Personalized radiation therapy for glioblastoma.

Glioblastoma is the most common primary brain tumor with an estimated 14,000 Americans diagnosed with this disease annually. This disease is treated with maximal surgical resection followed by adjuvant radiation therapy. Radiation therapy was initially delivered to the whole brain and with no concurrent or adjuvant systemic therapy. Advances in imaging and treatment delivery have allowed for partial brain irradiation to minimize radiation dose to normal structures, as well as sparing structures important for memory such as the hippocampus, decreasing morbidity and toxicity. While there is no consensus on the optimal radiation volume needed to successfully treat glioblastoma, there is consensus that the tumor bed with margin is preferable to treatment of the whole brain. Additionally, advances in knowledge regarding tumor biology have demonstrated the benefit of concurrent and adjuvant chemotherapy, as well as demonstrated that methylation of genes in the tumor can predispose greater responsiveness to chemotherapy. The following review describes the advancements in specific radiation techniques that have been used to improve the therapeutic ratio for management of glioblastoma and methods used to personalize radiation treatment for patients based on genomic markers as well as clinical factors. The review also describes future investigations that are currently taking place in order to enable a further improvement of clinical outcomes for patients with glioblastoma.

Radiation Pneumonitis, Really? A Case of Pulmonary Toxicity from CDK4/6 Inhibitor.

BACKGROUND/AIM: Radiation pneumonitis is a known complication of radiotherapy. It is also a rare complication of CDK4/6 inhibitors, and it can be difficult to differentiate the two. This is a report of a case of pulmonary toxicity from a CDK4/6 inhibitor, which was initially ascribed to radiation pneumonitis. CASE REPORT: A 77-year-old female was diagnosed with pneumonitis after receiving radiation to the thoracic spine. She had also been treated with abemaciclib. Upon review, the patient's lung mean dose was 11.54 Gy with a V20 of 17.02%, and the area of pneumonitis was largely outside of the treatment field. Abemaciclib was ceased. The patient was started on supportive oxygen as well as steroids. She no longer required oxygen and she was discharged from the hospital. Radiation pneumonitis is largely correlated with the volume of lung radiated and dose of radiation to the lung. CDK4/6 inhibitor pulmonary toxicity, while rare, is possible and will likely become more frequent with increasing use of these agents. CONCLUSION: Patients receiving CDK4/6 inhibitors are at an increased risk for pneumonitis. It can be confused with radiation pneumonitis and must be included in the differential diagnosis.

Prognostic Effect of Systemic Therapy and Radiation Therapy in Stage I Nodal Marginal Zone Lymphoma.

PURPOSE: Nodal marginal zone lymphoma (NMZL) localized to a single lymphatic region (ie, stage I) is a relatively rare diagnosis. Current guidelines permit these patients to be either observed or treated with systemic therapy (ST), radiation therapy (RT), or both modalities. The prognostic effect of ST or RT compared with observation has not been established. The purpose of this study was to assess the prognostic effect of therapy in stage I NMZL. METHODS AND MATERIALS: The National Cancer Database was queried (2004-2018) for all patients with stage I NMZL. Patients were stratified based on treatment received. Propensity score matching (PSM) was performed overall and for each disease site to create 1:1 matched cohorts of patients who received RT and those who did not. Kaplan-Meier analysis evaluated overall survival (OS). Univariable (UVA) and multivariable Cox proportional hazard analyses identified clinical and treatment factors prognostic for OS. Subset analysis excluded patients deceased within 1 month of diagnosis to account for immortal time bias. RESULTS: A total of 3201 patients (median age 67) met inclusion criteria. A total of 1042 patients (33%) were head/neck/face, 208 (7%) intrathoracic, 613 (19%) intra-abdominal, 382 (12%) axilla/upper extremity, 292 (9%) inguinal/lower extremity, 86 (3%) pelvic, and 578 (18%) unspecified. A total of 1562 patients (49%) received no treatment, 721 (23%) received ST alone, 799 (25%) received RT alone, and 119 (4%) received both ST and RT. After PSM, ST was not prognostic on UVA while RT was prognostic on both UVA and multivariable analysis. After PSM, the 5-year OS was 84% for those who received RT and 79% for those who did not (P = .026). On subset analysis, these findings remained statistically significant for the head/neck/face cohort and the axilla/upper extremity cohort. After accounting for immortal time bias and performing PSM on this subset, the 5-year OS was 82% for those who received RT and 77% for those who did not (P = .047). CONCLUSIONS: In the overall cohort, RT improved OS compared with no RT, and ST was not a factor associated with OS. A radiation oncologist should be consulted for all patients with stage I NMZL for multidisciplinary decision making.

Role of 21-Gene Recurrence Score in Predicting Prognostic Benefit of Radiation Therapy After Breast-Conserving Surgery for T1N0 Breast Cancer.

PURPOSE: The 21-gene RT-PCR recurrence score (RS) is performed in patients with hormone receptor-positive (ER+, PR+), human epidermal growth factor receptor 2 (HER2)-negative, N0 breast cancer to determine which patients will likely benefit from chemotherapy after breast-conserving surgery (BCS). The purpose of this study was to evaluate whether the RS can predict for patients likely to benefit from radiation therapy (RT) after BCS. METHODS AND MATERIALS: The National Cancer Database was queried (2004-2017) for female patients with pT1N0 ER+ PR+ HER2-negative breast cancer treated with BCS who had an available RS. Patients were stratified based on their RS (low risk [LR], 1-10; intermediate risk [IR], 11-25; high risk [HR], 26-100). For each RS cohort, propensity score matching was conducted to create 1:1 matched cohorts of patients who received RT and patients who did not. Kaplan-Meier analysis evaluated overall survival (OS). Univariable and multivariable (MVA) Cox proportional hazard analysis identified clinical and treatment factors prognostic for OS. RESULTS: A total of 79,040 patients met the selection criteria: 18,823 in the LR cohort, 52,341 in the IR cohort, and 7876 in the HR cohort. A total of 92% of patients received RT: 91% in the LR cohort, 93% in the IR cohort, and 92% in the HR cohort. After propensity score matching, the 5-year OS in the LR cohort was 95% for those who received RT and 93% for those who did not (P = .184). In the IR cohort, the 5-year OS was 95% for those who received RT and 93% for those who did not (P = .001). In the HR cohort, the 5-year OS was 95% for those who received RT and 84% for those who did not (P < .001). MVA demonstrated that RT was a positive prognostic factor for OS in both the IR cohort (P = .001) and HR cohort (P < .001). On MVA in the LR cohort, RT (P = .186) was not predictive of improved OS. CONCLUSIONS: An OS benefit was observed with the use of RT in patients with IR or HR RS but not in patients with LR RS. Future prospective evaluation is warranted.

Zonal Intratumoral Delivery of Nanoparticles Guided by Surface Functionalization.

Delivery of small molecules and anticancer agents to malignant cells or specific regions within a tumor is limited by penetration depth and poor spatial drug distribution, hindering anticancer efficacy. Herein, we demonstrate control over gold nanoparticle (GNP) penetration and spatial distribution across solid tumors by administering GNPs with different surface chemistries at a constant injection rate via syringe pump. A key finding in this study is the discovery of different zone-specific accumulation patterns of intratumorally injected nanoparticles dependent on surface functionalization. Computed tomography (CT) imaging performed in vivo of C57BL/6 mice harboring Lewis lung carcinoma (LLC) tumors on their flank and gross visualization of excised tumors consistently revealed that intratumorally administered citrate-GNPs accumulate in particle clusters in central areas of the tumor, while GNPs functionalized with thiolated phosphothioethanol (PTE-GNPs) and thiolated polyethylene glycol (PEG-GNPs) regularly accumulate in the tumor periphery. Further, PEG functionalization resulted in larger tumoral surface coverage than PTE, reaching beyond the outer zone of the tumor mass and into the surrounding stroma. To understand the dissimilarities in spatiotemporal evolution across the different GNP surface chemistries, we modeled their intratumoral transport with reaction-diffusion equations. Our results suggest that GNP surface passivation affects nanoparticle reactivity with the tumor microenvironment, leading to differential transport behavior across tumor zones. The present study provides a mechanistic understanding of the factors affecting spatiotemporal distribution of nanoparticles in the tumor. Our proof of concept of zonal delivery within the tumor may prove useful for directing anticancer therapies to regions of biomarker overexpression.

Prognostic Impact of Radiation Therapy in Pure Mucinous Breast Carcinoma.

PURPOSE: Pure Mucinous breast carcinoma (PMBC) is an invasive breast cancer with favorable prognosis. While pathology-specific guidelines exist for PMBC regarding adjuvant chemotherapy and endocrine therapy, no recommendations exist regarding locoregional treatment based on tumor histology. Prognostic impact of radiotherapy for patients with PMBC remains unclear. MATERIALS AND METHODS: The National Cancer Database was queried (2004-2017) for patients with pN0M0 PMBC who underwent lumpectomy. Chi-square testing compared categorical frequencies between patients who received radiotherapy versus those who did not. Propensity score matching created a 1:1 matched cohort of patients who received radiotherapy and patients who didn't. Kaplan-Meier analysis evaluated overall survival (OS). Cox proportional hazard analyses identified clinical and treatment factors prognostic for OS. RESULTS: 17,259 patients met selection criteria; 11,087 (74%) received radiotherapy while 3852 (26%) did not. After PSM, radiotherapy (HR 0.629; 95% CI 0.531-0.746), endocrine therapy (HR 0.676; 95% CI 0.567-0.805), black race (HR 0.703; 95% CI 0.498-0.991), and private insurance (HR 0.184; 95% CI 0.078-0.432) were favorable prognostic factors on multivariate Cox regression analysis while age ≥ 70 years (HR 2.668; 95% CI 1.903-3.740), tumor size > 20 mm (HR 1.964; 95% CI 1.613-2.391), and CDCC score > 0 (HR 1.770; 95% CI 1.474-2.126) were unfavorable prognostic factors. After PSM, 5-year OS was 86% for those who received radiotherapy and 81% for those who did not (P < .001). CONCLUSION: This is the largest study to date on PMBC and the prognostic impact of adjuvant radiotherapy. Radiotherapy is associated with a survival advantage, suggesting omission of radiotherapy is not warranted.

A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer.

PURPOSE: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. PATIENTS AND METHODS: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. RESULTS: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. CONCLUSIONS: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

21-Gene recurrence score predictive for prognostic benefit of radiotherapy in patients age ≥ 70 with T1N0 ER/PR + HER2- breast cancer treated with breast conserving surgery and endocrine therapy.

PURPOSE: Based on the results of the Cancer and Leukemia Group B (CALGB) 9343 trial, patients age ≥70 with T1N0 hormone receptor positive (ER/PR+), human epidermal growth factor receptor-2 negative (HER2-) breast cancer who are treated with breast conserving surgery (BCS) and endocrine therapy (ET) are candidates for omission of radiotherapy (RT). Because the CALGB 9343 trial did not stratify based on recurrence score (RS) test (Oncotype Dx), we conducted the present retrospective study to determine whether RS is predictive of who may benefit from RT following BCS in this cohort. MATERIALS AND METHODS: The National Cancer Database (NCDB) was queried (2004-2017) for patients age ≥ 70 with pT1N0 ER+/PR + HER2- breast cancer treated with BCS and ET. Patients were stratified based on their RS (low risk [LR] = 1-10, intermediate risk [IR] = 11-25, high risk [HR] = 26-99). Propensity score matching (PSM) created 1:1 matched cohorts of patients who received radiotherapy and those who did not. Kaplan-Meier analysis evaluated overall survival (OS). Univariable (UVA) and multivariable (MVA) Cox proportional hazard analyses identified clinical and treatment factors prognostic for OS. RESULTS: A total of 11,891 patients met the selection criteria: 3364 in the LR cohort, 7305 in the IR cohort, and 1222 in the HR cohort. A total of 79 % received RT: 77 % in the LR cohort, 79 % in the IR cohort, and 85 % in the HR cohort. Because PSM could not be efficiently performed in the HR cohort alone, the IR and HR cohort were merged (IRHR) for matching. After PSM, the 5-year OS in the LR cohort was 91 % for those who received RT and 89 % for those who did not (p = 0.605). In the IRHR cohort, the 5-year OS was 91 % for those who received RT and 87 % for those who did not (p = 0.003). On MVA in the LR cohort, RT (p = 0.727) was not predictive of improved OS. On MVA in the IRHR cohort, RT (p = 0.010) was a positive prognostic factor for OS. CONCLUSION: In this older cohort of patients, there is an OS benefit with the use of RT in patients with IRHR RS but not in patients with LR RS. Pending prospective evaluation, assessment of RS in this older subset of patients is recommended with consideration of RT when RS is ≥11.

Three-year outcomes of uveal melanoma treated with intra-operative ultrasound-guided iodine-125 brachytherapy using custom-built eye plaques.

Purpose: The aim of this study was to demonstrate that uveal melanoma (UM) treated with eye plaque brachytherapy (EPB) with intra-operative ultrasound (IOUS) guidance results in increased local control. Material and methods: A retrospective study was conducted among 212 patients with 214 UM tumors treated by iodine-125 EPB with IOUS guidance from 2013 to 2019. 85 Gy was prescribed to tumor apical height or 5 mm from inner sclera, whichever was greater. Lesions were treated to 95% of 85 Gy at 2 mm margin from tumor edge. Local failure (LF), distant metastasis (DM), and radiation-related toxicity were recorded. Results: Median tumor apical height was 3.3 mm. COMS stage was 90 small (42.1%), 81 medium (37.9%), and 43 large (20.1%). Most patients had gene expression profile (GEP) class available, with 119 (55.6%), 30 (14.0%), 55 (25.7%) cases classified as 1A, 1B, and 2, respectively. Median dose at apex for tumor height > 5 mm and ≤ 5 mm was 85.0 Gy and 120.6 Gy, respectively. Outcomes data for 180 patients with over 12 months follow-up were reported. Mean follow-up was 37.3 months. Rates of LF and DM were 0.0% and 12.2%, respectively. Actuarial estimates of 5-year DM for class 1A, 1B, and 2 tumors were 2.5%, 0.0%, and 57.8%, respectively. 87 patients (48.3%) developed radiation-related toxicities. Conclusions: The excellent local control rate amongst lesions ranging across all sizes and GEP classes emphasizes the importance of image-guided brachytherapy with IOUS. We report favorable 5-year DM rates compared to established rates. Acceptable rate and severity of radiation-related toxicities were observed.

Contemporary trends in management of uveal melanoma.

Purpose: In the management of uveal melanoma, eye plaque brachytherapy (EPBT) has replaced enucleation as the standard of care for small size tumors that require treatment, and for medium size tumors. In the modern era, EPBT is being utilized more frequently for certain large tumors as well. While there is prospective randomized evidence to support utilization of EPBT for tumors of appropriate dimensions, it is unclear what the actual practice patterns are across the United States. The purpose of this publication was to look at contemporary trends in the management of uveal melanoma across the United States to determine whether practices are appropriately adopting EPBT, and to investigate demographic and socio-economic factors that might be associated with deviations from this standard of care. Material and methods: The National Cancer Database was queried (2004-2015) for patients with uveal melanoma. Data regarding tumor characteristics and treatment were collected. Two-sided Pearson χ2 test was used to compare categorical frequencies between patients who received globe preserving treatments vs. those who received enucleation. Multivariable logistic regression modeling was used to determine characteristics predictive for receiving enucleation. Results: The enucleation rate for small/medium tumors (≤ 10 mm apical height and ≤ 16 mm basal diameter) decreased from 20% in 2004 to 10% in 2015. The EPBT rate for large tumors increased from 30% in 2004 to 45% in 2015. Numerous demographic and socio-economic factors were found to be associated with higher rates of enucleation. Conclusions: The overall trend across the nation is a decreased enucleation rate for small/medium tumors, and an increased EPBT rate for large tumors. A fraction of patients who should be candidates for EPBT are instead receiving enucleation, and in this study, we have shown that certain adverse demographic factors are associated with this.

Prognostic and predictive impact of MGMT promoter methylation status in high risk grade II glioma.

BACKGROUND: MGMT promoter methylation has been associated with favorable prognosis and survival outcomes in patients with glioblastoma and WHO grade III glioma. However, the effects of promoter methylation of MGMT in patients with WHO grade II gliomas have not been established. The purpose of the current study is to evaluate the prognostic impact and predictive values of MGMT methylation in patients with grade II glioma. METHODS: The National Cancer Database (NCDB) was queried (2004-2016) for patients with newly diagnosed grade II glioma. Demographics and clinical characteristics of these patients were examined. Statistics included Kaplan-Meier overall survival (OS) analysis alongside Cox proportional hazards modeling. RESULTS: A total of 11,223 patients met the selection criteria; 1252 patients (11%) had MGMT testing. Of the patients who had MGMT testing, 58.5% were MGMT methylated (mMGMT), and 43.5% were MGMT unmethylated (uMGMT). mMGMT patients had greater median overall survival (77.3 months) than both uMGMT patients (42.6 months) and patients with no MGMT status reported (61.9 months (p < 0.001 for both). mMGMT was also associated with improved OS, when compared to patients with uMGMT, for patients receiving adjuvant chemoradiation or adjuvant radiation therapy. CONCLUSIONS: This is the largest study to date demonstrating both the prognostic and predictive impact of MGMT methylation on patients with grade II glioma. The current results show that mMGMT is a prognostic factor and possibly a predictive biomarker for grade II glioma patients. MGMT methylation status can be used to determine and stratify patients by risk levels, and thus select patients for treatment intensification. IMPORTANCE OF STUDY: The present study is the largest to date examining the prognostic and predictive significance of MGMT methylation (mMGMT) in patients with WHO grade II glioma. The results suggest that mMGMT is prognostic with increasing overall survival rates for patients with mMGMT compared to uMGMT patients. The results also suggest that mMGMT is predictive as shown by improved overall survival in patients receiving gross total resection, adjuvant chemoradiation or adjuvant radiation therapy, but no difference was observed in patients receiving adjuvant chemotherapy or no adjuvant treatment.

Fracture liaison services in Ireland-how do we compare to international standards?

In this first na tional survey of public hospitals in The Republic of Ireland, we found fracture liaison services (FLS) to be heterogeneous, limited in many cases and poorly supported. A national strategy is urgently needed to support the implementation and operation of an FLS, and thus help reduce the burden of fragility fractures for patients and the healthcare system. INTRODUCTION: Fragility/low-trauma fractures are a global concern, whose incidence is rising as the population ages. Many are preventable, and people with a prior fragility fracture are at particularly high risk of further fractures. This patient group is the target of the International Osteoporosis Foundation (IOF) Capture the Fracture campaign, advocating global adoption of fracture liaison services (FLS), with the aim of preventing secondary fragility fractures. We wished to determine the current availability and standards of an FLS in Ireland, ahead of the launch of a National FLS database. METHODS: We devised a questionnaire encompassing the thirteen IOF standards for an FLS and asked all 16 public hospitals with an orthopaedic trauma unit in Ireland, to complete for the calendar year 2019 in patients aged ≥ 50 years. RESULTS: All sites returned the questionnaire, i.e. 100% response rate. Nine hospitals stated that they have an FLS, additionally one non-trauma hospital running a FLS responded, and were included. These 10 FLS had identified and managed 3444 non-hip fractures in the year 2019. This figure represents 19% of the expected non-hip fragility fracture numbers occurring annually in Ireland. Implementation of the IOF standards was very variable. All sites reported being inadequately resourced to provide a high-quality service necessary to be effective. CONCLUSION: The existence and functioning of FLS in Ireland are heterogeneous and suboptimal. A national policy to support the implementation of this programme in line with international standards of patient care is urgently needed.

Quantifying the rate and predictors of occult lymph node involvement in patients with clinically node-negative non-small cell lung cancer.

PURPOSE: It is essential to evaluate the risk of occult lymph node (LN) disease in early-stage non-small cell lung cancer (NSCLC), especially because delivering stereotactic ablative radiotherapy (SABR) assumes no occult spread. This study was designed to assist clinicians in roughly quantifying this risk for cN0 NSCLC. METHODS: The National Cancer Data Base was queried for cN0 cM0 lung squamous cell or adenocarcinoma who underwent surgery and LN dissection without neoadjuvant therapy. Statistics included multivariable logistic regression to evaluate factors associated with pN + disease. RESULTS: 109,964 patients were included. For tumors with size ≤1.0, 1.1-2.0, 2.1-3.0, 3.1-4.0, 4.1-5.0, 5.1-6.0, 6.1-7.0, and >7.0 cm, the pN + rate was 4.4, 7.7, 12.9, 18.0, 20.2, 22.5, 24.4, and 26.4%, respectively. When examining patients with more complete LN dissections (defined as removal of at least 10 LNs), the respective values were 6.6, 11.5, 17.6, 25.3, 26.8, 29.7, 30.7, and 31.6%. Moderately-poorly differentiated disease and adenocarcinomas were associated with a higher rate of pN + disease (p < .001 for both). For every cm increase in tumor size, the relative occult nodal risk increased by 10-14% (p < .001). For every elapsed day from initial diagnosis, the relative risk increased by ∼1% (p < .001). Graphs with best-fit lines were created based on tumor size, histology, and differentiation to aid physicians in estimating the pN + risk. CONCLUSIONS: This nationwide study can allow clinicians to roughly estimate the rate of occult LN disease in cN0 NSCLC. These data can also assist in guiding enrollment on randomized trials of SABR ± immunotherapy, individualizing follow-up imaging surveillance, and patient counseling to avoid post-diagnosis delays.

DMSA-SPECT: A Novel Approach to Nephron Sparing SBRT for Renal Cell Carcinoma.

PURPOSE: Stereotactic body radiation therapy (SBRT) treatment planning for renal cell carcinoma requires accurate delineation of tumor from normal tissue due to the radiosensitivity of normal renal cortical tissue. Tc-99m dimercapto succinic acid (DMSA) renal imaging is a functional imaging technique that precisely differentiates normal renal cortical tissue from tumor. There are no prior publications reporting using this imaging modality for SBRT treatment planning. METHODS AND MATERIALS: A 59-year-old female with stage IV renal cell carcinoma progressed on systemic therapy and was dispositioned to primary cytoreduction with SBRT. She had baseline renal dysfunction and her tumor was 9 cm without clear delineation from normal tissue on conventional imaging. DMSA-single-photon emission computerized tomography (SPECT)/computed tomography (CT) was used for treatment planning. RESULTS: DMSA-SPECT/CT precisely delineated normal renal cortical tissue from tumor. Three months after treatment, labs were stable and DMSA-SPECT/CT was unchanged. The treated lesion had markedly decreased positron emission tomography avidity. CONCLUSIONS: DMSA-SPECT or SPECT/CT can be incorporated into radiation therapy planning for renal lesions to improve target delineation and better preserve renal function.

Time Interval to Initiation of Whole-Brain Radiation Therapy in Patients With Small Cell Lung Cancer With Brain Metastasis.

PURPOSE: Patients with small cell lung cancer (SCLC) who have brain metastases require whole-brain radiation therapy (WBRT). When there is no emergent indication for WBRT, patients may receive systemic therapy first and WBRT afterward. In scenarios when systemic therapy is initiated first, it has not been previously investigated whether delaying WBRT is harmful. METHODS AND MATERIALS: The National Cancer Database was queried (2004-2016) for patients with SCLC with brain metastases who received 30 Gy in 10 fractions of WBRT. Patients were divided into groups based on whether they received early WBRT (3-14 days after initiation of chemotherapy) or late WBRT (15-90 days after initiation of chemotherapy). Demographic and clinicopathologic categorical variables were compared between those who had early WBRT (3-14 days) and those who had late WBRT (15-90 days). Factors predictive for late WBRT were determined. Overall survival (OS), which was defined as days from diagnosis to death, was evaluated and variables prognostic for OS were determined. RESULTS: A total of 1082 patients met selection criteria; 587 (54%) had early WBRT and 495 (46%) received late WBRT. Groups were similarly distributed aside from days from initiating chemotherapy to initiating WBRT (P < .001). The early WBRT group had a median of 7 days (interquartile range [IQR], 5-10 days) from initiating chemotherapy to initiating WBRT and the late WBRT group had a median of 34 days (IQR, 21-57 days). On binary logistic regression analysis, a longer time interval between diagnosis and the start of systemic therapy was predictive for later WBRT. Median OS was 8.7 months for early WBRT and 7.5 months for late WBRT (hazard ratio [HR], 1.165; P = .008). Early WBRT (P = .02), female sex (P = .045), and private insurance (P = .04) were favorable prognostic factors for OS on multivariable analysis, whereas older age (P = .006) was an unfavorable prognostic factor. CONCLUSIONS: Patients with SCLC and brain metastases who received early WBRT were found to have a modest improvement in OS compared with patients who received late WBRT. These findings suggest that early WBRT should be offered to patients who have brain metastases, even in the absence of an indication for emergent WBRT.

Hyaluronate-Thiol Passivation Enhances Gold Nanoparticle Peritumoral Distribution When Administered Intratumorally in Lung Cancer.

Biofouling is the unwanted adsorption of cells, proteins, or intracellular and extracellular biomolecules that can spontaneously occur on the surface of metal nanocomplexes. It represents a major issue in bioinorganic chemistry because it leads to the creation of a protein corona, which can destabilize a colloidal solution and result in undesired macrophage-driven clearance, consequently causing failed delivery of a targeted drug cargo. Hyaluronic acid (HA) is a bioactive, natural mucopolysaccharide with excellent antifouling properties, arising from its hydrophilic and polyanionic characteristics in physiological environments which prevent opsonization. In this study, hyaluronate-thiol (HA-SH) (MW 10 kDa) was used to surface-passivate gold nanoparticles (GNPs) synthesized using a citrate reduction method. HA functionalized GNP complexes (HA-GNPs) were characterized using absorption spectroscopy, scanning electron microscopy, zeta potential, and dynamic light scattering. GNP cellular uptake and potential dose-dependent cytotoxic effects due to treatment were evaluated in vitro in HeLa cells using inductively coupled plasma-optical emission spectrometry (ICP-OES) and trypan blue and MTT assays. Further, we quantified the in vivo biodistribution of intratumorally injected HA functionalized GNPs in Lewis Lung carcinoma (LLC) solid tumors grown on the flank of C57BL/6 mice and compared localization and retention with nascent particles. Our results reveal that HA-GNPs show overall greater peritumoral distribution (** p < 0.005, 3 days post-intratumoral injection) than citrate-GNPs with reduced biodistribution in off-target organs. This property represents an advantageous step forward in localized delivery of metal nano-complexes to the infiltrative region of a tumor, which may improve the application of nanomedicine in the diagnosis and treatment of cancer.

Interparticle Forces of a Native and Encapsulated Metal-Organic Framework and Their Effects on Colloidal Dispersion.

The colloidal properties of suspended metal-organic frameworks (MOFs) are critical for device fabrication and application. Herein, van der Waals attractive, electric double layer repulsive, and steric repulsive forces of a native and encapsulated MOF are quantified for the first time. The van der Waals attractive forces were investigated by conducting environmental ellipsometric porosimetry (EEP) and spectroscopic ellipsometry (SE) on submicron, optical-quality nanoparticle films. The repulsive forces were determined from colloid and material characterization measurements. These data were used to predict suspension properties via extended Derjaguin, Landau, Verwey, and Overbeek theory. The state of dispersion was quantified for comparison with theoretical predictions for nine solvents. The MOF encapsulated with a surface-selective modification showed superior suspension in hydrophobic solvents. These findings should expedite the formulation of MOF colloidal suspensions for future works.

The impact of HER2-directed targeted therapy on HER2-positive DCIS of the breast.

BACKGROUND: In invasive breast cancer, HER2 is a well-established negative prognostic factor. However, its significance on the prognosis of ductal carcinoma in situ (DCIS) of the breast is unclear. As a result, the impact of HER2-directed therapy on HER2-positive DCIS is unknown and is currently the subject of ongoing clinical trials. In this study, we aim to determine the possible impact of HER 2-directed targeted therapy on survival outcomes for HER2-positive DCIS patients. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven DCIS diagnosed from 2004-2015. Patients were divided into two groups based on the adjuvant therapy they received: systemic HER2-directed targeted therapy or no systemic therapy. Statistics included multivariable logistic regression to determine factors predictive of receiving systemic therapy, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS. RESULTS: Altogether, 1927 patients met inclusion criteria; 430 (22.3%) received HER2-directed targeted therapy; 1497 (77.7%) did not. Patients who received HER2-directed targeted therapy had a higher 5-year OS compared to patients that did not (97.7% vs. 95.8%, p = 0.043). This survival benefit remained on multivariable analysis. Factors associated with worse OS on multivariable analysis included Charlson-Deyo Comorbidity Score ≥ 2 and no receipt of hormonal therapy. CONCLUSION: In this large study evaluating HER2-positive DCIS patients, the receipt of HER2-directed targeted therapy was associated with an improvement in OS. The results of currently ongoing clinical trials are needed to confirm this finding.

Postmastectomy radiation therapy following pathologic complete nodal response to neoadjuvant chemotherapy: A prelude to NSABP B-51?

PURPOSE: The utility of post-mastectomy radiotherapy (PMRT) in women with a nodal complete response (CRn) to neoadjuvant chemotherapy (NAC) is unknown. The NSABP B-51 trial is evaluating this question, but has not reported results thus far. Therefore, we sought to answer this question with the National Cancer Database. METHODS: The National Cancer Database was queried for women with cT1-4N1-3M0 breast cancer who had undergone NAC and were ypN0 upon mastectomy. Statistics included multivariable logistic regression, Kaplan-Meier overall survival (OS) analysis, Cox proportional hazards modeling, and construction of forest plots. RESULTS: Of 14,690 women, 10,092 (69%) underwent adjuvant PMRT and 4598 (31%) did not. The median follow-up was 55.6 months. In all patients, the 10-year OS was 76.3% for PMRT and 78.6% without (p = 0.412). There were no notable effects of PMRT on OS based on age or the axillary management (number of nodes removed). Specifically, in the NSABP B-51 population of cT1-3 cN1 patients, the 10-year OS was 82.6% for PMRT and 80.0% without (p = 0.250). PMRT benefitted women with increasing cT stage (i.e. cT3-4), increasing ypT stages (with the exception of ypT4 potentially owing to small sample sizes), and cN3 cases (p < 0.05 for all). CONCLUSIONS: In the absence of published results from NSABP B-51, this assessment of over 14,000 women from a contemporary US database revealed that PMRT may be most useful for a "moderately-high" risk group - women with more advanced primary and/or nodal disease at diagnosis, yet with tumor biology favorable enough that the disease does not progress or remain stable after NAC. The OS findings notwithstanding, this study cannot exclude potential differences between groups in recurrence-free survival, which is the primary endpoint of NSABP B-51, While the results of the NSABP B-51 will confirm optimal management for patients with limited nodal disease having a CRn following NAC, the present results suggest PMRT should remain the standard of care for more advanced disease than NSABP B-51 eligibility criteria.

Outcomes following stereotactic radiosurgery or whole brain radiation therapy by molecular subtype of metastatic breast cancer.

BACKGROUND: This study quantified clinical outcomes by molecular subtype of metastatic breast cancer (BC) following whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS). Doing so is important for patient counseling and to assess the potential benefit of combining targeted therapy and brain radiotherapy for certain molecular subtypes in ongoing trials. MATERIALS AND METHODS: The National Cancer Database was queried for BC (invasive ductal carcinoma) cases receiving brain radiotherapy (divided into WBRT and SRS ). Statistics included multivariable logistic regression to determine factors associated with SRS delivery, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling. RESULTS: Of 1,112 patients, 186 (16.7%) received SRS and 926 (83.3%) underwent WBRT. Altogether, 410 (36.9%), 195 (17.5%), 162 (14.6%), and 345 (31.0%) were ER+/HER2-, ER+/HER2+, ER-/HER2+, and ER-/HER2-, respectively. In the respective molecular subtypes, the proportion of subjects who underwent SRS was 13.4%, 19.4%, 24.1%, and 15.7%. Respective OS for WBRT patients were 12.9, 22.8, 10.6, and 5.8 months; corresponding figures for the SRS cohort were 28.3, 40.7, 15.0, and 12.9 months (p < 0.05 for both). When comparing OS between treatment different histologic subtypes, patients with ER-/HER2+ and ER-/HER2- disease had worse OS than patients with ER+/HER2- disease, for both patients treated with SRS and for patients treated with WBRT. CONCLUSIONS: Molecular subtype may be a useful prognostic marker to quantify survival following SRS/WBRT for metastatic BC. Patients with HER 2-enriched and triple-negative disease had the poorest survival following brain irradiation, lending credence to ongoing studies testing the addition of targeted therapies for these subtypes.