Association of patient socioeconomic status with outcomes after palliative treatment for disseminated cancer.

BACKGROUND: Palliative treatment has been associated with improved quality of life and survival for a wide variety of metastatic cancers. However, it is unclear whether the benefits of palliative treatment are uniformly experienced across the US cancer population. We evaluated patterns and outcomes of palliative treatment based on socioeconomic, sociodemographic and treating facility characteristics. METHODS: Patients diagnosed between 2008 and 2019 with Stage IV primary cancer of nine organ sites were analyzed in the National Cancer Database. The association between identified variables, and outcomes concerning the administration of palliative treatment were analyzed with multivariable logistic regression and Cox proportional hazard models. RESULTS: Overall 238,995 (23.6%) of Stage IV patients received palliative treatment, which increased over time for all cancers (from 20.7% in 2008 to 25.6% in 2019). Palliative treatment utilization differed significantly by region (West less than Northeast, OR: 0.55 [0.54-0.56], p < 0.001) and insurance payer status (uninsured greater than private insurance, OR: 1.35 [1.32-1.39], p < 0.001). Black race and Hispanic ethnicity were also associated with lower rates of palliative treatment compared to White and non-Hispanics respectively (OR for Blacks: 0.91 [0.90-0.93], p < 0.001 and OR for Hispanics: 0.79 [0.77-0.81] p < 0.001). CONCLUSIONS: There are important differences in the utilization of palliative treatment across different populations in the United States. A better understanding of variability in palliative treatment use and outcomes may identify opportunities to improve informed decision making and optimize quality of care at the end-of-life.

Perioperative morbidity and 3-year survival in non-intubated thoracoscopic surgery: a propensity matched analysis.

Background: Non-intubated thoracoscopic surgery with spontaneous breathing is rarely utilized, but may have several advantages over standard intubation, especially in those with significant cardiopulmonary comorbidities. In this study we evaluate the safety, feasibility, and 3-year survival of thoracoscopic surgery without endotracheal intubation for oncologic and non-oncologic indications. Methods: All consecutive patients [2018-2022] selected for lung resection or other pleural space intervention under local anesthesia and sedation were compared to a cohort undergoing elective thoracoscopic procedures with endotracheal intubation. A propensity-score matched cohort was used to compare perioperative outcomes and 3-year overall survival. Results: A total of 72 patients underwent thoracoscopic surgery without intubation compared to 1,741 who were intubated. Non-intubated procedures included 19 lobectomies (26.4%), 9 segmentectomies (12.5%), 25 wedge resections (34.7%), and 19 pleural or mediastinal resections (26.4%). Non-intubated patients had a lower average body mass index (BMI; 24.6 vs. 27.1 kg/m2, P<0.001) and a higher comorbidity burden. Primary lung cancer was the indication in 30 (41.7%) non-intubated patients. The non-intubated cohort had no operative or 30-day mortality. After propensity-score matching, there was no significant difference in pre-operative factors. In propensity-score matched analysis, non-intubated patients had shorter median total operating room time (109 vs. 159 min, P<0.001) and procedure time (69 vs. 119 min, P<0.001). Peri-operative morbidity was rare and did not differ between intubated and non-intubated patients. There was no significant difference in 3-year survival associated with non-intubation in the propensity-score matched cohorts (95% vs. 89%, P=0.10) or in a Cox proportional hazard model [hazard ratio (HR), 1.15; 95% confidence interval (CI): 0.36-3.67; P=0.81]. Conclusions: Non-intubated thoracoscopic surgery is safe and feasible in carefully selected patients for both benign and oncologic indications.

Overall survival in low-comorbidity patients with stage I non-small cell lung cancer who chose stereotactic body radiotherapy compared to surgery.

OBJECTIVE: To evaluate trends in the utilization of stereotactic body radiotherapy (SBRT) and to compare overall survival (OS) of patients with early-stage non-small cell lung cancer (NSCLC) undergoing SBRT versus those undergoing surgery. METHODS: The National Cancer Database was queried for patients without documented comorbidities who underwent surgical resection (lobectomy, segmentectomy, or wedge resection) or SBRT for clinical stage I NSCLC between 2012 and 2018. Peritreatment mortality and 5-year OS were compared among propensity score-matched cohorts. RESULTS: A total of 30,658 patients were identified, including 24,729 (80.7%) who underwent surgery and 5929 (19.3%) treated with SBRT. Between 2012 and 2018, the proportion of patients receiving SBRT increased from 15.9% to 26.0% (P < .001). The 30-day mortality and 90-day mortality were higher among patients undergoing surgical resection versus those receiving SBRT (1.7% vs 0.3%, P < .001; 2.8% vs 1.7%, P < .001). In propensity score-matched patients, OS favored SBRT for the first several months, but this was reversed before 1 year and significantly favored surgical management in the long term (5-year OS, 71.0% vs 41.8%; P < .001). The propensity score-matched analysis was repeated to include only SBRT patients who had documented refusal of a recommended surgery, which again demonstrated superior 5-year OS with surgical management (71.4% vs 55.9%; P < .001). CONCLUSIONS: SBRT is being increasingly used to treat early-stage lung cancer in low-comorbidity patients. However, for patients who may be candidates for either treatment, the long-term OS favors surgical management.

Respect the Middle Lobe: Perioperative Risk of Bilobectomy Compared With Lobectomy and Pneumonectomy.

BACKGROUND: In some cases of right-sided lung cancer, tumor extension, bronchial involvement, or pulmonary artery infiltration may necessitate bilobectomy. Although the middle lobe is believed to represent a fraction of total lung function, the morbidity and mortality associated with bilobectomy is not well described. METHODS: We retrospectively identified patients in The Society of Thoracic Surgeons Database who underwent lobectomy, bilobectomy, or pneumonectomy for lung cancer from 2009 to 2017. The primary outcome was 30-day perioperative mortality. We performed propensity matching by patient demographics, comorbidities, and perioperative variables for each surgical type against bilobectomy and ran Cox proportional hazard models. Secondary outcomes of 30-day morbidity and mortality of upper vs lower bilobectomy were also compared. RESULTS: Within the study period 2911 bilobectomy, 65,506 lobectomy, and 3370 pneumonectomy patients met the inclusion criteria. Patients undergoing pneumonectomy and bilobectomy had fewer comorbidities than lobectomy patients. After propensity matching 30-day mortality of bilobectomy was comparable with left pneumonectomy (hazard ratio [HR], 1.35; 95% CI, 0.95-1.91; P = .09) and significantly worse than left (HR, 0.40; 95% CI, 0.29-0.56; P < .0001) or right (HR, 0.43; 95% CI, 0.31-0.59; P < .0001) lobectomy. Bilobectomy was associated with a survival advantage compared with right pneumonectomy (HR, 2.54; 95% CI, 1.72-3.74; P < .0001). Thirty-day morbidity was higher for bilobectomy compared with lobectomy, and upper bilobectomy had a significant unadjusted 30-day mortality advantage compared with lower bilobectomy (98.3% vs 97%, P = .04). CONCLUSIONS: The morbidity and mortality of bilobectomy is significantly worse than lobectomy and is comparable with left pneumonectomy. The addition of middle lobectomy to a pulmonary resection is not without risk and should be carefully considered during preoperative risk stratification.

Assessment of a collaborative treatment model for trimodal management of esophageal cancer.

Background: Patients with esophageal cancer often receive care in a collaborative (multi-institutional) treatment model as opposed to a single institutional model. The effect of a collaborative model on the quality of trimodality therapy and survival is unknown. Methods: The National Cancer Database (NCDB) was used to identify patients receiving neoadjuvant chemoradiotherapy (CRT) followed by esophagectomy for esophageal cancer between 2012-2017. Patients who received neoadjuvant therapy and surgery at a single institution were compared to those that received collaborative treatment across multiple institutions. Outcomes included adherence to guideline recommended multiagent chemotherapy, receipt of 41.4-50.4 Gy of radiation, R0 resection, pathologic complete response (pCR), and 5-year survival. Sociodemographics, comorbidities, and tumor characteristics were assessed in bivariate and multivariable analysis. Results: Among 8,396 patients identified, 39% received treatment at a single institution, while 61% received collaborative treatment. Median travel distance to the site of esophagectomy was two times greater for patients receiving collaborative treatment (30 vs. 15 miles; P<0.001). Patients in the collaborative cohort were less likely to receive guideline-recommended multiagent chemotherapy (85% vs. 96%; P<0.001) and 41.4-50.4 Gy of radiation (89% vs. 91%; P=0.01). R0 resection rates were similar (94.4% vs. 93.7%; P=0.17). Patients who received collaborative treatment had an increased rate of pCR (24% vs. 22%; P=0.02). Overall, 90-day and 5-year survival were 92.9% and 42.6% respectively and did not differ significantly between the two groups. Conclusions: Collaborative trimodality treatment of esophageal cancer is a common and reasonable practice model, which may alleviate patient travel burden with only a modest impact on the quality of CRT, pCR, 90-day survival, and 5-year survival.

Association Between Metastatic Pattern and Prognosis in Stage IV Gastric Cancer: Potential for Stage Classification Reform.

PURPOSE: This study aims to clarify the association between metastatic pattern and prognosis in stage IV gastric cancer, with a focus on patients presenting with metastases limited to nonregional lymph nodes. METHODS: In this retrospective cohort study, the National Cancer Database was used to identify patients ≥ 18 years of age diagnosed with stage IV gastric cancer between 2016 and 2019. Patients were stratified according to pattern of metastatic disease at diagnosis: nonregional lymph nodes only ("stage IV-nodal"), single systemic organ ("stage IV-single organ"), or multiple organs ("stage IV-multi-organ"). Survival was assessed by Kaplan-Meier curves and multivariable Cox models in unadjusted and propensity score-matched samples. RESULTS: Overall, 15,050 patients were identified, including 1,349 (8.7%) stage IV-nodal patients. Most patients in each group received chemotherapy [68.6% of stage IV-nodal patients, 65.2% of stage IV-single organ patients, and 63.5% of stage IV-multi-organ patients (p = 0.003)]. Stage IV-nodal patients exhibited better median survival (10.5 months, 95% CI 9.7-11.9, p < 0.001) than single organ (8.0, 95% CI 7.6-8.2) and multi-organ (5.7, 95% CI 5.4-6.0) patients. In the multivariable Cox model, stage IV-nodal patients also exhibited better survival (HR 0.79, 95% CI 0.73-0.85, p < 0.001) than single organ (reference) and multi-organ (HR 1.27, 95% CI 1.22-1.33, p < 0.001) patients. CONCLUSIONS: Nearly 9% of clinical stage IV gastric cancer patients have their distant disease confined to nonregional lymph nodes. These patients were managed similarly to other stage IV patients but experienced a better prognosis, suggesting opportunities to introduce M1 staging subclassifications.

Utilization and Outcomes of Radiation in Stage IV Esophageal Cancer.

Introduction: For patients with stage IV esophageal cancer, esophageal radiation may be used selectively for local control and palliation. We aimed to understand patterns of radiation administration among patients with stage IV esophageal cancer and any potential survival associations. Methods: In this retrospective cohort study, the National Cancer Database was queried for patients with metastatic stage IV esophageal cancer diagnosed between 2016 and 2019. Patterns of radiation use were identified. Survival was determined through Kaplan-Meier analysis of propensity score-matched pairs of patients who did and did not receive radiotherapy and time-to-event models. Results: Overall, 12,088 patients with stage IV esophageal cancer were identified, including 32.7% who received esophageal radiation. The median age was 65 (interquartile range [IQR]: 58-73) years, and 82.6% were male. Among the irradiated patients, the median total radiation dose was 35 (IQR: 30-50) Gy administered in a median of 14 (IQR: 10-25) fractions given in 22 (IQR: 14-39) days. Overall, esophageal radiation was not associated with better survival (log-rank p = 0.41). When stratified by radiation dose, a survival advantage (over no radiation) was found in the 1144 patients (29% of the irradiated patients) who received 45 to 59.9 Gy (time ratio = 1.28, 95% confidence interval: 1.20-1.37, p < 0.001) and the 88 patients (2.2%) who received 60 to 80 Gy (time ratio = 1.37, 95% confidence interval: 1.11-1.69, p = 0.003). Conclusions: One-third of the patients with metastatic stage IV esophageal cancer in the National Cancer Database received esophageal radiation. Most received a radiation dose that, although consistent with palliative regimens, was not associated with a survival advantage. Further study is warranted to understand the indications for radiation in stage IV esophageal cancer and potentially reevaluate the most appropriate radiation dose for palliation.

Nonregional Lymph Nodes as the Only Metastatic Site in Stage IV Esophageal Cancer.

Introduction: Metastatic involvement of at least one nonregional lymph node currently renders patients with esophageal cancer as having stage IV disease. However, the management and outcomes of patients whose sole determinant of stage IV status is nonregional lymph nodes (abbreviated as "stage IV-nodal" disease) have not been fully characterized. Methods: In this retrospective cohort study, the National Cancer Database was queried to identify patients 18 years of age or older who were diagnosed with stage IV esophageal cancer between 2016 and 2019. Survival was assessed by Kaplan-Meier analysis and Cox models in the overall sample and a propensity-matched sample. Patients with "stage IV-nodal" disease were compared with patients with systemic metastases involving a single organ or multiple organs. Results: Overall, 11,589 patients with clinical stage IV esophageal cancer were identified, including 1331 (11.5%) patients with stage IV-nodal disease. Patients with stage IV-nodal disease were more likely to receive chemotherapy (77%) than those with single systemic organ metastases (64%) and multiorgan metastases (63%) (p < 0.0001); patients with stage IV-nodal disease were also more likely to receive radiation (49%) than those with single systemic organ metastases (40%) and multiorgan metastases (39%) (p < 0.0001). Squamous cell carcinoma (OR = 1.58, 95% confidence interval [CI]: 1.34-1.86, p < 0.0001) and academic facility type (OR = 1.24, 95% CI: 1.09-1.4, p = 0.0009) were associated with higher likelihood of the stage IV-nodal presentation. Patients with stage IV-nodal disease experienced superior survival (hazard ratio = 0.72, 95% CI: 0.66-0.78, p < 0.0001) than those with stage IV-single systemic metastases (reference group) and stage IV-multiorgan disease (hazard ratio = 1.30, 95% CI: 1.24-1.37). Conclusions: Approximately 12% of patients with stage IV esophageal cancer lack systemic metastases at presentation. These patients with stage IV-nodal disease are more likely to receive treatment and experience superior survival. Further study of the stage IV-nodal population and consideration of a potential stage IV subclassification system is justified.

Evaluation of gastroesophageal reflux disease and hiatal hernia as risk factors for lobectomy complications.

Objective: Up to 40% of lobectomies are complicated by adverse events. Gastroesophageal reflux disease (GERD) and hiatal hernia have been associated with morbidity across a range of clinical scenarios, yet their relation to recovery from pulmonary resection is understudied. We evaluated GERD and hiatal hernia as predictors of complications after lobectomy for lung cancer. Methods: Lobectomy patients at Yale-New Haven Hospital between January 2014 and April 2021 were evaluated for predictors of 30-day postoperative complications, pneumonia, atrial arrhythmia, readmission, and mortality. Multivariable regression models included sociodemographic characteristics, body mass index, surgical approach, cardiopulmonary comorbidities, hiatal hernia, GERD, and preoperative acid-suppressive therapy as predictors. Results: Overall, 824 patients underwent lobectomy, including 50.5% with a hiatal hernia and 38.7% with GERD. The median age was 68 [interquartile range, 61-74] years, and the majority were female (58.4%). At least 1 postoperative complication developed in 39.6% of patients, including atrial arrhythmia (11.7%) and pneumonia (4.1%). Male sex (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.11-2.06, P = .01), age ≥70 years (OR, 1.55; 95% CI, 1.13-2.11, P = .01), hiatal hernia (OR, 1.40; 95% CI, 1.03-1.90, P = .03), and intraoperative packed red blood cells (OR, 4.80; 95% CI, 1.51-15.20, P = .01) were significant risk factors for developing at least 1 postoperative complication. Hiatal hernia was also a significant predictor of atrial arrhythmia (OR, 1.64; 95% CI, 1.02-2.62, P = .04) but was not associated with other adverse events. Conclusions: Our findings indicate that hiatal hernia may be a novel risk factor for complications, especially atrial arrhythmia, following lobectomy that should be considered in the preoperative evaluation of lung cancer patients.

Immunotherapy After Chemotherapy and Radiation for Clinical Stage III Lung Cancer.

Importance: The 2017 international PACIFIC trial established a role for immunotherapy after chemoradiation for unresectable stage III non-small cell lung cancer (NSCLC). However, in the US, patients with NSCLC commonly differ from clinical trial populations in terms of age, health, access to care, and treatment course, which may all factor into the efficacy of immunotherapy. Objective: To determine the outcomes of immunotherapy use in unresectable stage III NSCLC in the general US population. Design, Setting, and Participants: This cohort study analyzed the National Cancer Database for patients diagnosed with clinical stage III NSCLC between 2015 and 2017 with follow-up through the end of 2018 who were treated with chemotherapy and radiation. Data were analyzed January 2022. Main Outcomes and Measures: Mortality hazard in a multivariable Cox proportional hazards model and survival among a propensity-matched sample treated with chemotherapy and radiation, with and without immunotherapy. Results: A total of 23 811 patients with clinical stage III NSCLC with median (IQR) age 66 (59-72) years met inclusion criteria (10 454 [43.9%] women; 564 [2.4%] Asian, 2930 [12.3%] Black, 20 077 [84.3%] White patients), including 209 (16.1%) patients with multiple comorbidities and 1297 (5.4%) immunotherapy recipients. Immunotherapy after chemotherapy and radiation was associated with reduced mortality (hazard ratio [HR], 0.74; 95% CI, 0.67-0.82; P < .001). Among a propensity-matched sample, immunotherapy was associated with superior 3-year survival (52% [1297 patients at 0 months, 56 patients at 36 months] vs 44% [2594 patients at 0 months, 173 patients at 36 months]; P < .001). The treatment of 833 patients who received immunotherapy (64.2%) differed from the PACIFIC trial protocol, including 221 patients (17.0%) who received radiation doses outside of the protocol range and 731 patients (56.4%) who started immunotherapy more than 6 weeks after radiation was completed. The survival advantage of immunotherapy persisted when initiated up to 12 weeks after radiation was completed (HR, 0.75; 95% CI, 0.61-0.92). Among patients who received radiation outside the PACIFIC protocol range, the survival advantage of immunotherapy was not significant (HR, 0.87; 95% CI, 0.69-1.01). Conclusions and Relevance: In this cohort study, immunotherapy after chemotherapy and radiation for stage III NSCLC was associated with a survival advantage in the general US population despite two-thirds of patients treated differently than the PACIFIC protocol. The findings suggest there may be flexibility in the timing of immunotherapy initiation after radiation; further study is warranted to clarify the clinical benefits of immunotherapy.

Association Between Food and Drug Administration Approval and Disparities in Immunotherapy Use Among Patients With Cancer in the US.

Importance: Clinical trials and compassionate use agreements provide selected patients with access to potentially life-saving treatments before approval by the Food and Drug Administration (FDA). Approval from the FDA decreases a number of access barriers; however, it is unknown whether FDA approval is associated with increases in the equitable use of novel therapies and reductions in disparities in use among patients with cancer in the US. Objective: To assess the association between FDA drug approval and disparities in the use of immunotherapy across health, sociodemographic, and socioeconomic strata before and after approval of the first checkpoint inhibitors for the treatment of patients with cancer in the US. Design, Setting, and Participants: This cohort study used data from the National Cancer Database to examine the use of immunotherapy across health, sociodemographic, and socioeconomic strata before and after FDA approval of the first checkpoint inhibitor therapies. A total of 402 689 patients 20 years or older who were diagnosed with stage IV non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or melanoma of the skin between January 1, 2007, and December 31, 2018 (specific years varied by tumor type), were included. Exposures: Patient health (Charlson-Deyo comorbidity score and age), sociodemographic characteristics (sex, race, and ethnicity), and socioeconomic (insurance status and household income based on zip code of residence) characteristics. Main Outcomes and Measures: The association of patient characteristics with receipt of immunotherapy was evaluated in the 4 years before and the 3 years immediately after FDA approval using multivariable logistic regression modeling. Results: Among 402 689 patients (median [IQR] age, 68 [60-76 years]; 225 081 men [55.9%]), 347 233 had NSCLC, 43 714 had RCC, and 11 742 patients had melanoma. A total of 47 527 patients (11.8%) were Black, 15 763 (3.9%) were Hispanic, 375 874 (93.3%) were non-Hispanic, 335 833 (83.4%) were White, and 16 553 (4.1%) were of other races. Before FDA approval, 6271 patients (3.2%) with NSCLC, 1155 patients (4.8%) with RCC, and 504 patients (8.6%) with melanoma received immunotherapy compared with 23 908 patients (15.6%) with NSCLC, 3890 patients (19.7%) with RCC, and 1143 patients (19.3%) with melanoma after FDA approval. Before FDA approval, sociodemographic and socioeconomic characteristics were associated with variable immunotherapy administration by tumor type. For example, among those with NSCLC, Black patients were less likely to receive immunotherapy than White patients (odds ratio [OR], 0.78; 95% CI ,0.71-0.85; P < .001); among those with RCC, uninsured patients were less likely to receive immunotherapy than privately insured patients (OR, 0.31; 95% CI, 0.20-0.48; P < .001). After FDA approval, most disparities persisted, but several narrowed (eg, Black patients with NSCLC: OR, 0.87 [95% CI, 0.83-0.91; P < .001]; uninsured patients with RCC: OR, 0.60 [95% CI, 0.48-0.75; P < .001]). Although many disparities remained, some gaps across socioeconomic characteristics appeared to widen (eg, patients with NSCLC in the lowest vs highest income quartile: OR, 0.80; 95% CI, 0.76-0.83; P < .001), and new gaps emerged (eg, Black patients with RCC: OR, 0.82; 95% CI, 0.72-0.93; P = .003). Conclusions and Relevance: In this cohort study, disparities in immunotherapy use existed across a number of sociodemographic and socioeconomic characteristics among patients with NSCLC, RCC, and melanoma before FDA approval, including during the important period when clinical trials were accruing patients. Although FDA approval was associated with a significant increase in the use of immunotherapy, gaps persisted, suggesting that FDA approval may not eliminate disparities in the use of novel therapies.

Revisiting Indications for Brain Imaging During the Clinical Staging Evaluation of Lung Cancer.

Introduction: Available guidelines are inconsistent as to whether patients with newly diagnosed clinical stage II NSCLC should receive routine brain imaging. Methods: The National Cancer Database was queried for the prevalence of isolated brain metastases among patients with newly diagnosed NSCLC in 2016 and 2017. Patients with metastases in locations other than the brain were excluded. The prevalences were then stratified by clinical T and N classifications and further stratified into a summary stage, which was calculated based on T and N classifications. The summary stage represents the clinical stage that would have been available at the time of decision for brain imaging. Results: A total of 6,949 of 149,958 patients (4.6%) with clinical stages I, II, III, or brain-limited stage IV NSCLC had dissemination limited to the brain. As T and N stages increased, prevalence of brain metastases generally increased. Among patients with node-negative (N0) NSCLC, the prevalence of brain-only metastases increased from 1.2% in patients with T1a to 3.8% among patients with T4 (p < 0.001). Among patients with T1a, the prevalence of brain-only metastases increased from 1.2% for patients with N0 to 7.9% for patients with N3 (p < 0.001). The prevalence of brain-limited metastases generally increased with increasing summary stage. The prevalence of brain-only metastases among patients with stage IA was 1.7% whereas that among patients with stage IIIA was 6.7% (p < 0.001). Of note, the prevalence of brain-limited metastases was approximately 6% for both summary stages II and III. Conclusions: Considering the similarity in prevalence of isolated brain metastases and the potential hazards associated with brain imaging in early stage NSCLC, practitioners may consider a more liberal use of brain imaging when interpreting conflicting guidelines.

Stereotactic radiosurgery and fractionated radiotherapy for spinal arteriovenous malformations - A systematic review of the literature.

Spinal arteriovenous malformations (AVMs) comprise a group of complex vascular lesions whose treatment with microsurgery or transarterial embolization can be challenging. Stereotactic radiosurgery is a well-established treatment for intracranial AVMs, and spinal radiosurgery and fractionated radiotherapy are common treatments for spinal tumors of both primary and metastatic origin. The use of radiosurgery and fractionated radiotherapy for the treatment of spinal arteriovenous malformations, however, has been infrequently reported. Spinal stereotactic radiosurgery is emerging as a promising option for the treatment of these lesions. We conducted a systematic review of English language articles reporting one or more cases of spinal radiosurgery or fractionated radiotherapy for the treatment of spinal arteriovenous fistulas (AVFs) or arteriovenous malformations. Eight unique studies comprising 64 patients were identified. All treated lesions consisted primarily of spinal AVMs, either intramedullary or metameric. Most were treated with CyberKnife technology. Marginal doses in the most current studies ranged from 18 to 21 Gy given over 2-4 fractions. In aggregate, good outcomes were reported in 92.2% with no instances of post-treatment hemorrhage over a mean follow-up time of 46.8 months. Angiographic follow-up showed the nidus to be obliterated in 16%, decreased in 44.6%, and unchanged in 39.3%. Stereotactic radiosurgery for spinal arteriovenous malformations holds promise as a safe and potentially effective option in the treatment of these rare but complex lesions.

General solutions to decompose heterogeneous compositions using antibody afucosylation as a model system.

Methods involving the use of mathematical models of competitive ligand-receptor binding to characterize mixtures of ligands in terms of compositions and properties of the component ligands have been developed. The associated mathematical equations explicitly relate component ligand physical-chemical properties and mole fractions to measurable properties of the mixture including steady state binding activity, 1/Kd,apparent or equivalently 1/EC50, and kinetic rate constants kon,apparent and koff,apparent allowing: (1) component ligand physical property determination and (2) mixture property predictions. Additionally, mathematical equations accounting for combinatorial considerations associated with ligand assembly are used to compute ligand mole fractions. The utility of the methods developed is demonstrated using published experimental ligand-receptor binding data obtained from mixtures of afucosylated antibodies that bind FcγRIIIa (CD16a) to: (1) extract component ligand physical property information that has hitherto evaded researchers, (2) predict experimental observations, and (3) provide explanations for unresolved experimental observations. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:500-510, 2017.

Challenges with afucosylation content in antibody-based drugs: Guidance provided by mathematical modeling.

The theory of competitive ligand-receptor binding has been used to analyze the effect of afucosylation-based antibody heterogeneity on Fc-FcγRIIIa ligand-receptor binding activity. In vitro activity is found to represent a linear combination of the component antibody activities, weighted by the relative concentrations of the different afucosylated antibody forms. An analysis of ELISA binding activity data has allowed for the dissection of the activity contributions of the different afucosylated antibodies, revealing that the heterogeneous afucosylated antibody exhibits greater activity, on a per mole basis, when compared to the homogeneous afucosylated antibody. The ratio of the afucosylated antibody equilibrium dissociation constants is computed to be KAF /KA ≈ 0.6-0.9, where KAF and KA denote the dissociation equilibrium constant of the heterogeneous and the homogeneous afucosylated antibodies, respectively. Our analysis also reveals that, in general, activity scales quadratically with the afucosylated glycan content of a sample. Linear activity-afucosylated glycan fraction correlations reported in the literature are shown to represent specific cases of this general scaling and result from oversimplifying the underlying antibody concentration distributions. The implications of our findings for drug development are also discussed.