Association of External Ventricular Drain Wean Strategy with Shunt Placement and Length of Stay in Subarachnoid Hemorrhage: A Prospective Multicenter Study.

BACKGROUND: Survivors of aneurysmal subarachnoid hemorrhage (SAH) face a protracted intensive care unit (ICU) course and are at risk for developing refractory hydrocephalus with the need for a permanent ventriculoperitoneal shunt (VPS). Management of the external ventricular drain (EVD) used to provide temporary cerebrospinal fluid diversion may influence the need for a VPS, ICU length of stay (LOS), and drain complications, but the optimal EVD management approach is unknown. Therefore, we sought to determine the effect of EVD discontinuation strategy on VPS rate. METHODS: This was a prospective multicenter observational study at six neurocritical care units in the United States. The target population included adults with suspected aneurysmal SAH who required an EVD. Patients were preassigned to rapid or gradual EVD weans based on their treating center. The primary outcome was the rate of VPS placement. Secondary outcomes were EVD duration, ICU LOS, hospital LOS, and drain complications. RESULTS: A rapid EVD wean protocol was associated with a lower rate of VPS placement, including a delayed posthospitalization shunt, in an adjusted Cox proportional analysis (hazard ratio 0.52 [p = 0.041]) and adjusted logistic regression model (odds ratio 0.43 [95% confidence interval 0.18-1.03], p = 0.057). A rapid wean was also associated with 2.1 fewer EVD days (p = 0.007) and saved an estimated 2.5 ICU days (p = 0.049), as compared with a gradual wean protocol. There were fewer nonfunctioning EVDs in the rapid group (odds ratio 0.32 [95% confidence interval 0.11-0.92]). Furthermore, we found that the time to first wean and the number of weaning attempts were important independent covariates that affected the likelihood of receiving a VPS and the duration of ICU admission. CONCLUSIONS: A rapid EVD wean was associated with decreased rates of VPS placement, decreased ICU LOS, and decreased drain complications in survivors of aneurysmal SAH. These findings suggest that a randomized multicentered controlled study comparing rapid vs. gradual EVD weaning protocols is justified.

Deconstructing Poststroke Delirium in a Prospective Cohort of Patients With Intracerebral Hemorrhage.

OBJECTIVES: Poststroke delirium may be underdiagnosed due to the challenges of disentangling delirium symptoms from underlying neurologic deficits. We aimed to determine the prevalence of individual delirium features and the frequency with which they could not be assessed in patients with intracerebral hemorrhage. DESIGN: Prospective observational cohort study. SETTING: Neurocritical Care and Stroke Units at a university hospital. PATIENTS: Consecutive patients with intracerebral hemorrhage from February 2018 to May 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An attending neurointensivist performed 257 total daily assessments for delirium on 60 patients (mean age 68.0 [SD 18.4], 62% male, median intracerebral hemorrhage score 1.5 [interquartile range 1-2], delirium prevalence 57% [n = 34]). Each assessment included the Confusion Assessment Method for the ICU, Intensive Care Delirium Screening Checklist, a focused bedside cognitive examination, chart review, and nurse interview. We characterized individual symptom prevalence and established delirium diagnoses using Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria, then compared performance of the Confusion Assessment Method for the ICU and Intensive Care Delirium Screening Checklist against reference-standard expert diagnosis. Symptom fluctuation (61% of all assessments), psychomotor changes (46%), sleep-wake disturbances (46%), and impaired arousal (37%) had the highest prevalence and were never rated "unable to assess," while inattention (36%), disorientation (27%), and disorganized thinking (18%) were also common but were often rated 'unable to assess' (32%, 43%, and 44% of assessments, respectively), most frequently due to aphasia (32% of patients). Including nonverbal assessments of attention decreased the frequency of 'unable to assess' ratings to 11%. Since the Intensive Care Delirium Screening Checklist may be positive without the presence of symptoms that require verbal assessment, it was more accurate (sensitivity = 77%, specificity = 97%, area under the receiver operating characteristic curve, 0.87) than the Confusion Assessment Method for the ICU (sensitivity = 41%, specificity = 88%, area under the receiver operating characteristic curve, 0.64). CONCLUSIONS: Delirium is common after intracerebral hemorrhage, but severe neurologic deficits may confound its assessment and lead to underdiagnosis. The Intensive Care Delirium Screening Checklist's inclusion of nonverbal features may make it more accurate than the Confusion Assessment Method for the ICU in patients with neurologic deficits, but novel tools designed for such patients may be warranted.

Validation of NRG oncology/RTOG-0129 risk groups for HPV-positive and HPV-negative oropharyngeal squamous cell cancer: Implications for risk-based therapeutic intensity trials.

BACKGROUND: Radiation Therapy Oncology Group (RTOG)-0129 recursive partitioning analysis was the basis for risk-based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors' knowledge, the question of whether RTOG-0129 overall survival (OS) estimates for low-risk, intermediate-risk, and high-risk groups are similar in other data sets or applicable to progression-free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG-0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups. METHODS: Prospective randomized clinical trials were analyzed retrospectively. RTOG-0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG-0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible. RESULTS: There was a total of 260 patients and 287 patients, respectively, from RTOG-0129 and RTOG-0522, with median follow-ups for surviving patients of 7.9 years (range, 1.7-9.9 years) and 4.7 years (range, 0.1-7.0 years), respectively. Previous OS differences in RTOG-0129 persisted at 5 years. In RTOG-0522, the 5-year OS rates for the low-risk, intermediate-risk, and high-risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5-year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG-0522 among a subgroup of patients considered to be at very good risk (p16-positive disease, smoking history of ≤10 pack-years, and classified with T1-T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5-year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group. CONCLUSIONS: RTOG-0129 risk groups persisted at 5 years and were reproducible in RTOG-0522. However, there was variability in the estimates. These data underscore the importance of long-term follow-up and appropriate patient selection in therapeutic deintensification trials.

External beam radiotherapy with or without concurrent chemotherapy in advanced or recurrent non-anaplastic non-medullary thyroid cancer.

BACKGROUND AND OBJECTIVES: To review clinical outcomes and toxicities in locally advanced differentiated thyroid cancer patients treated with external beam radiotherapy (EBRT) with or without concurrent chemotherapy (CCRT). METHODS: Between 1990 and 2012, 66 patients with gross residual/unresectable non-anaplastic non-medullary thyroid cancer were treated with EBRT. RESULTS: The median overall survival was 42.0 months. The overall locoregional progression-free survival (LPFS) at 3 years was 77.3%. CCRT resulted in a non-significant improvement in LPFS (90.0% vs. 73.0%, P = 0.347). Poorly differentiated histology had significantly improved LPFS (89.4% vs. 66.1%, P = 0.020), despite a significantly worse distant metastasis-free survival (43.9% vs. 82.5%, P = 0.023). Acute treatment-related toxicity included dermatitis, mucositis, and dysphagia with grade three rates of 12.1%, 19.7%, and 16.7%, respectively. The incidence of late toxicity was low. CCRT was only associated with a significant greater rate of acute grade 3 hoarseness (10.0% vs. 0.0%, P = 0.033), but with no difference in the rate of grade 2 late toxicity. CONCLUSIONS: EBRT is a safe and effective treatment modality with 90% LPFS at 3 years in patients with gross residual or unresectable non-anaplastic, non-medullary thyroid carcinoma treated with CCRT. Further incorporation of EBRT with concurrent chemotherapy may result in improved disease control.

Long-term regional control in the observed neck following definitive chemoradiation for node-positive oropharyngeal squamous cell cancer.

Traditionally, patients treated with chemoradiotherapy for node-positive oropharyngeal squamous cell carcinoma (N+ OPSCC) have undergone a planned neck dissection (ND) after treatment. Recently, negative post-treatment positron-emission tomography (PET)/computed tomography (CT) imaging has been found to have a high negative predictive value for the presence of residual disease in the neck. Here, we present the first comprehensive analysis of a large, uniform cohort of N+ OPSCC patients achieving a PET/CT-based complete response (CR) after chemoradiotherapy, and undergoing observation, rather than ND. From 2002 to 2009, 302 patients with N+ OPSCC treated with 70 Gy intensity-modulated radiation therapy and concurrent chemotherapy underwent post-treatment clinical assessment including PET/CT. CR was defined as no evidence of disease on clinical examination and post-treatment PET/CT. ND was reserved for patients with

Disparities in Decompressive Cranial Surgery Utilization in Severe Traumatic Brain Injury Patients without a Primary Extra-Axial Hematoma: A U.S. Nationwide Study.

OBJECTIVE: Decompressive craniectomy is recommended to reduce mortality in severe traumatic brain injury (TBI). Disparities exist in TBI treatment outcomes; however, data on disparities pertaining to decompressive craniectomy utilization is lacking. We investigated these disparities, focusing on race, insurance, sex, and age. METHODS: Hospitalizations (2004-2014) were retrospectively extracted from the Nationwide Inpatient Sample. The criteria included are as follows: age ≥18 years and indicators of severe TBI diagnosis. Poor outcomes were defined as discharge to institutional care and death. Multivariable logistic regression models were used to assess the effects of race, insurance, age, and sex, on craniectomy utilization and outcomes. RESULTS: Of 349,164 hospitalized patients, 6.8% (n = 23,743) underwent craniectomy. White (odds ratio [OR] = 0.50, 95% confidence interval [CI] = 0.44-0.57; P < 0.001) and Black (OR = 0.45, 95% CI = 0.32-0.64; P = 0.003) Medicare beneficiaries were less likely to undergo craniectomy. Medicare (P < 0.0001) and Medicaid beneficiaries (P < 0.0001) of all race categories had poorer outcomes than privately insured White patients. Black (OR = 1.2, 95% CI = 1.08-2.34; P = 0.001) patients with private insurance and Black (OR = 1.39, 95% CI = 1.22-1.58; P < 0.0001) Medicaid beneficiaries had poorer outcomes than privately insured White patients (P < 0.0001). Older patients (OR = 0.74, 95%, CI = 0.71-0.76; P < 0.001) were less likely to undergo craniectomy and were more likely to have poorer outcomes. Females (OR = 0.82, 95% CI = 0.76-0.88; P < 0.001) were less likely to undergo craniectomy. CONCLUSIONS: There are disparities in race, insurance status, sex, and age in craniectomy utilization and outcome. This data highlights the necessity to appropriately address these disparities, especially race and sex, and actively incorporate these factors in clinical trial design and enrollment.

Marker-assisted enhancement of bacterial blight (Xanthomonas oryzae pv. oryzae) resistance in a salt-tolerant rice variety for sustaining rice production of tropical islands.

Introduction: Bacterial blight (BB) caused by Xanthomonas oryzae pv. oryzae is a major disease of rice, specially in the tropical regions of the world. Developing rice varieties with host resistance against the disease is the most effective and economical solution for managing the disease. Methods: Pyramiding resistance genes (Xa4, xa5, xa13,and Xa21) in popular rice varieties using marker-assisted backcross breeding (MABB) has been demonstrated as a cost-effective and sustainable approach for establishing durable BB resistance. Here, we report our successful efforts in introgressing four resistance genes (Xa4, xa5, xa13, and Xa21) from IRBB60 to CARI Dhan 5, a popular salt-tolerant variety developed from a somaclonal variant of Pokkali rice, through functional MABB. Results and discussion: Both BB and coastal salinity are among the major challenges for rice production in tropical island and coastal ecosystems. Plants with four, three, and two gene pyramids were generated, which displayed high levels of resistance to the BB pathogen at the BC3F2 stage. Under controlled salinity microplot environments, the line 131-2-175-1223 identified with the presence of three gene pyramid (Xa21+xa13+xa5) displayed notable resistance across locations and years as well as exhibited a salinity tolerance comparable to the recurrent parent, CARI Dhan 5. Among two BB gene combinations (Xa21+xa13), two lines, 17-1-69-334 and 46-3-95-659, demonstrated resistance across locations and years, as well as salt tolerance and grain production comparable to CARI Dhan 5. Besides salinity tolerance, five lines, 17-1-69-179, 46-3-95-655, 131-2-190-1197, 131-2-175-1209, and 131-2-175-1239, exhibited complete resistance to BB disease. Following multilocation testing, potential lines have been identified that can serve as a prospective candidate for producing varieties for the tropical Andaman and Nicobar Islands and other coastal locations, which are prone to BB and coastal salinity stresses.

Venous Thromboembolism Risk and Outcomes Following Decompressive Craniectomy in Severe Traumatic Brain Injury: An Analysis of the Nationwide Inpatient Sample Database.

OBJECTIVE: Traumatic brain injury (TBI) is a risk factor for venous thromboembolism (VTE). The risk of VTE after decompressive craniectomy (DC) and its effects on the outcomes are unknown. We assessed the incidence of VTE, associated risk factors, and effects on the outcomes. METHODS: Using the National Inpatient Sample database, the hospitalizations of patients aged ≥18 years with a severe TBI diagnosis from 2004 to 2014 were extracted. The outcome was discharge status without mortality. Multivariable logistic and linear regressions were used. RESULTS: Of the 349,165 TBI hospitalizations, 23,813 (6.82%) had undergone DC and 14,175 (4.06%) had developed VTE. The VTE incidence was higher after DC compared with no DC (6.14% vs. 3.91%; P < 0.0001). DC (odds ratio [OR], 1.29; P < 0.005) was an independent predictor for the development of VTE. Age (OR, 1.26; P < 0.005), chronic lung disease (OR, 1.58; P < 0.05), electrolyte imbalance (OR, 1.43; P < 0.05), liver disease (OR, 0.10; P < 0.05), urinary tract infection (OR, 1.56; P < 0.05), pneumonia (OR, 2.03; P < 0.0001), and sepsis (OR, 1.57; P < 0.05) were significantly associated with the development of VTE. Obesity (OR, 2.09; P > 0.05) and spine injury (OR, 2.03; P > 0.05) showed a trend toward significance. VTE was associated with worse discharge outcomes (OR, 1.40; P < 0.05), longer lengths of stay (OR, 1.01; P < 0.00001), and higher costs (P < 0.0001). CONCLUSIONS: Our study showed an independent association between DC and an increased risk of VTE for patients with severe TBI. The development of VTE after DC increased the proportion of poor outcomes, prolonged the length of stay, and increased the hospitalization costs. Older patients with obesity, an electrolyte imbalance, chronic lung disease, spine injury, and infections were at a greater risk of VTE after DC. These risk factors could help in considering VTE prophylaxis for these patients.

Association of Early White Blood Cell Trend with Outcomes in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: An increasing white blood cell (WBC) count in early course of aneurysmal subarachnoid hemorrhage (SAH) can indicate a systemic inflammatory state triggered by the initial insult. We sought to determine the significance of the early WBC trend as a potential predictor of outcomes. METHODS: We analyzed a cohort of consecutive patients with aneurysmal SAH. The WBC values in first 5 days of admission, plus relevant clinical and imaging data, and modified Rankin Scale (mRS) at 3 months after hospital discharge were retrieved and analyzed. Favorable outcome was defined as mRS 0-3. The association between WBC counts and outcomes including mRS and delayed cerebral ischemia (DCI) was determined using binary logistic regression models. We used receiver operating characteristic curve analysis to assess accuracy of WBC in predicting outcomes. RESULTS: We included 167 patients in final analysis. Mean age was 56.4 (standard deviation [SD] 14.8) years, and 65% (109) of patients were female. Peak WBC was greater in patients with poor functional outcome (mean 17 × 109 cells/L, SD 6.4 vs. 13.5 × 109 cells/L SD 4.7). Combining peak WBC with modified Fisher scale slightly increased accuracy in predicting DCI (area under the curve 0.670, 95% confidence interval 0.586-0.755) compared with each component alone. CONCLUSIONS: WBC count in the early course of SAH may have prognostic values in predicting DCI and functional outcome. WBC count monitoring may be used in conjunction with other clinical and radiographic tools to stratify patients with SAH into high- and low-risk groups to tailor neuromonitoring and treatment strategies.

Common biomarkers of physiologic stress and associations with delirium in patients with intracerebral hemorrhage.

PURPOSE: To examine associations between physiologic stress and delirium in the setting of a direct neurologic injury. MATERIALS AND METHODS: We obtained initial neutrophil-to-lymphocyte ratio (NLR), glucose, and troponin in consecutive non-comatose patients with non-traumatic intracerebral hemorrhage (ICH) over 1 year, then used multivariable regression models to determine associations between each biomarker and incident delirium. Delirium diagnoses were established using DSM-5-based methods, with exploratory analyses further categorizing delirium as first occurring <24 h ("early-onset") or > 24 h after presentation ("later-onset"). RESULTS: Of 284 patients, delirium occurred in 55% (early-onset: 39% [n = 111]; later-onset: 16% [n = 46]). Patients with delirium had higher NLR (mean 9.0 ± 10.4 vs. 6.4 ± 5.5; p = 0.01), glucose (mean 146.5 ± 59.6 vs. 129.9 ± 41.4 mg/dL; p = 0.008), and a higher frequency of elevated troponin (>0.05 ng/mL; 21% vs. 10%, p = 0.02). In adjusted models, elevated NLR (highest quartile: OR 3.4 [95% CI 1.5-7.8]), glucose (>180 mg/dL: OR 3.1 [95% CI 1.1-8.2]), and troponin (OR 3.0 [95% CI 1.2-7.2]) were each associated with delirium, but only initial NLR was specifically associated with later-onset delirium and with delirium in non-mechanically ventilated patients. CONCLUSIONS: Stress-related biomarkers corresponding to multiple organ systems are associated with ICH-related delirium. Early NLR elevation may also predict delayed-onset delirium, potentially implicating systemic inflammation as a contributory delirium mechanism.

Short- and long-term opioid use in survivors of subarachnoid hemorrhage.

OBJECTIVES: Opioids are frequently used for analgesia in patients with acute subarachnoid hemorrhage (SAH) due to a high prevalence of headache and neck pain. However, it is unclear if this practice may pose a risk for opioid dependence, as long-term opioid use in this population remains unknown. We sought to determine the prevalence of opioid use in SAH survivors, and to identify potential risk factors for opioid utilization. METHODS: We analyzed a cohort of consecutive patients admitted with non-traumatic and suspected aneurysmal SAH to an academic referral center. We included patients who survived hospitalization and excluded those who were not opioid-naïve. Potential risk factors for opioid prescription at discharge, 3 and 12 months post-discharge were assessed. RESULTS: Of 240 SAH patients who met our inclusion criteria (mean age 58.4 years [SD 14.8], 58% women), 233 (97%) received opioids during hospitalization and 152 (63%) received opioid prescription at discharge. Twenty-eight patients (12%) still continued to use opioids at 3 months post-discharge, and 13 patients (6%) at 12-month follow up. Although patients with poor Hunt and Hess grades (odds ratio 0.19, 95% CI 0.06-0.57) and those with intraventricular hemorrhage (odds ratio 0.38, 95% CI 0.18-0.87) were less likely to receive opioid prescriptions at discharge, we did not find significant differences between patients who had long-term opioid use and those who did not. CONCLUSION: Opioids are regularly used in both the acute SAH setting and immediately after discharge. A considerable number of patients also continue to use opioids in the long-term. Opioid-sparing pain control strategies should be explored in the future.

Characterization and clinical validation of patient-specific three-dimensional printed tissue-equivalent bolus for radiotherapy of head and neck malignancies involving skin.

PURPOSE: Megavoltage radiotherapy to irregular superficial targets is challenging due to the skin sparing effect. We developed a three-dimensional bolus (3DB) program to assess the clinical impact on dosimetric and patient outcomes. MATERIALS AND METHODS: Planar commercial bolus (PCB) and 3DB density, clarity, and net bolus effect were rigorously evaluated prior to clinical implementation. After IRB approval, patients with cutaneous or locally advanced malignancies deemed to require bolus for radiotherapy treatment were treated with custom 3DB. RESULTS: The mean density of 3DB and PCB was of 1.07 g/cm 3 and 1.12 g/cm3, respectively. 3DB optic clarity was superior versus PCB at any material thickness. Phantom measurements of superficial dose with 3DB and PCB showed excellent bolus effect for both materials. 3DB reduced air gaps compared with PCB - particularly in irregular areas such as the ear, nose, and orbit. A dosimetric comparison of 3DB and PCB plans showed equivalent superficial homogeneity for 3DB and PCB (3DB median HI 1.249, range 1.111-1.300 and PCB median HI 1.165, range 1.094-1.279), but better conformity with 3DB (3DB median CI 0.993, range 0.962-0.993) versus PCB (PCB median CI 0.977, range 0.601-0.991). Patient dose measurements using 3DB confirm the delivered superficial dose was within 1% of the intended prescription (95% CI 97-102%; P = 0.11). CONCLUSIONS: 3DB improves radiotherapy plan conformity, reduces air gap volume in irregular superficial areas which could affect superficial dose delivery, and provides excellent dose coverage to irregular superficial targets.

Arrival blood pressure in hypertensive and non-hypertensive spontaneous intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Hypertension is a known risk factor for intracerebral hemorrhage (ICH), but it is unclear whether blood pressure (BP) at hospital arrival can be used to distinguish hypertensive ICH from non-hypertensive etiologies. PATIENTS AND METHODS: We performed a single-center cohort study using data from consecutive ICH patients over 12 months. ICH characteristics including etiology were prospectively adjudicated by two attending neurologists. Using adjusted linear regression models, we compared first recorded systolic BPs (SBP) and mean arterial pressures (MAP) in patients with hypertensive vs. other ICH etiologies. We then used area under the ROC curve (AUC) analysis to determine the accuracy of admission BP in differentiating between hypertensive and non-hypertensive ICH. RESULTS: Of 311 patients in our cohort (mean age 70.6 ± 15.6, 50% male, 83% white), the most frequent ICH etiologies were hypertension (50%) and cerebral amyloid angiopathy (CAA; 22%). Mean SBP and MAP for patients with hypertensive ICH was 175.1 ± 32.9 mmHg and 120.4 ± 22.9 mmHg, respectively, compared to 156.4 ± 28.0 mmHg and 109.6 ± 20.3 mmHg in non-hypertensive ICH (p < .001). Adjusted models showed that hypertensive ICH patients had higher BPs than those with CAA (mean SBP difference 10.7 mmHg [95% CI 0.8-20.5]; mean MAP difference 8.1 mmHg [1.1-15.0]) and especially patients with other non-CAA causes (mean SBP difference 23.9 mmHg [15.3-32.4]; mean MAP difference 14.5 mmHg [8.5-20.6]). However, on a patient-level, arrival BP did not reliably discriminate between hypertensive and non-hypertensive etiologies (AUC 0.660 [0.599-0.720]). CONCLUSIONS: Arrival BP differs between hypertensive and non-hypertensive ICH but should not be used as a primary determinant of etiology, as hypertension may be implicated in various subtypes of ICH.

The impact of delirium on withdrawal of life-sustaining treatment after intracerebral hemorrhage.

OBJECTIVE: To determine the impact of delirium on withdrawal of life-sustaining treatment (WLST) after intracerebral hemorrhage (ICH) in the context of established predictors of poor outcome, using data from an institutional ICH registry. METHODS: We performed a single-center cohort study on consecutive patients with ICH admitted over 12 months. ICH features were prospectively adjudicated, and WLST and corresponding hospital day were recorded retrospectively. Patients were categorized using DSM-5 criteria as never delirious, ever delirious (either on admission or later during hospitalization), or persistently comatose. We determined the impact of delirium on WLST using Cox regression models adjusted for demographics and ICH predictors (including Glasgow Coma Scale score), then used logistic regression with receiver operating characteristic curve analysis to compare the accuracy of ICH score-based models with and without delirium category in predicting WLST. RESULTS: Of 311 patients (mean age 70.6 ± 15.6, median ICH score 1 [interquartile range 1-2]), 50% had delirium. WLST occurred in 26%, and median time to WLST was 1 day (0-6). WLST was more frequent in patients who developed delirium (adjusted hazard ratio 8.9 [95% confidence interval (CI) 2.1-37.6]), with high rates of WLST in both early (occurring ≤24 hours from admission) and later delirium groups. An ICH score-based model was strongly predictive of WLST (area under the curve [AUC] 0.902 [95% CI 0.863-0.941]), and the addition of delirium category further improved the model's accuracy (AUC 0.936 [95% CI 0.909-0.962], p = 0.004). CONCLUSION: Delirium is associated with WLST after ICH regardless of when it occurs. Further study on the impact of delirium on clinician and surrogate decision-making is warranted.

Linear Accelerator-Based Radiotherapy Simulation Using On-Board Kilovoltage Cone-Beam Computed Tomography for 3-Dimensional Volumetric Planning and Rapid Treatment in the Palliative Setting.

BACKGROUND: Palliation of advanced disease using radiotherapy can create difficult clinical situations where standard computed tomography simulation and immobilization techniques are not feasible. We developed a linear accelerator-based radiotherapy simulation technique using nonstandard patient positioning for head and neck palliation using on-board kilovoltage cone-beam computed tomography for 3-D volumetric planning and rapid treatment. Material and Methods: We proved cone-beam computed tomography simulation feasibility for semi-upright patient positioning using an anthropomorphic phantom on a clinical Elekta-Synergy linear accelerator. Cone-beam computed tomography imaging parameters were optimized for high-resolution image reconstruction and to ensure mechanical clearance. The patient was simulated using a cone-beam computed tomography-based approach and the cone-beam computed tomography digital imaging and communications in medicine file was imported to the treatment planning software to generate radiotherapy target volumes. Rapid planning was achieved by using a 3-level bulk density correction for air, soft tissue, and bone set at 0, 1.0, and 1.4 g/cm3, respectively. RESULTS: Patient volumetric imaging was obtained through cone-beam computed tomography simulation and treatment was delivered as planned without incident. Bulk density corrections were verified against conventionally simulated patients where differences were less than 1%. Conclusion: We successfully developed and employed a semi-upright kilovoltage cone-beam computed tomography-based head and neck simulation and treatment planning method for 3-D conformal radiotherapy delivery. This approach provides 3-D documentation of the radiotherapy plan and allows tabulation of quantitative spatial dose information which is valuable if additional palliative treatments are needed in the future. This is a potentially valuable technique that has broad clinical applicability for benign and palliative treatments across multiple disease sites-particularly where standard supine simulation and immobilization techniques are not possible.

Intermittent CSF drainage and rapid EVD weaning approach after subarachnoid hemorrhage: association with fewer VP shunts and shorter length of stay.

OBJECTIVE: There is variability and uncertainty about the optimal approach to the management and discontinuation of an external ventricular drain (EVD) after subarachnoid hemorrhage (SAH). Evidence from single-center randomized trials suggests that intermittent CSF drainage and rapid EVD weans are safe and associated with shorter ICU length of stay (LOS) and fewer EVD complications. However, a recent survey revealed that most neurocritical care units across the United States employ continuous CSF drainage with a gradual wean strategy. Therefore, the authors sought to determine the optimal EVD management approach at their institution. METHODS: The authors reviewed records of 200 patients admitted to their institution from 2010 to 2016 with aneurysmal SAH requiring an EVD. In 2014, the neurocritical care unit of the authors' institution revised the internal EVD management guidelines from a continuous CSF drainage with gradual wean approach (continuous/gradual) to an intermittent CSF drainage with rapid EVD wean approach (intermittent/rapid). The authors performed a retrospective multivariable analysis to compare outcomes before and after the guideline change. RESULTS: The authors observed a significant reduction in ventriculoperitoneal (VP) shunt rates after changing to an intermittent CSF drainage with rapid EVD wean approach (13% intermittent/rapid vs 35% continuous/gradual, OR 0.21, p = 0.001). There was no increase in delayed VP shunt placement at 3 months (9.3% vs 8.6%, univariate p = 0.41). The intermittent/rapid EVD approach was also associated with a shorter mean EVD duration (10.2 vs 15.6 days, p < 0.001), shorter ICU LOS (14.2 vs 16.9 days, p = 0.001), shorter hospital LOS (18.2 vs 23.7 days, p < 0.0001), and lower incidence of a nonfunctioning EVD (15% vs 30%, OR 0.29, p = 0.006). The authors found no significant differences in the rates of symptomatic vasospasm (24.6% vs 20.2%, p = 0.52) or ventriculostomy-associated infections (1.3% vs 8.8%, OR 0.30, p = 0.315) between the 2 groups. CONCLUSIONS: An intermittent CSF drainage with rapid EVD wean approach is associated with fewer VP shunt placements, fewer complications, and shorter LOS compared to a continuous CSF drainage with gradual EVD wean approach. There is a critical need for prospective multicenter studies to determine if the authors' experience is generalizable to other centers.

Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury.

Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.

Modeling the Cellular Response of Lung Cancer to Radiation Therapy for a Broad Range of Fractionation Schedules.

Purpose: To demonstrate that a mathematical model can be used to quantitatively understand tumor cellular dynamics during a course of radiotherapy and to predict the likelihood of local control as a function of dose and treatment fractions.Experimental Design: We model outcomes for early-stage, localized non-small cell lung cancer (NSCLC), by fitting a mechanistic, cellular dynamics-based tumor control probability that assumes a constant local supply of oxygen and glucose. In addition to standard radiobiological effects such as repair of sub-lethal damage and the impact of hypoxia, we also accounted for proliferation as well as radiosensitivity variability within the cell cycle. We applied the model to 36 published and two unpublished early-stage patient cohorts, totaling 2,701 patients.Results: Precise likelihood best-fit values were derived for the radiobiological parameters: α [0.305 Gy-1; 95% confidence interval (CI), 0.120-0.365], the α/ß ratio (2.80 Gy; 95% CI, 0.40-4.40), and the oxygen enhancement ratio (OER) value for intermediately hypoxic cells receiving glucose but not oxygen (1.70; 95% CI, 1.55-2.25). All fractionation groups are well fitted by a single dose-response curve with a high χ2 P value, indicating consistency with the fitted model. The analysis was further validated with an additional 23 patient cohorts (n = 1,628). The model indicates that hypofractionation regimens overcome hypoxia (and cell-cycle radiosensitivity variations) by the sheer impact of high doses per fraction, whereas lower dose-per-fraction regimens allow for reoxygenation and corresponding sensitization, but lose effectiveness for prolonged treatments due to proliferation.Conclusions: This proposed mechanistic tumor-response model can accurately predict overtreatment or undertreatment for various treatment regimens. Clin Cancer Res; 23(18); 5469-79. ©2017 AACR.