acetabulum open reduction internal fixation (ORIF): A survey of orthopaedic traumatologists.

OBJECTIVE: The purpose of this study was to assess the practices related to obtaining postoperative pelvic CT scans following acetabular ORIF and revision surgery rates. DESIGN: A 20-question survey published on the Orthopaedic Trauma Association (OTA) website assessed each surgeon's preference and rationale for or against the routine use of postoperative CT scans for acetabular fractures. PARTICIPANTS: Fellowship-trained orthopaedic traumatologists. MAIN OUTCOME MEASUREMENTS: We examined the percentage of surgeons ordering routine postoperative CT scans, surgeon demographics, and revision surgery rates based on these routine CT scan results. RESULTS: Responses were received from 57 surgeons. Practices varied regarding postoperative CT scans, with 16 surgeons (28%, Group A) routinely ordering them and 41 surgeons (72%, Group B) not ordering them on all patients. No significant difference in surgeon demographics were found between the groups. Majority of Group A report a revision surgery rate of <1% based on the results of the postoperative CT. Group A report routine postoperative scans were obtained to assess reduction, hardware placement, identify intra-articular fragments, and for educational purposes. Group B did not obtain routine postoperative CTs due to the following: unlikely to change postoperative treatment, adequate reduction and instrumentation placement assessed intraoperatively and by postoperative radiographs, and increased radiation exposure and cost to patients. Group B did report obtaining postop CT scans on select patients, with inadequate intraoperative imaging and postoperative neurological changes being the most common indications. CONCLUSION: The routine use of postoperative CTs following open reduction internal fixation of acetabular fractures is a controversial topic. While we recognize the role for postoperative CT scans in select patients, our study questions the clinical utility of these scans in all patients and in conclusion do not recommend this protocol.

Targeting the IL4 receptor with MDNA55 in patients with recurrent glioblastoma: Results of a phase IIb trial.

BACKGROUND: MDNA55 is an interleukin 4 receptor (IL4R)-targeting toxin in development for recurrent GBM, a universally fatal disease. IL4R is overexpressed in GBM as well as cells of the tumor microenvironment. High expression of IL4R is associated with poor clinical outcomes. METHODS: MDNA55-05 is an open-label, single-arm phase IIb study of MDNA55 in recurrent GBM (rGBM) patients with an aggressive form of GBM (de novo GBM, IDH wild-type, and nonresectable at recurrence) on their 1st or 2nd recurrence. MDNA55 was administered intratumorally as a single dose treatment (dose range of 18 to 240 ug) using convection-enhanced delivery (CED) with up to 4 stereo-tactically placed catheters. It was co-infused with a contrast agent (Gd-DTPA, Magnevist®) to assess distribution in and around the tumor margins. The flow rate of each catheter did not exceed 10µL/min to ensure that the infusion duration did not exceed 48 h. The primary endpoint was mOS, with secondary endpoints determining the effects of IL4R status on mOS and PFS. RESULTS: MDNA55 showed an acceptable safety profile at doses up to 240 µg. In all evaluable patients (n = 44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A subgroup (n = 32) consisting of IL4R High and IL4R Low patients treated with high-dose MDNA55 (>180 ug) showed the best benefit with mOS of 15 months, OS-12 of 55%. Based on mRANO criteria, tumor control was observed in 81% (26/32), including those patients who exhibited pseudo-progression (15/26). CONCLUSIONS: MDNA55 demonstrated tumor control and promising survival and may benefit rGBM patients when treated at high-dose irrespective of IL4R expression level.Trial Registration: Clinicaltrials.gov NCT02858895.

Routine Postoperative Computed Tomography Scans Following Posterior Pelvic Fixation of Pelvic Ring Fractures: A Survey of (OTA) Orthopaedic Traumatologists.

OBJECTIVE: To assess practices related to ordering computed tomography (CT) scans routinely after posterior pelvic ring fixation and revision surgery rates. DESIGN: A 20-question cross-sectional survey. PARTICIPANTS: Fellowship-trained orthopaedic traumatologists. MAIN OUTCOME MEASUREMENTS: (1) Percentage of surgeons ordering a routing postoperative CT after posterior pelvic ring fixation, (2) Revision surgery rates based on routine CT scan results. RESULTS: Responses were received from 57 surgeons. Practices varied regarding postoperative CT scans, with 20 surgeons (35%, group A) routinely ordering them and 37 surgeons (65%, group B) not ordering them on all patients. Group A were younger and with less years of experience than those in Group B. Most group A surgeons report a revision surgery rate of <1% based on results of the postoperative CT. Group A report routine postoperative scans were obtained to assess reduction, instrumentation placement, and for educational purposes. Group B did not obtain routine postoperative CTs because of the following: unlikely to change postoperative treatment course, adequate reduction and instrumentation placement assessed intraoperatively and by postoperative radiographs, and increased radiation exposure and cost to patients. Group B did report obtaining postop CT scans on select patients, with postoperative neurological deficit being the most common indication. CONCLUSIONS: The routine use of postoperative CTs following posterior fixation of pelvic ring fractures is a controversial topic. Although we recognize the role for postoperative CT scans in select patients, our study questions the clinical utility of these scans in all patients and in conclusion do not recommend this protocol.

Assessing tobramycin levels and renal function following the implantation of CaSO4 beads impregnated with tobramycin: A prospective cohort study.

This study aimed to evaluate the risk of serum tobramycin concentrations exceeding therapeutic levels after administration of calcium sulfate (CaSO4) beads containing either 240 mg or 400 mg tobramycin and 1000 mg vancomycin. This single-center, prospective. This single-center, prospective study included included Piedmont Columbus, Regional orthopedic surgery patients. Following the implantation of tobramycin into CaSO4 beads, serially measured serum tobramycin concentrations were evaluated after 6, 12, 24, and 48 hours. In addition to that, serum tobramycin concentration was evaluated after 5 days. None of the patients who received 240 mg tobramycin-impregnated beads had a tobramycin level >2 µg/mL. Six hours after implantation, the tobramycin level in 2 out of 2 (100%) patients who received 400 mg of tobramycin-impregnated beads was >2 µg/mL. One day following the surgery, the median serum creatinine was 0.85 mg/dL, with an interquartile range of 0.73 to 1.04 mg/dL. No cases of acute kidney injury were observed. This cohort demonstrated that non-nephrotoxic serum tobramycin levels could be achieved in CaSO4 beads mixed with 240 mg or 400 mg of tobramycin.

Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence.

Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiotherapy-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors, including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21-/- mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and to promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in preirradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in preirradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy. SIGNIFICANCE: This study uncovers mechanisms by which radiotherapy can promote GBM recurrence by inducing senescence in non-neoplastic brain cells, suggesting that senolytic therapy can blunt recurrent GBM growth and aggressiveness.

Modified RANO, Immunotherapy RANO, and Standard RANO Response to Convection-Enhanced Delivery of IL4R-Targeted Immunotoxin MDNA55 in Recurrent Glioblastoma.

PURPOSE: The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM). PATIENTS AND METHODS: A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied. RESULTS: A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, P < 0.0001; HR = 0.3) and mRANO (P < 0.0001; HR = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, P = 0.47; central, P = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements (P = 0.017), but not central measurements (P = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (R2 = 0.66, P < 0.0001) and centrally determined reads (R2 = 0.57, P = 0.0007). CONCLUSIONS: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.

Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET.

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.

Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma.

Evofosfamide (Evo or TH302) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard, which has shown safety and signals of efficacy in a prior phase 1 study in recurrent glioblastoma. We performed a dual center single-arm Phase II study to expand on the safety and efficacy of Evo plus bevacizumab in bevacizumab refractory glioblastoma. 33 patients with bevacizumab refractory GBM received Evo 670 mg/m2 in combination with Bevacizumab 10 mg/kg IV every 2 weeks. Assessments included adverse events, response, and survival. Median age of patients was 47 (range 19-76) and 24 (69%) were male. At the time of study entry, 9 (26%) had ongoing corticosteroid use. ECOG performance status was 0 or 1 in 83% of patients. Patients were mostly heavily pretreated with 77% have three or more prior regimens. A total of 12 patients (36%) suffered grade 3-4 drug associated adverse event (AE); no grade 5 AE were reported. Of the 33 evaluable patients, best response was PR in 3 (9%), SD in 14 (43%), and PD in 16 (48%) with responses confirmed by a second reviewer. Median time to progression of disease was 53 days (95% CI 42-113) and Median time to death was 129 days (95% CI 86-199 days). Progression free survival at 4 months (PFS-4) on Evo-Bev was 31%, which was a statistically significant improvement over the historical rate of 3%. The median overall survival of patients receiving Evo-Bevacizumab was 4.6 months (95% CI 2.9-6.6). The progression free survival of patients on Evo-Bevacizumab met the primary endpoint of progression free survival at 4 months of 31%, although the clinical significance of this may be limited. Given the patient population and Phase II design, these clinical outcomes will need further validation.

Transcranial Direct Current Stimulation (tDCS) Can Alter Cortical Excitability of the Lower Extremity in Healthy Participants: A Review and Methodological Study.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been used to alter cortical excitability of the lower extremity (LE) and to influence performance on LE tasks like ankle tracking accuracy; but no study, to our knowledge, ever reported a significant change in cortical excitability relative to sham-tDCS. Additionally, because several different electrode montages were used in previous studies, it is difficult to know how stimulation should be applied to achieve this effect. Our objective was to determine whether active-tDCS alters cortical excitability of the LE and ankle tracking accuracy relative to sham-tDCS in healthy participants. The efficacy of two electrode montages and two conductance mediums were compared. METHODS: A triple-blind, fully randomized, within-subjects study was conducted with healthy participants (N=18, 24.2 (6.6) years). Cortical recruitment curves and measures of ankle tracking accuracy for the dominant lower extremity were obtained before and after participants received active-tDCS at 2 milliamps for 20 minutes using montage-medium combinations of M1-SO:Saline, M1-SO:Gel, C1-C2:Saline, and C1-C2:Gel and a sham-tDCS condition (M1-SO: Saline). RESULTS: The motor evoked potential maximum of the recruitment curve was significantly lower for active than sham-tDCS, but only for the M1-SO:Saline combination. No other significant differences in the recruitment curve parameters or in ankle tracking were found. CONCLUSIONS: This is the first study to our knowledge to demonstrate a significant difference in cortical excitability of the LE between active and sham-tDCS conditions. Given the order in which the experimental procedures occurred, the result is consistent with the concept of a homeostatic plasticity response.

Lost to Follow-Up: Complications of an Invasive Giant Prolactinoma.

Invasive giant prolactinomas are a rare type of prolactin-secreting tumors. Most lactotroph adenomas, including giant prolactinomas, consist of the sparsely granulated subtype and respond well to medical therapy with dopamine agonists. Proptosis due to intra-orbital tumor extension and ischemic infarction are two rare complications associated with these tumors. We report a case of a 51-year-old woman with a 30-year history of a macroprolactinoma who was lost to follow-up and returned with severe proptosis, a 10-cm invasive sellar mass on imaging, and markedly elevated serum prolactin levels, consistent with invasive giant prolactinoma. She was initially managed with dopamine agonists followed by palliative debulking of the tumor, which microscopically demonstrated a highly proliferative neoplasm predominantly consisting of sparsely granulated lactotroph adenoma with a minor component of the rare and aggressive acidophil stem cell adenoma subtype. Postoperatively, she developed a large left middle cerebral artery infarct and ultimately died. This case is notable in that it demonstrates the aggressive nature of invasive giant prolactinomas when not treated and highlights two rare findings in patients with this tumor: orbital invasion and ischemic infarct.

A Review of the Analgesic Benefi ts and Potential Complications Related to Epidural Corticosteroid Injections.

The Institute of Medicine has reported that greater than 115 million adults in the United States are living with some form of chronic pain. Back pain is the most prevalent and is associated with high individual morbidity and increased healthcare costs. One approach for the management of chronic back pain involves the injection of corticosteroids in the epidural space.This interventional approach requires advanced training with techniques that vary according to the level of the vertebral column where the injection is to be performed. The primary rationale for epidural steroid injection is to reduce the inflammation surrounding the spinal nerve root as it exits the neuroforamen.Injections are performed at levels that correspond most appropriately with the patient's clinical presentation,physical findings, and radiographic findings. Epidural steroid injections are considered safe and effective, and are supported by evidence for the treatment of radicular pain. Complications from epidural steroid injections are rare but can be catastrophic, including permanent disability and death. The focus of this article is to understand how technique and selection of specific corticosteroids used for epidural injection can manage chronic back and radicular pain effectively while minimizing risk that leads to unnecessary harm.

Radiation-Induced DNA Damage Cooperates with Heterozygosity of TP53 and PTEN to Generate High-Grade Gliomas.

Glioblastomas are lethal brain tumors that are treated with conventional radiation (X-rays and gamma rays) or particle radiation (protons and carbon ions). Paradoxically, radiation is also a risk factor for GBM development, raising the possibility that radiotherapy of brain tumors could promote tumor recurrence or trigger secondary gliomas. In this study, we determined whether tumor suppressor losses commonly displayed by patients with GBM confer susceptibility to radiation-induced glioma. Mice with Nestin-Cre-driven deletions of Trp53 and Pten alleles were intracranially irradiated with X-rays or charged particles of increasing atomic number and linear energy transfer (LET). Mice with loss of one allele each of Trp53 and Pten did not develop spontaneous gliomas, but were highly susceptible to radiation-induced gliomagenesis. Tumor development frequency after exposure to high-LET particle radiation was significantly higher compared with X-rays, in accordance with the irreparability of DNA double-strand breaks (DSB) induced by high-LET radiation. All resultant gliomas, regardless of radiation quality, presented histopathologic features of grade IV lesions and harbored populations of cancer stem-like cells with tumor-propagating properties. Furthermore, all tumors displayed concomitant loss of heterozygosity of Trp53 and Pten along with frequent amplification of the Met receptor tyrosine kinase, which conferred a stem cell phenotype to tumor cells. Our results demonstrate that radiation-induced DSBs cooperate with preexisting tumor suppressor losses to generate high-grade gliomas. Moreover, our mouse model can be used for studies on radiation-induced development of GBM and therapeutic strategies. SIGNIFICANCE: This study uncovers mechanisms by which ionizing radiation, especially particle radiation, promote GBM development or recurrence.

Oropharyngeal CSF Leak Secondary to Anterior Cervical Discectomy and Fusion.

We present a case of an oropharyngeal cerebrospinal fluid (CSF) fistula in a patient that presented with headache, rhinorrhea, and pneumocephalus years after an anterior cervical discectomy and fusion. Imaging suggested a defect in the fovea ethmoidalis, but endoscopic surgery revealed the defect in the oropharynx. A second procedure was performed to remove the spinal hardware and repair the leak. This case is not only unique in the literature but also highlights the importance of maintaining a broad differential diagnosis to include rare complications and shows that despite dramatic improvements in imaging, locating CSF leaks still presents a challenge.

Ambulatory care-sensitive emergency visits among patients with medical home access.

OBJECTIVES: To characterize patterns of emergency department (ED) utilization for ambulatory care-sensitive conditions (ACSCs) among patients with established care within a patient-centered medical home. STUDY DESIGN: Retrospective chart review using Michigan Medicine's (formerly University of Michigan Health System) electronic health record. METHODS: Ten general medicine (GM) physicians reviewed 256 ambulatory care-sensitive ED encounters that occurred between January 1, 2014, and December 31, 2014, among patients of a GM medical home. Physician reviewers abstracted from the medical record the day and time of ED presentation and the source of ED referral (eg, patient self-referral vs physician referral). Physicians assessed the appropriateness of the care location (eg, ED vs primary care). Interrater reliability was assessed using the kappa statistic, and the χ2 test was used to assess differences in the appropriateness of the care location according to ED referral source. RESULTS: Compared with all other days of the week, the fewest number of ED visits occurred on weekend days, and nearly half of patients (48%) presented to the ED after daytime hours, which were defined as 8 am to 3:59 pm. The majority (n = 185; 72%) of patients were self-referred to the ED. The ED was considered the appropriate care location in more than half (53%) of the reviewed cases. Among the 119 cases considered appropriate for GM management, the majority (86%) were self-referred to the ED. CONCLUSIONS: Patients with ACSCs often presented to the ED without contacting their medical home. Frequently, the ED is the most appropriate location given symptoms at presentation.

Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study.

Background: Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev-refractory GBM. Methods: Twenty-eight patients with Bev-refractory GBM were enrolled in a dose escalation study receiving from 240 mg/m2 (cohort 1) to 670 mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev. Patients deemed surgical candidates underwent a single dose of Evo or placebo with pimonidazole immediately prior to surgery for biomarker evaluation, followed by dose escalation upon recovery. Assessments included adverse events, response, and survival. Results: Evo plus Bev was well tolerated up to and including the maximum dose of 670 mg/m2, which was determined to be the recommended phase II dose. Overall response rate was 17.4%, with disease control (complete response, partial response, and stable disease) observed in 14 (60.9%) of the 23 patients. The ratio of enhancement to non-enhancement was significant on log-rank analysis with time to progression (P = 0.023), with patients having a ratio of less than 0.37 showing a median progression-free survival of 98 days versus 56 days for those with more enhancement. Conclusions: Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation.