Impact of Frailty on Outcomes after Chimeric Antigen Receptor T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma.

The literature is limited regarding outcomes in older adults and frail patients receiving BCMA-directed chimeric antigen receptor T cell therapy (CAR-T) for relapsed or refractory multiple myeloma. Here we describe the safety and efficacy of CAR-T in these clinically important subgroups treated in a real-world setting. Frailty was defined as a frail score ≥2 using the simplified frailty index (score based on age + Eastern Cooperative Oncology Group [ECOG] Performance Status + Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI]). Of the 136 patients analyzed (age range, 41 to 81 years), 83 (61%) were considered frail at the time of CAR-T infusion. Compared to the nonfrail group, the frail group had higher proportions of patients with renal insufficiency (18% versus 6%), high-risk cytogenetics (45% versus 35%), extramedullary disease (51% versus 43%), and ECOG Performance Status ≥2 (18% versus 2%), and worse HCT-CI (3 versus 1). Although patients in the frail group had a higher incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (39% versus 17%), the incidences of all- grade cytokine release syndrome (CRS), as well as high-grade CRS and ICANS, were similar in the 2 groups. With a median follow-up of 7 months, the median progression-free survival was 6.9 months in the frail group versus 11.1 months in the nonfrail group (P = .028). The median overall survival was 14 months in the frail group and was not reached in the nonfrail group (P = .025). This study highlights the tolerable safety and reasonable efficacy of CAR-T for frail myeloma patients in a real-world practice. Although the frail patients did not experience any excessive high-grade toxicities, they did have inferior efficacy outcomes.

Safety and Efficacy of Teclistamab in Patients with Relapsed/Refractory Multiple Myeloma: A Real-World Experience.

Teclistamab is a B cell maturation antigen (BCMA)-directed bispecific antibody approved for relapsed/refractory multiple myeloma (RRMM) on the basis of the phase I/II MajesTEC-1 trial. Here we report clinical outcomes with standard-of-care teclistamab in a real-world RRMM population. A total of 106 patients from 5 academic centers who received teclistamab from August 2022 to August 2023 were included in this retrospective analysis, 83% of whom would have been considered ineligible for the MajesTEC-1 trial. All patients were triple-class exposed, 64% were penta-class refractory, and 53% had received prior BCMA-directed therapy. Cytokine release syndrome was observed in 64% of patients, and only 1 event was grade ≥3, whereas immune effector cell-associated neurotoxicity syndrome was observed in 14% of patients (3 events were grade 3 or 4). One-third (31%) of patients experienced at least 1 infection, with nearly half of these infections graded as severe (grade ≥3). The overall response rate (ORR) was 66%, and the complete or better response rate was 29%. The ORR was 47% for patients with extramedullary disease (EMD), 59% for patients with prior BCMA-directed therapy exposure, and 68% for patients with penta-refractory disease. At a median follow-up of 3.8 months, the median progression-free survival (PFS) was 5.4 months (95% CI, 3.4 months to not reached), while median overall survival was not reached. Patients with Eastern Cooperative Oncology Group Performance Status ≥2, EMD, and age ≤70 years had inferior PFS on multivariable analysis. Our study demonstrates reasonable safety and good efficacy of teclistamab in patients with RRMM treated in a real-world setting.

Combination of EGFR-Directed Tyrosine Kinase Inhibitors (EGFR-TKI) with Radiotherapy in Brain Metastases from Non-Small Cell Lung Cancer: A 2010-2019 Retrospective Cohort Study.

INTRODUCTION: Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM. METHODS: A retrospective review of NSCLCBM patients diagnosed during 2010-2019 at a tertiary-care US center was performed and reported following the 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other. RESULTS: A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17-0.84, p = 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82, p = 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08, p = 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09, p = 0.07). CONCLUSIONS: NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS.

First- versus Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases.

Introduction: Up to 50% of non-small cell lung cancer (NSCLC) harbor EGFR alterations, the most common etiology behind brain metastases (BMs). First-generation EGFR-directed tyrosine kinase inhibitors (EGFR-TKI) are limited by blood-brain barrier penetration and T790M tumor mutations, wherein third-generation EGFR-TKIs, like Osimertinib, have shown greater activity. However, their efficacy has not been well-studied in later therapy lines in NSCLC patients with BMs (NSCLC-BM). We sought to compare outcomes of NSCLC-BM treated with either first- or third-generation EGFR-TKIs in first-line and 2nd-to-5th-line settings. Methods: A retrospective review of NSCLC-BM patients diagnosed during 2010-2019 at Cleveland Clinic, Ohio, US, a quaternary-care center, was performed and reported following 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic, histopathological, molecular characteristics, and clinical outcomes were collected. Primary outcomes were median overall survival (mOS) and progression-free survival (mPFS). Multivariable Cox proportional hazards modeling and propensity score matching were utilized to adjust for confounders. Results: 239 NSCLC-BM patients with EGFR alterations were identified, of which 107 received EGFR-TKIs after diagnosis of BMs. 77.6% (83/107) received it as first-line treatment, and 30.8% (33/107) received it in later (2nd-5th) lines of therapy, with nine patients receiving it in both settings. 64 of 107 patients received first-generation (erlotinib/gefitinib) TKIs, with 53 receiving them in the first line setting and 13 receiving it in the 2nd-5th lines of therapy. 50 patients received Osimertinib as third-generation EGFR-TKI, 30 in first-line, and 20 in the 2nd-5th lines of therapy. Univariable analysis in first-line therapy demonstrated mOS of first- and third-generation EGFR-TKIs as 18.2 and 19.4 months, respectively (p = 0.57), while unadjusted mPFS of first- and third-generation EGFR-TKIs was 9.3 and 13.8 months, respectively (p = 0.14). In 2nd-5th line therapy, for first- and third-generation EGFR-TKIs, mOS was 17.3 and 11.9 months, (p = 0.19), while mPFS was 10.4 and 6.08 months, respectively (p = 0.41). After adjusting for age, performance status, presence of extracranial metastases, whole-brain radiotherapy, and presence of leptomeningeal metastases, hazard ratio (HR) for OS was 1.25 (95% CI 0.63-2.49, p = 0.52) for first-line therapy. Adjusted HR for mOS in 2nd-to-5th line therapy was 1.60 (95% CI 0.55-4.69, p = 0.39). Conclusions: No difference in survival was detected between first- and third-generation EGFR-TKIs in either first or 2nd-to-5th lines of therapy. Larger prospective studies are warranted reporting intracranial lesion size, EGFR alteration and expression levels in primary tumor and brain metastases, and response rates.

Combined utility of p16 and BRAF V600E in the evaluation of spitzoid tumors: Superiority to PRAME and correlation with FISH.

BACKGROUND: Spitzoid melanocytic neoplasms are diagnostically challenging; criteria for malignancy continue to evolve. The ability to predict chromosomal abnormalities with immunohistochemistry (IHC) could help select cases requiring chromosomal evaluation. METHODS: Fluorescence in situ hybridization (FISH)-tested spitzoid neoplasms at our institution (2013-2021) were reviewed. p16, BRAF V600E, and preferentially expressed antigen in melanoma (PRAME) IHC results were correlated with FISH. RESULTS: A total of 174 cases (1.9F:1M, median age 28 years; range, 5 months-74 years) were included; final diagnoses: Spitz nevus (11%), atypical Spitz tumor (47%), spitzoid dysplastic nevus (9%), and spitzoid melanoma (32%). Sixty (34%) were FISH positive, most commonly with absolute 6p25 gain (RREB1 > 2). Dermal mitotic count was the only clinicopathologic predictor of FISH. Among IHC-stained cases, p16 was lost in 55 of 134 cases (41%); loss correlated with FISH positive (p < 0.001, Fisher exact test). BRAF V600E (14/88, 16%) and PRAME (15/56, 27%) expression did not correlate with FISH alone (p = 0.242 and p = 0.359, respectively, Fisher exact test). When examined together, however, p16-retained/BRAF V600E-negative lesions had low FISH-positive rates (5/37, 14%; 4/37, 11% not counting isolated MYB loss); all other marker combinations had high rates (56%-75% of cases; p < 0.001). CONCLUSIONS: p16/BRAF V600E IHC predicts FISH results. "Low-risk" lesions (p16+ /BRAF V600E- ) uncommonly have meaningful FISH abnormalities (11%). PRAME may have limited utility in this setting.

Readmission Rates Following Major Head and Neck Surgery With Concurrent Tracheostomy.

OBJECTIVES: To determine the influence of major head and neck procedures on readmission and complication rates following tracheostomy. METHODS: A retrospective cohort study using the 2005 to 2017 National Surgical Quality Improvement Program (NSQIP) database. Current Procedural Terminology codes were used to identify tracheostomy patients and to define the underlying head and neck procedure. Patients under the age of 18 and with unknown pre-operative variables were excluded. Univariate and multivariable analyses were performed. RESULTS: A total of 3240 tracheostomy patients undergoing major head and neck surgery were identified in NSQIP. The 30-day mortality rate was 104 (3.2%) and 258 (9.0%) patients were readmitted. 637 (19.7%) patients had an unplanned return to the operating room. There were 1606 (49.6%) non-tracheostomy specific complications, which included 850 (26.2%) medical and 1142 (35.2%) surgical complications. On multivariable analysis, we found that the underlying procedures did not impact the risk of readmission (P > .05 for all). The underlying procedure was also not associated with unplanned return to the operating room except for thyroidectomies, which had a lower risk than free tissue graft reconstruction (OR = 0.53 (95%CI 0.31, 0.88), P = .018). CONCLUSION: While almost 1 in every 2 patients had a complication following major head and neck surgery that included creation of a tracheostomy, the rate of readmission is comparatively low and is not associated with the underlying procedure. These findings should reassure head and neck surgeons that properly managed tracheostomies do not constitute a disproportionate risk of readmission.

A Phase 1 Study of Concurrent Neoadjuvant Pembrolizumab Plus Chemoradiation Followed by Consolidation Pembrolizumab in Patients With Resectable Stage IIIA NSCLC.

Introduction: Evidence supports the addition of immunotherapy to definitive chemoradiation for unresectable stage IIIA NSCLC. Adding pembrolizumab to neoadjuvant chemoradiation in patients with resectable stage IIIA NSCLC requires study for safety and feasibility. Methods: Patients with resectable stage IIIA NSCLC received neoadjuvant cisplatin, etoposide, and pembrolizumab concurrently with thoracic radiotherapy of 45 Gy in 25 fractions. Patients without progression underwent resection followed by 6 months of consolidation pembrolizumab. Safety and feasibility were defined as less than or equal to 30% grade 3 or higher pulmonary toxicity or any grade 4 or 5 nonhematologic toxicity. A total of 10 patients were to be enrolled initially. If less than or equal to two patients had events, another 10 were to be enrolled. Results: The study closed after enrolling nine patients. The median age was 66 (range: 49-76) years. A total of 67% were female. Median follow-up was 38.3 months. Serious adverse events occurred in seven patients, including two grade 5 events: one sudden cardiac arrest in the neoadjuvant phase and one fatal pneumocystis pneumonia after resection. Eight patients were assessable for response. The overall response rate was 67%. Six underwent complete resection. Four achieved pathologic complete response, whereas one additional patient had complete nodal clearance. Median progression-free survival has not been reached. The 3-year overall survival was 64%. Conclusions: Adding pembrolizumab to neoadjuvant concurrent cisplatin, etoposide, and radiotherapy in resectable stage IIIA NSCLC resulted in an encouraging pathologic complete response rate. Higher-than-expected toxicities necessitated trial closure after meeting the rule for infeasibility. The relationship of grade 5 events to the addition of pembrolizumab is unclear.

Outcomes After Oral Cavity and Oropharyngeal Salvage Surgery.

OBJECTIVES: Investigate outcomes following oral cavity and oropharyngeal salvage surgery. METHODS: Adult patients who underwent salvage surgery for recurrent squamous cell carcinoma of the oral cavity and oropharynx from 1996 to 2018 were analyzed using multivariable Cox proportional hazards regression. Disease-free survival (DFS), overall survival (OS), associated factors, and basic quality measures were analyzed. RESULTS: One hundred and eight patients (72% oral cavity, 28% oropharynx) were followed for a median of 17.9 months. Median DFS and OS were 9.9 and 21 months, respectively. Surgery with adjuvant chemoradiotherapy compared to surgery alone (hazard ratio [HR] = 0.15, 95% confidence interval [CI]: 0.03-0.78) and negative margins (HR = 0.36, 95% CI: 0.14-0.90) were associated with better DFS, while lymphovascular space invasion (LVSI) (HR = 2.66, 95% CI: 1.14-6.19) and higher stage (III vs. I-II, HR = 3.94, 95% CI: 1.22-12.71) were associated with worse DFS. Higher stage was associated with worse OS (HR = 3.79, 95% CI: 1.09-13.19). Patients were hospitalized for a median of 8 days with 24% readmitted within 30 days. A total of 72% and 38% of patients, respectively, underwent placement of a feeding tube or tracheostomy. CONCLUSIONS: After oral cavity and oropharyngeal salvage surgery, adjuvant chemoradiotherapy, negative margins, negative LVSI, and lower stage were associated with a lower risk of recurrence. Only lower-stage disease was associated with improved survival. The majority of patients had feeding tubes, half underwent free tissue transfer, a third required tracheostomy, and a quarter was readmitted. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1984-1992, 2022.

The impact of socioeconomic disparities on the use of upfront autologous stem cell transplantation for mantle cell lymphoma.

Using the National Cancer Database, we identified 10,290 patients with newly diagnosed mantle cell lymphoma (MCL) treated with chemotherapy with or without upfront autologous stem cell transplantation (ASCT). Only 17% of patients underwent ASCT. Patients who underwent ASCT were younger and more likely to have lower comorbidity scores, private insurance, higher income and education, and treatment received at an academic facility. On multivariable analysis, age, comorbidity index, insurance type, the transition of care, facility type, distance to facility, and diagnosis year were predictive for ASCT use. ASCT use was associated with improved 5-year overall survival in younger (82% vs. 64%, p < .001) and older (70% vs. 40%, p < .001) patients, which was retained in the matched propensity score and 12-month analyses. Female gender, the diagnosis year ≥2009, private insurance, higher income, and education were associated with superior survival, whereas Black race and higher comorbidities predicted inferior survival.

Association between hypertension requiring medication and 30-day outcomes in head and neck microvascular surgery.

BACKGROUND: Hypertension has been shown to be both a protective factor and a risk factor for complications in head and neck reconstructive surgery. METHODS: Retrospective analysis of microvascular free tissue transfer patients using the National Surgical Quality Improvement Program database. RESULTS: Hypertensive patients (n = 1598; 46.9%) had a significantly higher rate of complications, including pneumonia (p < 0.001), myocardial infarction (p = 0.003), and intra/post-operative transfusion (p < 0.001). In a multivariable model, hypertension was associated with returning to the operating room (OR = 1.45 [95% CI 1.20, 1.76], p < 0.001), post-operative medical complications (OR = 1.53 [95% CI 1.24, 1.90], p < 0.001), and surgical complications (OR = 1.17 [95% CI 1.00, 1.37], p = 0.047). However, no difference in 30-day readmission was found (p > 0.05). CONCLUSIONS: Hypertension is a modifiable risk factor for post-operative complications in head and neck free tissue transfer, in which prospective studies are required to establish causation. This study may serve as an impetus for proactive recommendations to manage hypertension before undergoing head and neck microvascular surgery.

Personalized Prediction Model to Risk Stratify Patients With Myelodysplastic Syndromes.

PURPOSE: Patients with myelodysplastic syndromes (MDS) have a survival that can range from months to decades. Prognostic systems that incorporate advanced analytics of clinical, pathologic, and molecular data have the potential to more accurately and dynamically predict survival in patients receiving various therapies. METHODS: A total of 1,471 MDS patients with comprehensively annotated clinical and molecular data were included in a training cohort and analyzed using machine learning techniques. A random survival algorithm was used to build a prognostic model, which was then validated in external cohorts. The accuracy of the proposed model, compared with other established models, was assessed using a concordance (c)index. RESULTS: The median age for the training cohort was 71 years. Commonly mutated genes included SF3B1, TET2, and ASXL1. The algorithm identified chromosomal karyotype, platelet, hemoglobin levels, bone marrow blast percentage, age, other clinical variables, seven discrete gene mutations, and mutation number as having prognostic impact on overall and leukemia-free survivals. The model was validated in an independent external cohort of 465 patients, a cohort of patients with MDS treated in a prospective clinical trial, a cohort of patients with paired samples at different time points during the disease course, and a cohort of patients who underwent hematopoietic stem-cell transplantation. CONCLUSION: A personalized prediction model on the basis of clinical and genomic data outperformed established prognostic models in MDS. The new model was dynamic, predicting survival and leukemia transformation probabilities at different time points that are unique for a given patient, and can upstage and downstage patients into more appropriate risk categories.

Defining the Economic Burden of Perioperative Venous Thromboembolism in Inflammatory Bowel Disease in the United States.

BACKGROUND: Patients with IBD are at increased risk of venous thromboembolism. OBJECTIVE: This study aims to define the economic burden associated with inpatient venous thromboembolism after surgery for IBD that presently remains undefined. DESIGN: This study is a retrospective, cross-sectional analysis using the National Inpatient Sample from 2004 to 2014. SETTING: Participating hospitals across the United States were sampled. PATIENTS: The International Classification of Diseases, 9th Revision codes were used to identify patients with a primary diagnosis of IBD. INTERVENTIONS: Major abdominopelvic bowel surgery was performed. MAIN OUTCOME MEASURES: The primary outcome measured was the occurrence of inpatient venous thromboembolism. Univariate and multivariable patient- and hospital-level logistic regression models were used to compare patient characteristics, hospital characteristics, and outcomes between venous thromboembolism and non-venous thromboembolism cohorts. Total average direct costs were then compared between cohorts, and the resulting difference was extrapolated to the national population. RESULTS: Of 26,080 patients included, inpatient venous thromboembolism was identified in 581 (2.2%). On multivariable analysis, diagnosis of ulcerative colitis, transfer status, length of preoperative hospitalization, and insurance status were independently associated with inpatient venous thromboembolism. Patients with venous thromboembolism were observed to be associated with an increased median length of stay (17.6 vs 6.7 days; p < 0.001) and higher inpatient mortality (5.0% vs 1.1%; OR 4.7, SE 3.2-7.0; p < 0.001). After adjusting for clinically relevant covariates, the additional cost associated with each inpatient venous thromboembolism was $31,551 (95% CI, $29,136-$33,965). LIMITATIONS: Our study is limited by the administrative nature of the National Inpatient Sample database, which limits our ability to evaluate the impact of clinical covariates (eg, use of venous thromboembolism chemoprophylaxis, steroid use, and nutrition status). CONCLUSION: Inpatient venous thromboembolism in abdominopelvic surgery for IBD is an infrequent, yet costly, morbid complication. Given the magnitude of patient morbidity and economic burden, venous thromboembolism prevention should be a national quality improvement and research priority. See Video Abstract at http://links.lww.com/DCR/B544. DEFINICIN IMPACTO ECONMICO DE LA TROMBOEMBOLIA VENOSA PERIOPERATORIA EN LA ENFERMEDAD INFLAMATORIA INTESTINAL EN LOS ESTADOS UNIDOS: ANTECEDENTES:Pacientes con enfermedad inflamatoria intestinal (EII) tienen un mayor riesgo de tromboembolismo venoso (TEV).OBJETIVO:Definir el impacto económico de TEV hospitalaria después de la cirugía por EII, que en la actualidad permanece indefinida.DISEÑO:Un análisis transversal retrospectivo utilizando la Muestra Nacional de Pacientes Internos (NIS) de 2004 a 2014.ENTORNO CLINICO:Hospitales participantes muestreados en los Estados Unidos.PACIENTES:Se utilizaron los códigos de la 9ª edición de la Clasificación Internacional de Enfermedades (ICD-9) para identificar a los pacientes con diagnóstico primario de EII.INTERVENCIONES:Cirugía mayor abdominopélvica intestinal.PRINCIPALES MEDIDAS DE VALORACION:Incidencia de TEV en pacientes hospitalizados, utilizando modelos de regresión logística univariado y multivariable a nivel de pacientes y hospitales para comparar las características de los pacientes, las características del hospital y los resultados entre las cohortes de TEV y no TEV. Se compararon los costos directos promedio totales entre cohortes y la diferencia resultante extrapolando a la población nacional.RESULTADOS:De 26080 pacientes incluidos, se identificó TEV hospitalario en 581 (2,2%). En análisis multivariable, el diagnóstico de colitis ulcerosa, el estado de transferencia (entre centros hospitalarios), la duración de la hospitalización preoperatoria y el nivel de seguro medico se asociaron de forma independiente con la TEV hospitalaria. Se observó que los pacientes con TEV se asociaron con un aumento de la duración media de la estancia (17,6 versus a 6,7 días; p <0,001) y una mayor mortalidad hospitalaria (5,0% versus a 1,1%; OR 4,7, SE 3,2 -7,0; p <0,001). Después de ajustar las covariables clínicamente relevantes, el costo adicional asociado con cada TEV para pacientes hospitalizados fue de $ 31,551 USD (95% C.I. $ 29,136 - $ 33,965).LIMITACIONES:Estudio limitado por la naturaleza administrativa de la base de datos del NIS, que limita nuestra capacidad para evaluar el impacto de las covariables clínicas (por ejemplo, el uso de quimioprofilaxis de TEV, el uso de esteroides y el estado nutricional).CONCLUSIÓN:TEV hospitalaria en la cirugía abdominopélvica para la EII es una complicación mórbida infrecuente, pero costosa. Debido a la magnitud de la morbilidad el impacto económico, la prevención del TEV debería ser una prioridad de investigación y para mejoría de calidad a nivel nacional. Consulte Video Resumen en http://links.lww.com/DCR/B544.

A Phase II Trial of Imatinib Mesylate as Maintenance Therapy for Patients With Newly Diagnosed C-kit-positive Acute Myeloid Leukemia.

INTRODUCTION: Adults with acute myeloid leukemia (AML) have a high rate of remission; however, more than 50% relapse. C-kit is expressed in approximately 60% of patients with de novo AML and represents a potential therapeutic target. MATERIALS AND METHODS: Patients with newly diagnosed AML received 12 months of imatinib mesylate as maintenance therapy after the completion of post-remission therapy. The primary objective was to determine whether this approach improved progression-free survival (defined as no relapse and no death) compared with historical controls. RESULTS: The median progression-free survival of patients < 60 years of age was 52.1 months (historical control, 13 months) and for patients ≥ 60 years of age was 10.7 months (historical control, 8 months). The median level of AF1q expression was high (9.59), and 84% of patients had moderate or high levels of drug-resistance factors. CONCLUSIONS: Imatinib maintenance therapy may improve the outcome of newly diagnosed patients with AML who are < 60 years of age.

Outcomes with Partial Breast Irradiation vs. Whole Breast Irradiation: a Meta-Analysis.

BACKGROUND: Several randomized trials have been performed comparing partial breast irradiation (PBI) and whole breast irradiation (WBI) though controversy remains, including regarding differences by PBI technique. We performed a meta-analysis to compare results between WBI versus PBI and between PBI techniques. METHODS: A systematic review was performed to identify modern randomized studies listed in MEDLINE from 2005 to 2020. PBI trials were divided into external beam radiation and brachytherapy techniques, with intraoperative radiation excluded. A Bayesian logistic regression model evaluated the risk of ipsilateral breast tumor recurrence (IBTR) and acute and chronic toxicities. The primary outcome was IBTR at 5 years with WBI compared with PBI. RESULTS: A total of 9758 patients from 7 studies were included (4840-WBI, 4918-PBI). At 5 years, no statistically significant difference in the rate of IBTR was noted between PBI (1.8%, 95% HPD 0.68-3.2%) and WBI (1.7%, 95% HPD 0.92-2.4%). By PBI technique, the 5-year rate of IBTR rate for external beam was 1.7% and 2.2% for brachytherapy. Rates of grade 2 + acute toxicity were 7.1% with PBI versus 47.5% with WBI. For late toxicities, grade 2/3 rates were 0%/0% with PBI compared with 1.0%/0% with WBI. CONCLUSIONS: IBTR rates were similar between PBI and WBI with no significant differences noted by PBI technique; PBI had reduced acute toxicities compared to WBI. Because studies did not provide toxicity data in a consistent fashion, definitive conclusions cannot be made with additional data from randomized trials needed to compare toxicity profiles between PBI techniques.

Real-world Outcomes of Cyclin-dependent Kinase Inhibitors Continued Beyond First Disease Progression in Hormone Receptor-positive Metastatic Breast Cancer.

BACKGROUND: CDK4/6 inhibitors (CDK4/6i), in combination with aromatase inhibitors, are United States Food and Drug Administration-approved for the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). The effectiveness of continuing them beyond first disease progression (PD) is currently unknown. This retrospective study evaluated the impact of the continuation of CDK4/6i beyond first PD in HR+/HER2- MBC using real-world experience. PATIENTS AND METHODS: A single-institution retrospective review of patients with HR+ MBC who received CDK4/6is from 2015 to 2018 and where CDK4/6is were continued beyond first PD. The primary outcome was progression-free survival (PFS) after initial PD on CDK4/6i therapy. RESULTS: Thirty women with HR+/HER2- MBC met eligibility criteria. Patients were identified from a prospective database of patients at the Cleveland Clinic Foundation who were prescribed CDK4/6is. The median age and follow-up duration were 47.5 years and 27 months, respectively. Most patients received palbociclib (PA)/letrozole as initial therapy (67%), followed by PA/fulvestrant (23%), and PA/other aromatase inhibitor (20%), and abemaciclib with either fulvestrant or letrozole (6%). As of January 31, 2019, 25 (83.3%) patients were still alive, and 19 (63%) patients had progressed. The estimated median PFS for continued CDK4/6i use beyond the first PD was 11.8 months (95% confidence interval, 5.34-13.13 months). CONCLUSIONS: Among a small cohort of patients with HR+ MBC in a non-clinical trial setting, continuation of CDK4/6i-endocrine treatment post initial PD was associated with a median PFS of about 12 months. Formal randomized clinical trials evaluating the continuation of CDK4/6is beyond the first PD are currently ongoing and will provide more answers to this important clinical question.

Impact of treatment modality on overall survival in women with advanced endometrial cancer: A National Cancer Database analysis.

OBJECTIVE: To evaluate overall survival (OS) in women with advanced endometrial cancer (EC) following chemotherapy alone (CT), neoadjuvant chemotherapy and interval debulking surgery (NACT + IDS) or primary cytoreductive surgery and chemotherapy (PCS + CT). METHODS: The National Cancer Database (NCDB) was queried for patients with stage III/IV EC from 2004 to 2015. Univariable and multivariable Cox proportional hazards analyses assessed the impact of treatment modality upon OS. RESULTS: Of 48,179 women identified, 5531 received CT (11.5%), 2614 NACT + IDS (5.4%) and 40,034 PCS + CT (83.1%). Median OS was 11.1 months for CT, 25.1 months for NACT + IDS and 60.9 months for PCS + CT (p < 0.001). On multivariate analysis, NACT + IDS (HR 0.44 (0.40, 0.49); p < 0.001) and PCS + CT (HR 0.32 (0.30, 0.35); p < 0.001) were associated with improved OS vs. CT alone. Age, African American race, income, higher Charlson comorbidity index and grade were predictors of worse OS (p < 0.001). On subgroup analysis by stage (III/IV) and histology (Type I/II), PCS + CT improved OS for all patients, compared to NACT + IDS (p < 0.001) and CT (p < 0.001). NACT + IDS was associated with improved OS vs. CT in stage III type I (HR 0.50; 95% CI 0.38, 0.67; p < 0.001), stage IV type I (HR 0.43; 95% CI 0.35, 0.52; p < 0.001), and stage IV type II EC (HR 0.43; 95% CI 0.36, 0.51; p < 0.001), but not stage III type II EC (HR 0.76; 95% CI 0.56, 1.03; p = 0.08). CONCLUSIONS: In women with advanced EC, PCS + CT is associated with improved OS compared to NACT + IDS or CT alone, regardless of stage or histology. Additionally, NACT + IDS is associated with superior OS in stage III type I and all stage IV EC compared to CT alone. Where feasible, surgery should be incorporated into treatment planning in women with advanced EC.

The Diminishing Impact of Margin Definitions and Width on Local Recurrence Rates following Breast-Conserving Therapy for Early-Stage Invasive Cancer: A Meta-Analysis.

BACKGROUND: The optimal tumor-free margin definition and width following breast-conserving therapy (BCT) for early-stage invasive cancers has been evaluated in previous meta-analyses and guidelines. We performed an updated meta-analysis to assess how improvements in treatment over time have affected the impact of margins on local recurrence (LR) rates over time. METHODS: A systematic literature review identified 38 eligible studies comprising 54,502 patients treated between 1968 and 2010. Inclusion criteria included patients treated with BCT and minimum follow-up of 50 months, pathologic definitions of margin status explicitly stated, and LR data in relation to margin status. Data were pooled using a Bayesian logistic regression model to evaluate the risk of LR in relation to both margin status and study enrollment periods. RESULTS: Median follow-up was 7.25 years. Absolute LR rates decreased over time for each margin width cohort, with maximum differences between negative margin groups of less than 1% for the most recent enrollment period. However, relative rates of LR between different margin groups remained stable over time. CONCLUSIONS: With an additional 22,000 patients compared with the previous meta-analysis, this updated meta-analysis supports the consensus guideline of "no tumor on ink" for the majority of patients. Additionally, while concerns exist regarding a benefit with wider margins from previous studies, the analysis demonstrates the impact of margin width on LR rates has declined substantially over time, with very small differences between the narrowest and widest margin groups in the most recent cohort. Hence, older studies appear to have limited value to inform current management guidelines.

The effect of Gamma Knife radiosurgery on large posterior fossa metastases and the associated mass effect from peritumoral edema.

OBJECTIVE: Gamma Knife radiosurgery (GKRS) as monotherapy is an option for the treatment of large (≥ 2 cm) posterior fossa brain metastases (LPFMs). However, there is concern regarding possible posttreatment increase in peritumoral edema (PTE) and associated compression of the fourth ventricle. This study evaluated the effects and safety of GKRS on tumor and PTE control in LPFM. METHODS: The authors performed a single-center retrospective review of 49 patients with 51 LPFMs treated with GKRS. Patients with at least 1 clinical and radiological follow-up visit were included. Tumor, PTE, and fourth ventricle volumetric measurements were used to assess efficacy and safety. Overall survival was a secondary outcome. RESULTS: Fifty-one lesions in 49 consecutive patients were identified; 57.1% of patients were male. At the time of GKRS, the median age was 61.5 years, and the median Karnofsky Performance Status score was 90. The median number of LPFMs and overall brain metastases were 1 and 2, respectively. The median overall tumor, PTE, and fourth ventricle volumes at diagnosis were 4.96 cm3 (range 1.4-21.1 cm3), 14.98 cm3 (range 0.6-71.8 cm3), and 1.23 cm3 (range 0.3-3.2 cm3), respectively, and the median lesion diameter was 2.6 cm (range 2.0-5.07 cm). The median follow-up time was 7.3 months (range 1.6-57.2 months). At the first follow-up, 2 months posttreatment, the median tumor volume decreased by 58.66% (range -96.95% to +48.69%, p < 0.001), median PTE decreased by 78.10% (range -99.92% to +198.35%, p < 0.001), and the fourth ventricle increased by 24.97% (range -37.96% to +545.6%, p < 0.001). The local control rate at first follow-up was 98.1%. The median OS was 8.36 months. No patient required surgical intervention, external ventricular drainage, or shunting between treatment and first follow-up. However, 1 patient required a ventriculoperitoneal shunt at 23 months from treatment. Posttreatment, 65.30% received our general steroid taper, 6.12% received no steroids, and 28.58% required prolonged steroid treatment. CONCLUSIONS: In this retrospective analysis, patients with LPFMs treated with GKRS had a statistically significant posttreatment reduction in tumor size and PTE and marked opening of the fourth ventricle (all p < 0.001). This study demonstrates that GKRS is well tolerated and can be considered in the management of select cases of LPFMs, especially in patients who are poor surgical candidates.

Venous thromboembolism in breast cancer patients receiving cyclin-dependent kinase inhibitors.

BACKGROUND: Venous thromboembolism (VTE) complicates several anticancer regimens including chemotherapy and antiangiogenic agents. Cyclin-dependent kinase inhibitors (CDKIs) are a new approach for hormone receptor-positive metastatic breast cancer (mBC). Reported VTE rates in randomized trials range from 0.6% to 5%, but these may underestimate actual rates observed in clinical practice. OBJECTIVES: Evaluate VTE rate and its association with outcomes in CDKIs patients. PATIENTS/METHODS: We conducted a retrospective cohort study of consecutive mBC patients who received any of three Food and Drug Administration (FDA)-approved CDKIs (palbociclib, ribociclib, abemaciclib) from January 2015 through December 2017. Venous thromboembolism including deep venous thrombosis (DVT), pulmonary embolism (PE), and visceral vein thrombosis (VVT) were identified by electronic medical record review. Overall survival (OS) and progression-free survival (PFS) were estimated and evaluated for association with VTE using Cox proportional hazard regression. RESULTS: We included 424 patients, with a median age at diagnosis of 55 years. Palbociclib was the most commonly used CDKI (n = 390, 91.8%). Venous thromboembolism during CDKIs occurred in 38 patients, 6.3% at year 1, including DVT in 52.6%, PE in 18.5%, and VVT in 15.8%. Median time to VTE was 314 days. Venous thromboembolism was associated with a trend to worse PFS and OS in multivariate analysis [PFS hazard ratio (HR) 1.40, 95% confidence interval (CI) 0.83-2.38, P = .21], OS (HR 1.70, 95% CI 0.95-2.98, P = .076). CONCLUSIONS: Venous thromboembolism rates with CDKI treatment in mBC in clinical practice are 2-fold to 5-fold greater than reported in registration trials and may be associated with worse outcomes.

Clinical outcomes of isolated distal deep vein thrombosis versus proximal venous thromboembolism in cancer patients: The Cleveland Clinic experience.

BACKGROUND: Previous studies suggest isolated distal deep vein thrombosis (IDDVT) has a self-limited clinical course. However, these studies excluded cancer patients, who remain a high-risk population. In addition, studies to evaluate the long-term clinical outcomes of IDDVT in cancer patients have been limited. Here, we report outcomes from our experience in treating cancer-associated IDDVT versus proximal venous thromboembolism (VTE). METHODS: We prospectively evaluated a cohort of patients referred to our cancer-associated thrombosis clinic from August 2014 through May 2018. We compared clinical characteristics, anticoagulation prescription, VTE recurrence, overall survival, major bleeding, and subsequent hospital admission between cancer patients with IDDVT and proximal VTE. A propensity score matching method was used to reduce bias from confounding variables. RESULTS: Of 1100 patients referred to the clinic, 124 IDDVT and 178 proximal VTE events were analyzed. After propensity score matching, 96 patients were included in each cohort. There was no difference in the rate of recurrent VTE between cancer patients with proximal VTE vs IDDVT, with or without matching (matched: hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.31-1.92; P = .58). There was no difference in overall survival between cancer patients with proximal VTE vs. IDDVT with or without matching (matched: HR, 1.18; 95% CI, 0.77-1.82; P = .45). Furthermore, subsequent hospital admissions and major bleeding events were similar between patients with proximal VTE events versus IDDVT. CONCLUSIONS: Cancer patients with IDDVT have similar outcomes as their proximal counterparts, including rate of recurrence and overall survival. These findings suggest treatment of cancer-associated IDDVT should mirror treatment of proximal events.